Effects of heavy metals on gut barrier integrity and gut microbiota

in Microbiota and Host
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Sweta Ghosh Department of Microbiology and Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville, Louisville, Kentucky, United States of America

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Syam P Nukavarapu Department of Biomedical Engineering and Department of Materials Science & Engineering, University of Connecticut, Storrs, Connecticut, United States of America

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Venkatakrishna Rao Jala Department of Microbiology and Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville, Louisville, Kentucky, United States of America

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Correspondence should be addressed to V R Jala; Email: jvrao001@louisville.edu
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Exposure to environmental pollutants such as heavy metals lead to significant damage in intestinal epithelial barrier, loss of microbial and immune homeostasis. The intestinal epithelial barrier protects and regulates the responses against several endogenous and exogenous factors including inflammatory cytokines, pathogens, toxins, and pollutants. Intestinal epithelial barrier dysfunction, immune dysregulation and microbial dysbiosis are associated with several gastrointestinal (GI)-related disorders including inflammatory bowel disease (IBD). The mechanisms and consequences of exposure to environmental toxins on gut barrier function and mucosal immune system are not fully understood. This review explores some of the recent findings of heavy metals and their effect on intestinal barrier function, microbiota, and their contributions to human health and pathogenesis of GI-related disorders such as IBD.

Abstract

Exposure to environmental pollutants such as heavy metals lead to significant damage in intestinal epithelial barrier, loss of microbial and immune homeostasis. The intestinal epithelial barrier protects and regulates the responses against several endogenous and exogenous factors including inflammatory cytokines, pathogens, toxins, and pollutants. Intestinal epithelial barrier dysfunction, immune dysregulation and microbial dysbiosis are associated with several gastrointestinal (GI)-related disorders including inflammatory bowel disease (IBD). The mechanisms and consequences of exposure to environmental toxins on gut barrier function and mucosal immune system are not fully understood. This review explores some of the recent findings of heavy metals and their effect on intestinal barrier function, microbiota, and their contributions to human health and pathogenesis of GI-related disorders such as IBD.

Introduction

The industrial revolution caused a significant increase in the release of several toxic chemicals into environment that became part of our food cycle. Epidemiological studies have suggested an association between metal pollution and worst health outcomes and increased risk for numerous disorders (Tchounwou et al. 2012, Chowdhury et al. 2018). Exposure to heavy metals through water, air, and foods affects different organs and causes nervous system disorders, skin lesions, vascular damage, immune system dysfunction, birth defects, cancer, and gastrointestinal (GI) and kidney dysfunction. Additionally, exposure to multiple metals may exert cumulative adverse effects on overall health.

The effects of metals on target organs vary from each other based on their route of exposure, amounts of metals (low vs high), duration of exposure as well as species. For instance, mice develop intestinal adenomas and carcinomas upon chronic exposure to high concentration of hexavalent chromium in drinking water, but not in rats (Thompson et al. 2013). Similarly, acute exposure to high-dose mercury and lead may induce kidney failure, abdominal colic pain, and bloody diarrhea. In contrast, chronic exposure at low doses regularly can cause complications such as neuropsychiatric disorders including fatigue, anxiety, and detrimental impacts on intelligence quotient (IQ) and intellectual function in children (Balali-Mood et al. 2021). Mechanistically, high-dose exposure to heavy metals leads to DNA damage, disrupts proteins and mechanisms involved in DNA synthesis and repair. Commonly, heavy metal-induced reactive oxygen species, suppression of oxidative stress and inactivation of critical metabolic enzymes are responsible for heavy metal-mediated adverse effects. However, the mechanism of actions of each metal may vary based on organ, tissue, and the cell types involved. Current review focuses on how heavy metal(s) exposure show impact on gut microbiota and gut barrier functions leading to GI-related disorders.

Recent studies have highlighted that the exposure to environmental pollutants leads to significant changes in the composition of gut microbiota (Breton et al. 2013b , Shao & Zhu 2020), epithelial barrier dysfunction, and increased intestinal inflammation (Celebi Sozener et al. 2020, Mitamura et al. 2021, Lindell et al. 2022). Microbial dysbiosis, gut barrier dysfunction, and immune dysregulation are associated with GI-related disorders including inflammatory bowel disease (IBD) (Martini et al. 2017, Guan, 2019), which comprises ulcerative colitis (UC) and Crohn’s disease (CD). Gut barrier consists of single layer of intestinal epithelial cells (IECs) that selectively allows transmigration of nutrients and protects from external challenges and pathogenic bacteria (Ghosh et al. 2021). Additionally, gut barrier mediates the cross talk between commensal microbes and immune system, and provides the first line of defense against pathogens, toxins, and environmental pollutants. Gut barrier dysfunction results in leakiness of bacteria and toxins, leading to immune imbalance at gut mucosal sites, which potentially promotes pathogenesis of GI-related disorders including IBD. The mechanisms and long-term impact of environmental toxins on gut barrier functions and related disorders are not fully understood. Gut microbiota and their metabolites can play an important role in regulation of the environmental toxins-mediated etiology and pathogenesis of GI disorders (Claus et al. 2016, Bist & Choudhary 2022). The use of probiotics has become as an attractive strategy to reduce the adverse effects of toxic metals (Duan et al. 2020). In this article, we review the structure of intestinal barrier and its impact upon exposure to heavy metals. The review also explores some of the possible mechanisms through which heavy metals interact and affect gut barrier function, microbiome and microbial metabolites.

Gut barrier dysfunction and systemic responses

Intestinal epithelial cells

The GI barrier consists of three key components: the mucus layer, the IEC layer, and the immunological barrier. Goblet cells (GC) are responsible for secretion of mucins, which create protective mucus layer (Kim & Ho 2010, Johansson et al. 2013). This mucus layer, composed of an outer and an inner layer, serves as the primary barrier against luminal microorganisms and foreign antigens (Thornton & Sheehan 2004, Bansil & Turner 2006, Leal et al. 2017). The mucus layer consists of glycoprotein sheets, featuring a densely packed inner layer and a less dense outer layer, that serve as a niche for various intestinal bacteria by acting as a carbon source for microbial metabolism (Johansson et al. 2013, Pelaseyed et al. 2014). The mucus functions as a barrier for hydrophilic solutes, which can only be transported via specific transporters (Turner 2009, Li et al. 2020). Mucins and their glycosylation status play a critical role in regulating gut barrier functions. Deficiencies in mucin production lead to defective gut barrier activities and promote GI-related disorders, including IBD, irritable bowel syndrome (IBS), and cancer.

The intestinal epithelium is composed of various cellular subtypes, such as enterocytes, Paneth cells, M cells, endocrine cells, and tuft cells, which collectively play essential roles in digestion, nutrient absorption, and protection against pathogens, among other functions (reviewed elsewhere (Clevers 2013, Peterson & Artis 2014, Okumura & Takeda 2017)). IEC junctions including tight junctions (TJs), adherens junctions (AJs), desmosomes, and gap junctions (GJ) are specialized structures present in the epithelial cell membranes. They establish contacts between IECs and regulate the transport of molecules based on their size and charge through the paracellular space (González-Mariscal et al. 2003, Van Itallie & Anderson 2014, Zihni et al. 2016). Defects in paracellular permeability are associated with several GI-related disorders (Odenwald & Turner 2013, Bischoff et al. 2014, Vermette et al. 2018, Vanuytsel et al. 2021).

Enterocytes, comprising over 80% of IECs, are polarized cells with microvilli expanding the absorptive surface. These cells are interconnected via several proteins that enable cell-to-cell adherence through formation of junctions. Enterocytes undergo apoptosis and are replaced by crypt-derived stem cells. It is known that the enterocytes regulate water and nutrient absorption, contribute to intestinal layer formation, macromolecular transportation, and digestion (Snoeck et al. 2005). They are involved in macromolecular transport via receptor-mediated endocytosis (Stern & Walker 1984, Snoeck et al. 2005). Increased inflammation, elicited by elevated TNF-α, accelerates enterocyte turnover and proliferation, leading to heightened shedding and apoptosis, potentially compromising the intestinal barrier and promoting bacterial translocation, particularly in conditions like IBD.

Paneth cells are another subset of differentiated secretory cells located at the base of the crypts of Lieberkuhn. Paneth cells are essential for enteric immune homeostasis and actively secrete antimicrobial peptides such as alpha defensins, lysozyme, and phospholipases A2 that limit bacterial numbers. Infants with necrotizing enterocolitis (NEC) have significantly decreased levels of Paneth cells compared to age-matched controls (Underwood 2012, McElroy et al. 2013). It was shown that depletion or dysfunction of Paneth cells in mouse models results in an NEC-like phenotype, indicating the importance of Paneth cell function in immature intestine (Sampath et al. 2017, Lueschow et al. 2018, Lueschow & McElroy 2020). Paneth cells can directly sense gut commensals and control intestinal barrier penetration in a myeloid differentiation marker 88 (MyD88)-dependent manner at the intestinal host–microbial interface (Vaishnava et al. 2008). Paneth cells depend on autophagy to control their secretion capacity of antimicrobial peptides. Mutations in genes like Atg16L1 disrupt this process, leading to reduced Paneth cell function, imbalanced gut microbiota, compromised barrier integrity, and an elevated risk of diseases such as Crohn's disease in humans (Cray et al. 2021).

M cells are specialized epithelial cells found in the gut-associated lymphoid tissue (GALT) of Peyer’s patches of the small intestine, isolated lymphoid follicles, colonic patches, and nasopharyngeal-associated lymphoid tissues (a.k.a. NALT) (Dillon & Lo 2019). These cells are involved in immune responses, especially antigen sampling, uptake of microorganisms and interact with dendritic cells or lymphocytes to initiate adaptive immunity. M cells deliver samples of foreign material from the lumen to organized mucosal lymphoid tissues. They interact closely with immune cells of Peyer’s patches and play an important role in the initiation of immunological response and tolerance. During chronic inflammation, increased levels of M cells were observed along with selective apoptosis of M cells, leading to elevated uptake of microorganisms and inflammation (Kucharzik et al. 2000b). Increased apoptosis of M cells during ileitis conditions leads to breakdown of intestinal barrier, resulting in translocation of bacteria and enhanced inflammation (Kucharzik et al. 2000a ).

Enteroendocrine cells representing 1% of the intestinal epithelium are also a type of intestinal secretary cells that mediate hormone release and are critical for digestion. Enteroendocrine cells are a major component of a specialized chemosensory system that can sense the intestinal microbiota and their metabolites. These cells secrete peptide hormones and classical cytokines to the surrounding immune cells and modulate both innate and adaptive immune systems. Enteroendocrine cells possess cytoplasmic processes in close proximity to the enteric nerve terminals and mediate several physiological functions including visceral hyperalgesia, intestinal motility, and synaptic transmission. Importantly, enteroendocrine hormones can modulate the intestinal epithelial barrier function through both transcellular and paracellular pathways (Yu et al. 2019).

Tuft cells are chemosensory sentinel cells that sense signals from the local milieu and communicate to immune cells within the intestine. These cells have been recently described to be critical in exerting an immune response against helminths (Allaire et al. 2018). The underlying mechanisms of these sensory signals are yet to be established. It is known that Tuft cells secrete IL-25 continuously to maintain type 2 innate lymphoid cells (ILC2) homeostasis. Helminth infection leads to increased levels of IL-25 production by tuft cells, which directly acts on ILC2 to release IL-13, which in turn acts on tuft cells and goblet cells to promote hyperplasia in an IL-13Rα1/IL-4αR-dependent manner. These series of activities lead to an increase in mucin levels to expel the parasite from the GI tract and protect the gut barrier (von Moltke et al. 2016, Ting & von Moltke 2019).

Tight junction proteins in gut epithelium

Claudins are 20–27 kDa tetraspan membrane proteins that contain four hydrophobic transmembrane domains with two extracellular loops and N- and C-terminal cytoplasmic domains (Van Itallie & Anderson 2006). The extracellular loops are responsible for homophilic and/or heterophilic TJ protein–protein interactions and the formation of ion-selective channels. The intracellular C-terminal domain anchors claudin to the cytoskeleton through interactions with PDZ-binding domain proteins including zonula occludens 1 (ZO-1), ZO-2, and ZO-3 (Morita et al. 1999). Thus far, at least 24 members of the claudin family have been reported. Claudins play an important role in ‘pore formation’ and ‘sealing (barrier forming)’ of the epithelium in the GI tract and classified as ‘pore’ vs ‘barrier-forming’ TJ proteins (Günzel & Yu 2013). The ‘pore’ forming claudins specifically increase paracellular permeability either for molecules of a certain size or of a certain charge (or both), and decrease transepithelial resistance but leave the epithelial barrier function against macromolecules intact (Günzel & Yu 2013). Similarly, ‘barrier-forming’ claudins decrease paracellular permeability and increase transepithelial resistance. It was also demonstrated that treatment with IL-17A protected against TNF-α-mediated barrier disruption in Caco-2 cells through regulating occludin, suggesting a direct role for IL-17 and IL-17R signaling on epithelial cells (Lee et al. 2015). In an independent study, Dr Rao’s group reported that the deficiency of occludin increased the susceptibility to ethanol-induced colonic mucosal barrier permeability and liver damage in mice (Mir et al. 2016). Moreover, inflammatory cytokines like TNF-α and IFN-γ are reported to downregulate intestinal epithelial barrier function by reorganizing several TJ proteins such as ZO-1, claudin 1, claudin 4, occludin, and JAM-A (Zolotarevsky et al. 2002). Th2 cytokines like IL-4 and IL-13 also cause an increase in intestinal permeability through induction of epithelial apoptosis and expression of the pore-forming TJ protein claudin 2 (Berin et al. 1999, Ceponis et al. 2000, Madden et al. 2002).

Adherens junction proteins in gut epithelium

AJs, also known as zonula adherens, are located on the lateral membrane of epithelial cells and maintain cell-to-cell contact, cell polarity, motility, and proliferation (Perez-Moreno et al. 2003, Hartsock & Nelson 2008). Interconnections between transmembrane proteins, intracellular adaptor proteins, and the cytoskeleton form AJ protein complexes. AJs are reported to present beneath TJs and are required for the assembly of TJs. TJs along with AJs are linked to the peri-junctional ring of cellular actin and myosin, leading to junction regulation via the cytoskeleton. AJs primarily consist of cadherin and catenin proteins that are linked to several intracellular cytoskeletal protein domains (Perez-Moreno et al. 2003). One of the most characterized AJ protein, E-cadherin binds to repeat regions of β-catenin, α-catenin, or γ-catenin (plakoglobin) at varying affinities based on phosphorylation states (Gumbiner 1996, Halbleib & Nelson 2006, Perez-Moreno & Fuchs 2006). Moreover, the functions of AJ and TJ proteins are regulated by myosin and actin proteins that form a dense ring, which encircles the cell. Activation of actomyosin contraction is regulated by phosphorylation of myosin II regulatory light chain (MLC) by MLC kinase (MLCK) and is implicated in AJ and TJ protein regulation. It has been demonstrated that MLCK-driven MLC phosphorylation is involved in signal transduction pathways that influence gut barrier function in response to diverse stimuli (Turner 2000, Shen et al. 2006, Cunningham & Turner 2012). In the case of IBD, decreased E-cadherin–catenin complexes lead to a loss of cell-to-cell adhesions along with impairment of the integrity of the mucosal barrier. Exposure of the mucosal immune system to luminal substances leads to inflammation and further increased gut barrier permeability (Mehta et al. 2015). Furthermore, modulation of intestinal permeability by oxidative stress leads to redistribution of E-cadherin and β-catenin (Rao et al. 2002, Rao 2008).

Desmosomes in gut epithelium

Desmosomes are located on the basolateral membrane and are known to provide mechanical support due to connections to the intracellular cytoskeletal framework (Gumbiner 1996, Green & Simpson 2007, Nekrasova & Green 2013). Desmosomes form links between adjacent cells and provide connection between intermediate filaments of the cell cytoskeletons. Desmosomes consist of the cadherin family of proteins, desmoglein and desmocollins (Gumbiner 1996, Nekrasova & Green 2013). Together with AJs, desmosomes maintain the integrity of the epithelium by imparting strong adhesive bonds. Studies revealed that desmoglein 2 (Dsg2), which is expressed in enterocytes, potentially contributes to the pathogenesis of CD (Spindler et al. 2015). It was demonstrated that Dsg2 regulates intestinal epithelial barrier function in enterocytes by modulating the p38MAPK signaling cascade (Ungewiss et al. 2017).

Gap junctions in gut epithelium

Gap junctions (GJ) form tiny connections between adjacent cells allowing passage of small molecules, ions and electrical signals (Goodenough & Paul 2009). Small molecules and ions diffuse through GJ channels that span the bilayers of both cells and the extracellular space that separate them. GJ are formed by head-to-head docking of proteins called connexins. Connexins are hexameric protein transmembrane complex that spans between membranes of adjacent cells (Goodenough et al. 1996). The gap inside the hexameric GJ protein passes the respective signal or molecule to the next cells. Ey et al. showed that during IEC injury, activated Toll-like receptor 2 drives connexin 43 protein synthesis and subsequently increases gap junctional intercellular communication, leading to increased epithelial permeability and related diseases (Ey et al. 2009).

In general, the dysfunction of gut epithelial cells can have far-reaching consequences, primarily stemming from disruptions in the mucus layer and junctional protein complexes within the gut epithelium. This dysfunction ultimately leads to an increase in intestinal permeability, allowing bacteria and bacterial endotoxins to leak through. This, in turn, triggers an elevation in the levels of inflammatory cytokines and recruitment of inflammatory cells. These interconnected events culminate in the development of microbial dysbiosis, a substantial rise in mucosal and systemic inflammation. These conditions, in turn, play a pivotal role in the onset and progression of various disorders, such as IBD, diabetes, neurological disorders, liver diseases, and various types of cancers, among others.

Microbiota is essential for gut barrier function

The gut microbiota is often referred to as an essential ‘organ’ due to the vast density and richness of microbial life that exist in the gut lumen (Eckburg et al. 2005). The composition of microbiota is influenced by several factors including but not limited to host genetics, age, dietary habits, drugs, environment, and lifestyles. Microbiota can be also passed from mother to child, with slight differences between delivery and postpartum birth (Palmer et al. 2007, Dominguez-Bello et al. 2010, Ursell et al. 2012). Germ-free (GF) mice exhibit significant deficiency in gut barrier function, suggesting the critical role of microbiota in development of gut barrier components (Parker et al. 2018, Wang et al. 2021). The inner mucus layer of GF mice is more penetrable to bacterial-sized beads compared to conventionally raised mice, suggesting defects in the mucin layer (Johansson et al. 2015). Introducing fecal commensal bacteria collected from conventionally raised mice into GF mice induces a normal colonic barrier structure by increasing the thickness of the colonic mucus layer and mucin glycosylation (Hayes et al. 2018). These studies demonstrated the importance of gut microbiota in developing gut mucus barrier and maintenance of homeostasis. It was shown that GF mice are more susceptible to epithelial injury as a result of an impaired intestinal barrier via downregulation of claudin 4, occludin, TFF3, and MUC3 protein expression and IL-22 secretion (Hernández-Chirlaque et al. 2016). It was observed that mice treated with broad-spectrum antibiotics, such as ampicillin, streptomycin, or clindamycin for 14 days showed reduced bacterial diversity and richness. These mice displayed an increase in gut permeability and decreased expression of intestinal TJ proteins such as ZO-1, occludin, and claudin 1 (Feng et al. 2019), reinforcing the importance of microbiota in gut barrier function. Now there is unequivocal evidence for the critical role of microbiota in the development and maintenance of gut barrier function. Hence, rebuilding a healthy gut microbiota, while maintaining the known resident commensals, is critical (Schmidt et al. 2018). Although the determination of ‘beneficial’ microbes seems to be a challenge, probiotics, prebiotics, and synbiotics may provide opportunities to restore intestinal homeostasis and enhance gut barrier function in addition to blocking of unwarranted inflammation and dysregulation (Gibson & Roberfroid 1995, Schrezenmeir & de Vrese 2001, Ghosh et al. 2022c, d ). The impact of microbial metabolites on gut barrier was reviewed elsewhere (Ghosh et al. 2021). Members of the gut microbiota influence the host metabolic and immune status by modulating nutrient metabolism, xenobiotic and drug metabolism, and production of antimicrobial metabolites that limit numbers of competing microbes for the same niche. Gut microbes and metabolites influence the structure of the GI tract, integrity of the gut barrier, and differentiation of various immune cell subsets (Jandhyala et al. 2015, Thursby & Juge 2017). However, most of the functions of individual species and metabolites remain unclear.

The mucosal immune system profoundly impacts gut barrier functions both in health and disease conditions (reviewed in Mazmanian et al. (2005), Arpaia et al. (2013), Konieczna et al. (2013), Allaire et al. (2018), Kayama & Takeda (2020), Zuo et al. (2020)). Microbial metabolites regulate host immunity by exploiting metabolite-specific immune cell receptors such as aryl hydrocarbon receptor (AhR), farnesoid X receptor, pregnane X receptor, membrane bile acid receptor (M-BAR/TGR5), purinergic receptor, and G-protein coupled receptors (GPR 41, GPR43, GPR109A) (Liu et al. 2022a, c ). These receptors play crucial roles in host–microbiota interactions and are expressed at various levels in different cell types such as IECs, innate lymphoid cells, macrophages, T cells, and dendritic cells (Furusawa et al. 2013). Functional immune responses often modulate gut barrier integrity; hence, the fine-tuning of gut microbiota to evoke necessary immune responses to alter intestinal barrier function is critical. The major confounding factors that disturb the composition of gut microbiota and gut barrier functions include exposure to heavy metals and associated disorders. The following sections review the current understanding of heavy metal exposure and their impact on gut barrier functions.

The role of heavy metals in regulation of gut microbiota and gut barrier function

Humans are exposed daily to numerous environmental chemicals, heavy metals, pesticides, organic pollutants, mycotoxins, food additives, and other contaminants (Celebi Sozener et al. 2020). Exposure to the heavy metals such as arsenic (As), lead (Pb), mercury (Hg), cadmium (Cd), and chromium (Cr) results in adverse health effects in humans and animals (Balali-Mood et al. 2021). Around 60% of ingested metals are absorbed by the intestine, resulting in severe oxidative stress and gut barrier damage, leading to increased intestinal inflammation (Feng et al. 2018, Assefa & Kohler 2020, Shao & Zhu 2020) (Fig. 1). The functional consequences of exposure to these environmental contaminants on the human gut microbiota are yet to be investigated. Table 1 summarizes the known effects of heavy metals on host health and gut microbiota. The importance of gut microbiota in the metabolism of heavy metals was demonstrated using GF mice. It was shown that heavy metals significantly accumulated in blood and target organs of GF mice compared to normal mice following exposure (Breton et al. 2013a ).

Figure 1
Figure 1

Effects of heavy metals on gut. Heavy metals such as arsenic (As), lead (Pb), mercury (Hg), cadmium (Cd), and chromium (Cr) lead to increased oxidative stress, altered gut microbial composition, and inflammation, potentially leading to gut leakiness and gut barrier dysfunction.

Citation: Microbiota and Host 2, 1; 10.1530/MAH-23-0015

Table 1

Effects of heavy metals on host health and gut microbiota.

Heavy metal Effect on health Changes in Gut microbiota
Increase Decrease
Arsenic Pathological changes in skin; gut barrier dysfunction; inflammation; carcinogenesis; microbial dysbiosis; cardiovascular diseases Bacteroidetes, Bifidobacterium, Faecalibaculum, Enterobacteriaceae, Gammaproteobacteria Firmicutes, Enterobacteriaceae
Lead Increased bodyweight; reduced MUC2, ZO-1, occludin, and claudin 1; increased gut permeability; elevated oxidative stress and inflammation; dysregulated hepatic metabolism; microbial dysbiosis; hepatotoxicity; nephrotoxicity Bacteroidetes,Clostridiaceae,Ruminococcus, Oscillibacter, Parabacteroides, Desulfovibrionaceae, ClostridiumXIVb, Barnesiella Firmicutes, Proteobacteria, Turicibacter, Akkermansia, Dehalobacterium, Lactococcus, Enterorhabdus, Caulobacterales
Mercury Neurotoxicity, oxidative stress and inflammation, leaky gut, mitochondrial dysfunction, increased lipid peroxidation, altered calcium homeostasis Firmicutes/Bacteroidetes ratio, Akkermansia Lactobacillus, Proteobacteria
Cadmium Inflammation; microbial dysbiosis; intestinal damage; junctional protein, mucus and glycan distribution alteration; hepatotoxicity; energy metabolism dysregulation; endocrine disruption; genome instability Bacteroidetes, Akkermansia muciniphila, Prevotella spp., Escherichia coli,Shigella Firmicutes, γ-Proteobacteria, A. muciniphila, Clostridium cocleatum, Lachnoclostridium
Chromium Oxidative stress, cancer, GI distress, microbial dysbiosis, DNA damage, lipid peroxidation, liver toxicity Bacteroidetes, Tenericutes, Prevotella, Clostridiales, S24-7, Actinobacteria Firmicutes, Lachnospiraceae

Arsenic

About 225 million people in over 70 countries in the world are chronically exposed to arsenic (Naujokas et al. 2013, Podgorski & Berg 2020), making it the cause of an environmental health crisis with no known treatment. In USA, about 3 million individuals are exposed to arsenic mostly through unregulated domestic well water used for drinking purposes (Ayotte et al. 2017). Arsenic is a group I human carcinogen and chronic exposure leads to toxic effects in multiple organs like liver, kidney, bladder, skin, and central nervous system (Banerjee 2011, IARC 2012, Hong et al. 2014, Hunt et al. 2014, Coryell et al. 2019, Garza-Lombo et al. 2019). While skin has been reported as the major target organ for arsenic with precancerous and cancerous outcomes (Hunt et al. 2014), recent data are shedding light on its adverse effects on lifestyle disorders including diabetes, cardiovascular diseases, and obesity (Navas-Acien et al. 2008, Moon et al. 2012, 2018, Chen & Karagas 2013, Grau-Perez et al. 2017, Bulka et al. 2017, Young et al. 2018, Farkhondeh et al. 2019). Recent studies highlighted that chronic exposure to arsenic has a significant impact on the GI system, leading to irritation, nausea, pain, and vomiting (Jomova et al. 2011) as well as perturbation of gut microbiome (Choiniere & Wang 2016b). Previous reports suggested that the chronic arsenic exposure abrogates the gut barrier function, with affected individuals exhibiting symptoms like dyspepsia, gastroenteritis, and chronic diarrhea (Guha Mazumder & Dasgupta 2011, Choiniere & Wang 2016a, Chiocchetti et al. 2019a,b, Fernández Fernández et al. 2019). In rodents, arsenic metabolites (e.g. monomethylarsonic acid) target the GI tract, leading to enlargement of the intestinal wall, edemas, hemorrhages, necrosis, and ulcerations as well as increase in the incidence of squamous metaplasia of absorptive epithelial cells of the colon and rectum (Arnold et al. 2003). Sub-chronic exposure to arsenic led to disruption of the colonic epithelial structure and barrier function (Chiocchetti et al. 2018). The transmission electron microscope (TEM) image of Caco-2 cells after arsenic exposure (As (III) ≥ 0.075 mg/L; As (V) ≥ 0.75 mg/L) for 14 days showed the disruption in microvillus structures, resulting in increased paracellular transport and barrier dysfunction (Chiocchetti et al. 2018). Trivalent forms of arsenic significantly induce inflammatory cytokines such as IL-6, IL-8, and TNF-α as well as oxidative stress in colon epithelial cells (Calatayud et al. 2013, 2014). Recently, it was shown that gut microbiota is required for full protection against acute arsenic toxicity using mouse models (Coryell et al. 2018). In this study, the authors showed that when mice were given the antibiotic cefoperazone before being exposed to inorganic sodium arsenate (iAsV), the inorganic arsenic (iAs) accumulated significantly in their organs. These mice also exhibited lower levels of iAs in their stools compared to the mice that did not receive antibiotics. Furthermore, in line with these findings, mice without gut microbiota (GF mice) exposed to iAs also showed higher levels of iAs in their organs compared to mice with normal microbiota. In essence, these studies suggest that gut microbiota is necessary for effectively processing/metabolizing iAs for excretion from the host’s body. This study also demonstrated that transplantation of human microbiota into GF mice protected them from arsenic-induced adverse effects. It was shown that functional arsenic detoxification enzyme (As3mt) and a specific bacterium called Faecalibacterium are essential for protection against acute arsenic toxicity in mouse models (Coryell et al. 2018). iAs speciation is significantly impacted by microbial-dependent iAs metabolism (reviewed in (Tsai et al. 2009, Kruger et al. 2013)). The iAs is transported through glycerol or phosphate transporters in bacteria. Arsenate can be reduced to arsenite, which may be expelled by ArsAB. Alternatively, arsenite can be methylated by ArsM to MMAs (III), DMAs (III) and TMAs. Briefly, biotransformation of iAs by microbes can be divided into four functional groups: (i) As(III) oxidation, (ii) iAs(V) reduction, (iii) iAs methylation and demethylation, and (iv) iAs transport (Zhao et al. 2019). The toxic forms of As(III)/MMAs(III) can be actively expelled from bacterial cells using arsenic transporters encoded by arsB, arsP, or acr3 (genes associated with resistance). Arsenic methylation, governed by arsM (related to resistance), results in the release of arsenic through volatilization or the formation of products like mono-, di-, or trimethylarsines. It is possible that lack of microbes in the host (either in antibiotic-treated or germ-free mice) failed to metabolize iAs and expel from host body, leading to the accumulation of iAs in target organs, including the GI tract.

Gut microbiome analysis of individuals exposed to arsenic revealed that abundance of pathogenic bacteria is positively correlated with and commensal gut bacteria are negatively correlated with increased arsenic concentration (Brabec et al. 2020, Chen et al. 2021). It was shown by Chi et al. that exposure to environmentally relevant levels of As (100 ppb) in mice led to significant changes in the functional metagenome. These include increase in the genes involved in energy metabolism, LPS synthesis, oxidative stress responses, and DNA repair (Chi et al. 2017). Additionally, arsenic exposure also enriched genes that encode conjugative transposon proteins, components of the multidrug efflux system, and the synthesis of multiple vitamins (Chi et al. 2017). Human gut microbiota can biochemically transform arsenic-containing compounds (arsenicals), leading to arsenic speciation and bioavailability (Lu et al. 2013, 2014, Yin et al. 2022). It is possible that either microbiota metabolizes arsenic to produce less-toxic arsenicals or microbial metabolites can counteract against arsenic-induced toxicity or organ damage. Our group showed that gut microbial metabolite urolithin A (UroA) protected colon epithelial cells against inorganic arsenic exposure by reducing inorganic trivalent arsenic (iAs3+)-induced oxidative stress and enhancing TJ proteins (Ghosh et al. 2022a,b). We have demonstrated that UroA protected from arsenic-induced cell death in colon epithelial cells and alleviated iAs3+-induced barrier dysfunction in both colon epithelial cell monolayers and a human 3D small intestinal tissue model. Importantly, UroA treatment significantly protected from arsenic-induced gut barrier permeability by enhancing TJ proteins such as zonula occludens 1, occludin, and claudin 4. Mechanistically, we showed that UroA treatment reduced iAs3+-induced reactive oxygen species (ROS) through regulating genes involved oxidative stress pathways. Further in vivo studies are required to determine the impact of metabolites in ameliorating arsenic-induced toxicities. Moreover, use of probiotics like Bifidobacterium and Lactobacillus modulated arsenic transformation abilities by enhancing excretion and detoxification (Liu et al. 2022b). It is pertinent to recall the epidemiological observation that people from Northport, WA, USA, who had chronic exposure to iAs had 15 times more IBD incidence than the national average (Pynn 2013). Therefore, targeting gut barrier dysfunction and inflammation simultaneously by beneficial microbiota and microbial metabolites would offer better protection against arsenic-induced adverse events.

Lead

A non-essential heavy metal, lead (Pb) exerts its toxic effects on several organs including liver, kidney, nervous system, cardiovascular, GI, and reproductive systems (Flora et al. 2012, Liu et al. 2021, Yu et al. 2021b). Soil contamination with gasoline and paint exposes humans to Pb-related toxicity. An epidemiological study by Lanphear et al. determined the concentrations of Pb in blood of adults aged 20 years or older and confirmed that low-level exposure to Pb was associated with risk factors for cardiovascular disease mortality in the USA (Lanphear et al. 2018). Pb-induced oxidative stress by ROS is one of the causes for Pb poisoning and related adverse health effects. Hence, the modulation of cellular thiols by antioxidants against ROS production has emerged as a key therapeutic approach (Flora et al. 2012). Several studies elaborated the adverse effects of Pb on GI tract and gut microbiota in several species. Mice exposed to low-dose (chronic model) or high-dose (acute model) Pb exhibited reduced colonic MUC2 levels, TJ proteins such as ZO-1, claudin 1, and occludin and increased intestinal permeability, suggesting its direct impact on GI functions (Zhai et al. 2019b). IEC damage was observed in honeybees when they were exposed to lead oxide (PbO) and/or cadmium oxide (CdO) nanoparticles for 9 days (Dabour et al. 2019). In these studies, they also showed using TEM methodologies that CdO and PbO induced cytological alterations in IECs (Dabour et al. 2019). Xia et al. showed that chronic exposure to Pb (15 weeks) induced gut microbial dysbiosis and metabolic disorder in mice (Xia et al. 2018). Especially, Pb exposure caused significant increase in the levels of hepatic triglycerides, total cholesterol as well as genes involved in lipid metabolism. Further, Pb exposure led to change in the structure and richness of the gut microbiota, especially relative abundance of Firmicutes and Bacteroidetes was altered compared to normal control mice (Xia et al. 2018). Even early exposure to Pb during developmental period enhanced the risk for obesity in adulthood by altering the gut microbiota independent of gender (Wu et al. 2016). Gao et al. demonstrated by using multi-omics approaches that Pb exposure affected gut microbiome trajectories including metabolic pathways in C57BL/6 mice (Gao et al. 2017). Fecal microbiota transplantation from donors supplemented with galactooligosaccharide (GOS) altered the gut microbiota composition and improved the recovery of the gut barrier function in mice after Pb exposure. Zhai et al. showed that the mice treated with antibiotics exhibited accumulation of higher levels of Pb in their blood and primary organs, along with reduced Pb levels in their feces (Zhai et al. 2019a) indicating importance of microbiota in clearance of Pb from host. Typically, certain gut microorganisms can boost the healing of intestinal mucosal injuries, support the balance of gut immunity, and contribute to the reduction of gut inflammation. It was shown that the Pb exposure leads to gut dysbiosis, resulting in a decrease in beneficial bacteria such as Akkermansia muciniphila, Faecalibacterium prausnitzii, and Oscillibacter ruminantium (Zhai et al. 2017). Interestingly, oral administration of these Pb-intolerant gut microbes, A. muciniphila, F. prausnitzii, and O. ruminantium reversed the Pb-induced toxicity in mouse models (Zhai et al. 2019a,b). Oral administration of these bacteria led to reduction in Pb burden in target organs and bloodstream and increased fecal Pb excretion in chronically Pb-exposed mice (Zhai et al. 2017). Moreover, oral supplementation of these Pb-intolerant gut microbes (especially F. prausnitzii and O. ruminantium) enhanced gut barrier function by upregulating TJPs such as ZO-1, occludin, and claudin 1 proteins in the colon and small intestine. Further, these treatments increased the levels of short-chain fatty acids (SCFAs), which have been shown to have a significant impact on gut barrier function. Mechanistically, treatment with these microbes significantly reduced Pb-induced hepatic and renal oxidative stress in mice. These studies further showed that the three Pb-intolerant gut microbe strains showed a high adsorption capacity for Pb2+ compared with E. coli K12 (Zhai et al. 2017). In summary, these findings indicate that gut microbiota can limit the absorption and accumulation of Pb in host tissues. When Pb-intolerant intestinal microbes like F. prausnitzii and O. ruminantium were orally administered to mice, there was a significant decrease in Pb accumulation and alleviate Pb toxicity. This underscores the significance of adjusting gut microbiota as a potential strategy for minimizing the Pb toxicity in the host. Pb exposure to GF mice resulted in increased accumulation of Pb in blood and organs compared to conventional SPF mice, suggesting that gut microbiota plays a major role in excretion of heavy toxic metals (Breton et al. 2013a). Recently, a human cohort study revealed that increased urinary Pb is associated with the presence of Proteobacteria, suggesting that environmental toxins potentially induce microbial dysbiosis and lead to adverse health in humans (Eggers et al. 2019). Further in-depth studies are required to define cause or consequence and mechanisms of actions of Pb in various disease conditions.

Mercury

Mercury (Hg) is a well-known biohazard that exists in the environment in its elemental form, as inorganic mercury, or as organic mercury (Rice et al. 2014). The most common and major source of Hg in the ecosystems is methylmercury (MeHg), i.e. Hg in its organic methylated form. MeHg is highly toxic, as it covalently binds to the glutathione and cysteine residues of any protein in the host system and causes alterations in the protein structure and function (Pinto et al. 2020). Mercury exposure causes DNA damage, induction of oxidative stress, mitochondrial dysfunction, increased lipid peroxidation, and altered calcium homeostasis at the cellular level. Mercury poisoning affects all organs, as it can readily pass into the circulation system, ultimately leading to death. Likewise, gut barrier permeability and microbial dysbiosis have been closely associated to exposure to mercury. Vázquez et al. showed that inorganic divalent mercury (Hg (II)) and MeHg can exert toxicity on IECs and mucosa by generating redox imbalance (Vazquez et al. 2014). Generation of ROS or reactive nitrogen species (RNS) and decrease in glutathione by mercury redistributed the F-actin and ZO-1 protein in the intestinal cells, resulting in elevated barrier permeability (Vazquez et al. 2014). It is shown that Hg exposure significantly downregulated expression of intercellular junction proteins like claudin 1, occludin, ZO-1, and junctional adhesion molecule 1 (JAM1) in colon epithelial cells. Hg also increased the intestinal cell volume and membrane permeability without any loss in cell viability; thus, it promotes the uptake of other toxic metals in same conditions (Aduayom et al. 2005). Bolan et al. reported that gut microbes like Escherichia coli and Lactobacillus acidophilus, or chelating agents (EDTA and 2,3-dimercapto-1-propanesulfonic acid (DMPS)) significantly reduced the Hg-induced permeability in in vitro GI/Caco-2 cell intestinal epithelium model (Bolan et al. 2021). It was suggested that microbiota-dependent protection against heavy metal-induced intestinal permeability may be associated with indirect intestinal sequestration of metals by gut bacteria through adsorption on bacterial surface (Bolan et al. 2021). Moreover, probiotics strain Lactobacillus brevis 23017 exhibits strong mercury-binding capacity, which may potentially reduce Hg exposure to the host cells and protects the gut barrier integrity against Hg-induced toxicity (Jiang et al. 2018). It was shown that the L. brevis 23017 reduced the Hg-induced inflammation and oxidative stress through regulating MAPK and NF-κB pathways (Jiang et al. 2018). Additionally, L. brevis 23017 supplementation maintained a normal mucosal barrier via modulation of TJ proteins. Depletion of gut microbiota by antibiotics significantly increased the levels of Hg accumulation in several organs like cerebellum, liver, and lungs in mice that are exposed to Hg in comparison with the mice that harbored normal microbiota (Seki et al. 2021). It was shown that MeHg is captured and inactivated by the hydrogen sulfide and hydrogen persulfide (by forming sulfur adducts to excrete out) produced by gut microbes, which resulted in reduced MeHg toxicity (Seki et al. 2021). Furthermore, gut microbes also regulate Hg biotransformation and bioaccumulation in freshwater fish (Micropterus salmoides), marine fish (Acanthopagrus latus), and polar bear (Ursus maritimus) (Watson et al. 2021, Yang et al. 2021b, Tan et al. 2022). Zhao et al. showed that subchronic oral mercury caused loss in body weight, intestinal injury and led to changes in gut microbiota and aggravated apoptosis in mice (Zhao et al. 2020). In case reports, it was shown that occupational exposure to mercury vapors led to increased episodes of disease reactivation in patients with chronic ulcerative colitis (Cummings & Rosenman 2006). It is interesting recall that mercury released from dental ‘silver’ fillings provoked an increase in mercury- and antibiotic-resistant bacteria in oral cavity and intestines (Summers et al. 1993). These mercury- and antibiotic-resistant isolates include Staphylococci, Enterococci, and members of the family Enterobacteriaceae. Mercury exposure led to generation of mercury and antibiotic resistance plasmids in the normal microbiota of primates (Summers et al. 1993). Further studies are required to define the effects of mercury on human GI system and its role in promoting GI-related disorders.

Cadmium

Cadmium (Cd) is a highly toxic environmental pollutant that majorly gets accumulated from cigarette smoking and diet. Cd exposure is related to several diseases like diabetes, chronic kidney disease, osteoporosis, obesity, liver disease, cardiovascular diseases, and cancer (Tellez-Plaza et al. 2012, Tinkov et al. 2017, 2018). Cd induces cytotoxicity by enhancing inflammation, gut barrier dysfunction, oxidative stress, endoplasmic reticulum stress, endocrine disruption, and genomic instability (Rafati Rahimzadeh et al. 2017). Several studies reported that exposure to Cd induced leaky gut, with an irregular distribution and reduced expression of TJ proteins like ZO-1, ZO-2, JAM-A, occludin, and claudin 1 in IECs and mice (Duizer et al. 1999, Rusanov et al. 2015, Zhai et al. 2016, Liu et al. 2020a). Relative changes in transepithelial/transendothelial electrical resistance (aka TEER) after high doses (100 and 300 μM) of Cd exposure were the result of damaged tight intercellular junctions and loss of the monolayer integrity (Rusanov et al. 2015). Even low-dose Cd exposure significantly caused gut microbial dysbiosis in mice and aggravated liver injury by increased intestinal permeability (Liu et al. 2020a). In this study, they showed that Cd exposure significantly downregulated the expression of TJ proteins such as ZO-1, JAM-A, and occludin, leading to increased intestinal permeability and liver injury. Importantly, it was shown that low Cd exposure led to decrease in the Akkermansia muciniphila, a commensal known to protect the gut barrier integrity, suggesting adverse impacts of Cd exposure in regulating gut microbiota composition (Liu et al. 2020a). Cd interfered with gut mucosa and goblet cells in a dose- and site-dependent manner in zebrafish (Danio rerio) (Motta et al. 2022). Cd altered the mucosal efficiency by changing localization and distribution of glycan residues and metallothionein expression in intestinal cells (Motta et al. 2022). Moreover, oral intake of Cd changed the adaptive immune activities in mice, leading to increased gut permeability, intestinal tissue damage, and inflammation. Importantly, Cd exposure reduced the population of the beneficial commensal Lactobacillus strain (Ninkov et al. 2015). It was shown that Cd exposure modified the gut–liver axis along with gut dysbiosis in ApoE4-KI males, which are the most susceptible mice strain to neurological damages (Zhang et al. 2021). Exposure to Cd in mice also modulated the levels of gut microbiota like Eisenbergiella, Blautia, ClostridiumXlVa, Lactobacillus, Bifidobacterium and decreased levels of microbial metabolites such as short chain fatty acids (e.g. butyrate) (Liu et al. 2014, Li et al. 2019). It was shown that Cd exposure in mice led to significant alteration in the gut microbiota population including several butyrate producers along with changes in the bile acid fraction of the gut metabolome (Li et al. 2019). Moreover, Cd exposure caused a decrease in the thickness of inner mucus layer and reduced the growth of Bacteroidetes, Lactobacillus, and Bifidobacterium followed by altered SCFA metabolism (Liu et al. 2014). Yang et al. showed that Cd exposure had adverse effects on liver, kidney, and ovary functions in adolescent rats. Moreover, their study unveiled alterations in the microbiota, characterized by decreased levels of Prevotella and Lachnoclostridium, and increased levels of Escherichia coli and Shigella (Yang et al. 2021a), whereas use of gut microbes like E. coli and Lactobacillus acidophilus reduced the Cd-mediated IEC permeability (Bolan et al. 2021). Probiotic Lactobacillus plantarum CCFM8610 also reduced that Cd-induced toxicity and intestinal motility dysfunction in mice with decreased Cd content in the tissues and blood of animals along with enhanced fecal cadmium excretion (Liu et al. 2020b). Moreover, Lactobacillus plantarum CCFM8610 exhibited excellent Cd binding and antioxidative capacity, which helped in protection of the Cd-mediated disruption of TJs in IECs. Overall, Cd exposure leads to gut microbial dysbiosis and exerts its impact on gut barrier integrity, leading to increased gut permeability and promoting GI-related disorders; supplementation of beneficial certain probiotics could protect from Cd-induced adverse effects.

Chromium

Chromium, a known mutagenic, metallic contaminant gets bioaccumulated in animals from solid waste disposal, pesticides, fertilizers, mining activities, and residues from industrial productions. Cr is available in multiple oxidation states, but trivalent and hexavalent forms are the most stable (Balali-Mood et al. 2021). Cr in trivalent state is required for lipid metabolism, protein metabolism and as a cofactor for insulin action, whereas hexavalent Cr is responsible for disease pathogenesis like organ failure, rhinitis, asthma, gut barrier dysfunction, and cancer. A recent meta-analysis from human study showed that Cr exposure increased mortality and occurrence of larynx, lung, thyroid, bone, kidney, bladder, and testicular cancer (Deng et al. 2019). Another human study reported that groundwater contamination of Cr caused severe GI distress and digestive problems in both male and females along with changes in hematological parameters like RBC and platelet counts (Sharma et al. 2012). Studies revealed that long-term exposure to Cr aggravated GI symptoms and body weight loss in colorectal cancer model with change in microbial abundance (Zhang et al. 2020). Moreover, Cr affected the GI tract of earthworm (Eisenia fetida) via nuclear damage in gut epithelia, with hemorrhage and ulceration (Tang et al. 2019). The TEM images revealed that the Cr-exposed earthworm contained subcellular injury with short, messy, and rough gut villus and damaged organelles. A recent study showed that exposure to hexavalent chromium in ducks led to gut barrier damage through downregulation of ZO-1, occludin, claudin 1, and MUC2 expression (Xing et al. 2022). Activation of NLRP3 inflammasome and generation of oxidative stress contributed to the shortening of the intestinal villi and gut barrier dysfunction. In mice with Cr-induced damage, the use of Lactobacillus plantarum TW1-1 reduced Cr accumulation and restored gut bacterial homeostasis (Wu et al. 2017). Cr exposure effectively dysregulated Bacteroidetes–Firmicutes homeostasis and increased the abundance of S24-7, Prevotella, and Clostridiales but lowered Lachnospiraceae. The lower butyrate producer Lachnospiraceae hampered the development of IECs, leading to inflammation and oxidative stress after Cr exposure in mice (Wu et al. 2017). Long-term Cr exposure also increased the presence of Firmicutes and Actinobacteriaand removed the presence of Deferribacteres, Intestinimonas,Butyricimonas, Butyricicoccus, Lachnospiraceae FCS020 group, and Ruminococcaceae V9D2013 group in chickens (Li et al. 2021). Several studies in Wistar rats and chickens proved that gut microbiota is essential for first line of defense against Cr toxicity and microbes may act as a prebiotic or probiotic to attenuate Cr toxicity (Shrivastava et al. 2005, Li et al. 2022, Wang et al. 2022b). Upreti et al. developed resistance to Cr up to 64 ppm in probiotic Lactobacilli strains with chronological chronic exposures. These probiotic strains showed no antibiotic resistance but ameliorated Cr-induced GI toxicity (Upreti et al. 2011). Thus, this study showed that alteration of microbial composition can be therapeutic for Cr-induced GI damage and toxicity.

Moreover, some metals like aluminum (Al) despite not having a high density like ‘heavy metals’ are considered toxic due to their level of toxicity. Aluminum is the most abundant metal element in the Earth’s crust, and continuous exposure to Al leads to bioaccumulation and severe toxicity in several tissues including the gut (Vignal et al. 2016). Studies have reported that excessive Al induced apoptosis of IECs and disrupted TJ proteins, leading to increased intestinal permeability and gut barrier dysfunction (Vignal et al. 2016, Hao et al. 2022). Damage of the gut barrier due to Al exposure leads to impaired immune system in affected individuals. Yu et al. reported that dietary Al exposure altered the human gut microbiota composition and that supplementation with probiotics like L. plantarum CCFM639 abrogated the toxicity of Al (Yu et al. 2021a). In Wistar rats, dietary intake of Al diminished the natural gut microbiota diversity and affected the physiological homeostasis (Wang et al. 2022a).

Outstanding questions and major challenges

  • What are the molecular and cellular mechanisms of heavy metal-mediated gut microbial dysbiosis and gut barrier dysfunction? Especially, how do heavy metals disrupt epithelial junctional proteins? Is the metal-induced oxidative stress solely responsible for long-term adverse effects that are observed in the GI tract?

  • How does microbiota regulate metal toxicity and is there any specific bacterium or bacterial consortium responsible for detoxification of specific metal toxicity? For example, is there any bacterial specificity for heavy metals that either increase or decrease toxicity? If so, what are the mechanisms for metal specificity?

  • What are interactions of microbial metabolites with heavy metals and their implications on gut barrier functions in humans? Especially, it will be interesting to determine whether direct supplementation of microbial metabolites renders benefits against heavy metal toxicity and helps overcome the microbial dysbiosis?

  • The effects of heavy metal exposure on skin and lung microbiome are less explored. It is important to evaluate these effects, as metals directly influence the pathogenesis of skin and respiratory disorders.

  • Developing appropriate models to investigate metal toxicity is a major challenge in this area of research. For instance, recapitulation of human exposure (low vs high) of heavy metals in animal models is a major constraint due to limitations in duration of exposure, and controlling the route of administration may not provide the complete array of effects observed in humans. Secondly, the metabolic rates of metals are significantly different between humans and animal models (mice or rats), which adds another layer of complexity. Thirdly, the effects of heavy metals on gut environment may not be detectable in early stages, but metal-induced gut barrier dysfunction may promote and cause other organ damage due to leakage of constant bacterial endotoxins and inflammatory cytokines. Therefore, developing methods and biomarkers to detect gut barrier functions would significantly aid in the design and development of therapeutics.

Summary

The gut epithelial barrier is the most important system for nutrient absorption and required for protection from exogenous pathobionts and environmental pollutants (Gillois et al. 2018, Ghosh et al. 2021). In homeostatic conditions, the gut microbiota and gut barrier play a protective role against toxic effects of environmental pollutants and reduce the risk factors for GI-related disorders. Nevertheless, several exogenous and endogenous factors such as diet, xenobiotics, heavy metals, and microbial dysbiosis as well as increased inflammation contribute to the enhanced barrier dysfunction and systemic toxicity. The extent and duration of exposure are crucial factors in determining the hazards that may jeopardize the host’s overall health. Failure to promptly address these issues could result in the continuous deterioration of epithelial barriers, posing an increased risk for a range of GI and non-GI disorders. Alterations in gut physiology, encompassing but not limited to the degradation of the mucus layer, disruption of junctional proteins, heightened intestinal permeability, inflammation, and microbial imbalances, are the underlying causes of gut barrier dysfunction and immune irregularities. Heavy metal exposure impairs the metabolic activity of the gut microbiome, giving rise to inflammatory responses and cellular damage. In contrast, the restoration of microbial equilibrium and the sequestration of heavy metals by specific microbiota hold potential benefits for the host. The concept of ‘Intestinal Bioremediation’ is emerging as a valuable tool for immobilizing toxic metals by selectively employing relevant microbes to shield against their harmful effects (George et al. 2021), although the precise mechanisms underpinning this microbiota-mediated defense against environmental pollutants continue to be under investigation. Recent research has unveiled that gut bacteria communicate with the host signaling system through metabolites, which in turn regulate intestinal immunity and barrier defense (Fig. 2). The vital role played by the gut microbiota in maintaining gut homeostasis can thwart the nonessential toxicity of heavy metals. Therefore, leveraging beneficial microbiota and their metabolites as a therapeutic approach holds great promise in treating pollutant-induced gut barrier dysfunction.

Figure 2
Figure 2

Effect of heavy metals on human health. Environmental pollutants such as arsenic (As), lead (Pb), mercury (Hg), cadmium (Cd), and chromium (Cr) lead to several adverse health effects. Heavy metal-induced loss of gut barrier integrity and microbial balance initiates inflammation and toxicity in host tissue and organs. Consumption of healthy diets and treatment with beneficial gut microbiota or microbial metabolites potentially mitigate the adverse effects of heavy metal toxicity and restore gut homeostasis.

Citation: Microbiota and Host 2, 1; 10.1530/MAH-23-0015

Declaration of interest

VRJ is one of the scientific cofounders of Artus Therapeutics. SG and SPN have no conflicts of interest to declare.

Funding

VRJ is supported by NIH/NCI (CA191683), NIH/NIGMS CoBRE grant (P20GM125504-01), NIH/NIEHS (P30ES030283), The Jewish Heritage Fund for Excellence Research Enhancement Grant, and UofL Health-BCC.

Author contribution statement

SG and VRJ collected the literature, conceptualized the review, and wrote the manuscript. SP contributed by conceptualizing, proofreading, and editing the manuscript.

Acknowledgements

VRJ is supported by NIH/NCI (CA191683), NIH/NIGMS CoBRE grant (P20GM125504-01), NIH/NIEHS, (P30ES030283), The Jewish Heritage Fund for Excellence Research Enhancement Grant, and UofL-Health Brown Cancer Center. The authors thank Dr Bodduluri Haribabu for proofreading the manuscript and insightful discussions. Images were prepared using Biorender.com.

References

  • Aduayom I, Denizeau F & & Jumarie C 2005 Multiple effects of mercury on cell volume regulation, plasma membrane permeability, and thiol content in the human intestinal cell line Caco-2. Cell Biology and Toxicology 21 163179. (https://doi.org/10.1007/s10565-005-0157-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Allaire JM, Crowley SM, Law HT, et al.2018 The intestinal epithelium: central Coordinator of Mucosal Immunity. Trends in Immunology 39 677696. (https://doi.org/10.1016/j.it.2018.04.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Arnold LL, Eldan M, Van Gemert M, et al.2003 Chronic studies evaluating the carcinogenicity of monomethylarsonic acid in rats and mice. Toxicology 190 197219. (https://doi.org/10.1016/s0300-483x(0300165-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Arpaia N, Campbell C, Fan X, et al.2013 Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504 451455. (https://doi.org/10.1038/nature12726)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Assefa S & & Kohler G 2020 Intestinal microbiome and metal toxicity. Current Opinion in Toxicology 19 2127. (https://doi.org/10.1016/j.cotox.2019.09.009)

  • Ayotte JD, Medalie L, Qi SL, et al.2017 Estimating the high-arsenic domestic-well population in the conterminous United States. Environmental Science and Technology 51 1244312454. (https://doi.org/10.1021/acs.est.7b02881)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Balali-Mood M, Naseri K, Tahergorabi Z, et al.2021 Toxic mechanisms of five heavy metals: mercury, lead, chromium, cadmium, and arsenic. Frontiers in Pharmacology 12 643972. (https://doi.org/10.3389/fphar.2021.643972)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Banerjee M, Bhattacharjee P & & Giri AK 2011 Arsenic-induced cancers: a review with special reference to gene, environment and their interaction. Genes and Environment 33 128140. (https://doi.org/10.3123/jemsge.33.128)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bansil R & & Turner BS 2006 Mucin structure, aggregation, physiological functions and biomedical applications. Current Opinion in Colloid and Interface Science 11 164170. (https://doi.org/10.1016/j.cocis.2005.11.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Berin MC, Yang PC, Ciok L, et al.1999 Role for IL-4 in macromolecular transport across human intestinal epithelium. American Journal of Physiology 276 C1046C1052. (https://doi.org/10.1152/ajpcell.1999.276.5.C1046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bischoff SC, Barbara G, Buurman W, et al.2014 Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterology 14 189. (https://doi.org/10.1186/s12876-014-0189-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bist P & & Choudhary S 2022 Impact of heavy metal toxicity on the gut microbiota and its relationship with metabolites and future probiotics strategy: a review. Biological Trace Element Research 200 53285350. (https://doi.org/10.1007/s12011-021-03092-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bolan S, Seshadri B, Keely S, et al.2021 Bioavailability of arsenic, cadmium, lead and mercury as measured by intestinal permeability. Scientific Reports 11 14675. (https://doi.org/10.1038/s41598-021-94174-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brabec JL, Wright J, Ly T, et al.2020 Arsenic disturbs the gut microbiome of individuals in a disadvantaged community in Nepal. Heliyon 6 e03313. (https://doi.org/10.1016/j.heliyon.2020.e03313)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Breton J, Daniel C, Dewulf J, et al.2013a Gut microbiota limits heavy metals burden caused by chronic oral exposure. Toxicology Letters 222 132138. (https://doi.org/10.1016/j.toxlet.2013.07.021)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Breton J, Massart S, Vandamme P, et al.2013b Ecotoxicology inside the gut: impact of heavy metals on the mouse microbiome. BMC Pharmacology and Toxicology 14 62. (https://doi.org/10.1186/2050-6511-14-62)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bulka CM, Mabila SL, Lash JP, et al.2017 Arsenic and obesity: a comparison of urine dilution adjustment methods. Environmental Health Perspectives 125 087020. (https://doi.org/10.1289/EHP1202)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Calatayud M, Devesa V & & Vélez D 2013 Differential toxicity and gene expression in Caco-2 cells exposed to arsenic species. Toxicology Letters 218 7080. (https://doi.org/10.1016/j.toxlet.2013.01.013)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Calatayud M, Gimeno-Alcañiz JV, Vélez D, et al.2014 Trivalent arsenic species induce changes in expression and levels of proinflammatory cytokines in intestinal epithelial cells. Toxicology Letters 224 4046. (https://doi.org/10.1016/j.toxlet.2013.09.016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Celebi Sozener Z, Cevhertas L, Nadeau K, et al.2020 Environmental factors in epithelial barrier dysfunction. Journal of Allergy and Clinical Immunology 145 15171528. (https://doi.org/10.1016/j.jaci.2020.04.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ceponis PJ, Botelho F, Richards CD, et al.2000 Interleukins 4 and 13 increase intestinal epithelial permeability by a phosphatidylinositol 3-kinase pathway. Lack of evidence for STAT 6 involvement. Journal of Biological Chemistry 275 2913229137. (https://doi.org/10.1074/jbc.M003516200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen F, Luo Y, Li C, et al.2021 Sub-chronic low-dose arsenic in rice exposure induces gut microbiome perturbations in mice. Ecotoxicology and Environmental Safety 227 112934. (https://doi.org/10.1016/j.ecoenv.2021.112934)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen Y & & Karagas MR 2013 Arsenic and cardiovascular disease: new evidence from the United States. Annals of Internal Medicine 159 713714. (https://doi.org/10.7326/0003-4819-159-10-201311190-00720)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chi L, Bian X, Gao B, et al.2017 The effects of an environmentally relevant level of arsenic on the gut microbiome and its functional metagenome. Toxicological Sciences 160 193204. (https://doi.org/10.1093/toxsci/kfx174)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chiocchetti GM, Vélez D & & Devesa V 2018 Effect of subchronic exposure to inorganic arsenic on the structure and function of the intestinal epithelium. Toxicology Letters 286 8088. (https://doi.org/10.1016/j.toxlet.2018.01.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chiocchetti GM, Domene A, Kühl AA, et al.2019a In vivo evaluation of the effect of arsenite on the intestinal epithelium and associated microbiota in mice. Archives of Toxicology 93 21272139. (https://doi.org/10.1007/s00204-019-02510-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chiocchetti GM, Velez D & & Devesa V 2019b Inorganic arsenic causes intestinal barrier disruption. Metallomics 11 14111418. (https://doi.org/10.1039/c9mt00144a)

  • Choiniere J & & Wang L 2016a Exposure to inorganic arsenic can lead to gut microbe perturbations and hepatocellular carcinoma. Acta Pharmaceutica Sinica. B 6 426429. (https://doi.org/10.1016/j.apsb.2016.07.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Choiniere J & & Wang L 2016b Exposure to inorganic arsenic can lead to gut microbe perturbations and hepatocellular carcinoma. Acta Pharmaceutica Sinica. B 6 426429. (https://doi.org/10.1016/j.apsb.2016.07.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chowdhury R, Ramond A, O'keeffe LM, et al.2018 Environmental toxic metal contaminants and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 362 k3310. (https://doi.org/10.1136/bmj.k3310)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Claus SP, Guillou H & & Ellero-Simatos S 2016 The gut microbiota: a major player in the toxicity of environmental pollutants? npj Biofilms and Microbiomes 2 16003. (https://doi.org/10.1038/npjbiofilms.2016.3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Clevers H 2013 The intestinal crypt, a prototype stem cell compartment. Cell 154 274284. (https://doi.org/10.1016/j.cell.2013.07.004)

  • Coryell M, Mcalpine M, Pinkham NV, et al.2018 The gut microbiome is required for full protection against acute arsenic toxicity in mouse models. Nature Communications 9 5424. (https://doi.org/10.1038/s41467-018-07803-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Coryell M, Roggenbeck BA & & Walk ST 2019 The human gut microbiome's influence on arsenic toxicity. Current Pharmacology Reports 5 491504. (https://doi.org/10.1007/s40495-019-00206-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cray P, Sheahan BJ & & Dekaney CM 2021 Secretory sorcery: Paneth cell control of intestinal repair and homeostasis. Cellular and Molecular Gastroenterology and Hepatology 12 12391250. (https://doi.org/10.1016/j.jcmgh.2021.06.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cummings CE & & Rosenman KD 2006 Ulcerative colitis reactivation after mercury vapor inhalation. American Journal of Industrial Medicine 49 499502. (https://doi.org/10.1002/ajim.20306)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cunningham KE & & Turner JR 2012 Myosin light chain kinase: pulling the strings of epithelial tight junction function. Annals of the New York Academy of Sciences 1258 3442. (https://doi.org/10.1111/j.1749-6632.2012.06526.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dabour K, Al Naggar Y, Masry S, et al.2019 Cellular alterations in midgut cells of honey bee workers (Apis millefera L.) exposed to sublethal concentrations of CDO or PbO nanoparticles or their binary mixture. Science of the Total Environment 651 13561367. (https://doi.org/10.1016/j.scitotenv.2018.09.311)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Deng Y, Wang M, Tian T, et al.2019 The effect of hexavalent chromium on the incidence and mortality of human cancers: a meta-analysis based on published epidemiological cohort studies. Frontiers in Oncology 9 24. (https://doi.org/10.3389/fonc.2019.00024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dillon A & & Lo DD 2019 M cells: intelligent engineering of mucosal immune surveillance. Frontiers in Immunology 10 1499. (https://doi.org/10.3389/fimmu.2019.01499)

  • Dominguez-Bello MG, Costello EK, Contreras M, et al.2010 Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. PNAS 107 1197111975. (https://doi.org/10.1073/pnas.1002601107)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Duan H, Yu L, Tian F, et al.2020 Gut microbiota: a target for heavy metal toxicity and a probiotic protective strategy. Science of the Total Environment 742 140429. (https://doi.org/10.1016/j.scitotenv.2020.140429)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Duizer E, Gilde AJ, Versantvoort CH, et al.1999 Effects of cadmium chloride on the paracellular barrier function of intestinal epithelial cell lines. Toxicology and Applied Pharmacology 155 117126. (https://doi.org/10.1006/taap.1998.8589)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eckburg PB, Bik EM, Bernstein CN, et al.2005 Diversity of the human intestinal microbial flora. Science 308 16351638. (https://doi.org/10.1126/science.1110591)

  • Eggers S, Safdar N, Sethi AK, et al.2019 Urinary lead concentration and composition of the adult gut microbiota in a cross-sectional population-based sample. Environment International 133 105122. (https://doi.org/10.1016/j.envint.2019.105122)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ey B, Eyking A, Gerken G, et al.2009 TLR2 mediates gap junctional intercellular communication through connexin-43 in intestinal epithelial barrier injury. Journal of Biological Chemistry 284 2233222343. (https://doi.org/10.1074/jbc.M901619200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Farkhondeh T, Samarghandian S & & Azimi-Nezhad M 2019 The role of arsenic in obesity and diabetes. Journal of Cellular Physiology 234 1251612529. (https://doi.org/10.1002/jcp.28112)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Feng P, Ye Z, Kakade A, et al.2018 A review on gut remediation of selected environmental contaminants: possible roles of probiotics and gut microbiota. Nutrients 11. (https://doi.org/10.3390/nu11010022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Feng Y, Huang Y, Wang Y, et al.2019 Antibiotics induced intestinal tight junction barrier dysfunction is associated with microbiota dysbiosis, activated NLRP3 inflammasome and autophagy. PLoS One 14 e0218384. (https://doi.org/10.1371/journal.pone.0218384)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fernández Fernández N, Estevez Boullosa P, Gómez Rodríguez A, et al.2019 A rare cause of gastric injury: arsenic intake. American Journal of Gastroenterology 114 1193. (https://doi.org/10.14309/ajg.0000000000000194)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Flora G, Gupta D & & Tiwari A 2012 Toxicity of lead: a review with recent updates. Interdisciplinary Toxicology 5 4758. (https://doi.org/10.2478/v10102-012-0009-2)

  • Furusawa Y, Obata Y, Fukuda S, et al.2013 Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504 446450. (https://doi.org/10.1038/nature12721)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gao B, Chi L, Mahbub R, et al.2017 Multi-omics reveals that lead exposure disturbs gut microbiome development, key metabolites, and metabolic pathways. Chemical Research in Toxicology 30 9961005. (https://doi.org/10.1021/acs.chemrestox.6b00401)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Garza-Lombo C, Pappa A, Panayiotidis MI, et al.2019 Arsenic-induced neurotoxicity: a mechanistic appraisal. Journal of Biological Inorganic Chemistry 24 13051316. (https://doi.org/10.1007/s00775-019-01740-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • George F, Mahieux S, Daniel C, et al.2021 Assessment of Pb(II), Cd(II), and Al(III) Removal Capacity of Bacteria from Food and Gut Ecological Niches: insights into Biodiversity to Limit Intestinal Biodisponibility of Toxic Metals. Microorganisms 9 II. (https://doi.org/10.3390/microorganisms9020456)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ghosh S, Whitley CS, Haribabu B, et al.2021 Regulation of intestinal barrier function by microbial metabolites. Cellular and Molecular Gastroenterology and Hepatology 11 14631482. (https://doi.org/10.1016/j.jcmgh.2021.02.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ghosh S, Banerjee M, Bodduluri H, et al.2022a Microbial metabolite mitigates arsenic induced oxidative stress, inflammation, and barrier dysfunction in gut epithelia. FASEB Journal 36. (https://doi.org/10.1096/fasebj.2022.36.s1.r3691)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ghosh S, Banerjee M, Haribabu B, et al.2022b Urolithin A attenuates arsenic-induced gut barrier dysfunction. Archives of Toxicology 96 9871007. (https://doi.org/10.1007/s00204-022-03232-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ghosh S, Moorthy B, Haribabu B, et al.2022c Cytochrome P450 1A1 is essential for the microbial metabolite, urolithin A-mediated protection against colitis. Frontiers in Immunology 13 1004603. (https://doi.org/10.3389/fimmu.2022.1004603)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ghosh S, Singh R, Vanwinkle ZM, et al.2022d Microbial metabolite restricts 5-fluorouracil-resistant colonic tumor progression by sensitizing drug transporters via regulation of FOXO3-FOXM1 axis. Theranostics 12 55745595. (https://doi.org/10.7150/thno.70754)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gibson GR & & Roberfroid MB 1995 Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. Journal of Nutrition 125 14011412. (https://doi.org/10.1093/jn/125.6.1401)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gillois K, Leveque M, Theodorou V, et al.2018 Mucus: an underestimated gut target for environmental pollutants and food additives. Microorganisms 6. (https://doi.org/10.3390/microorganisms6020053)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • González-Mariscal L, Betanzos A, Nava P, et al.2003 Tight junction proteins. Progress in Biophysics and Molecular Biology 81 144. (https://doi.org/10.1016/s0079-6107(0200037-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goodenough DA & & Paul DL 2009 Gap junctions. Cold Spring Harbor Perspectives in Biology 1 a002576. (https://doi.org/10.1101/cshperspect.a002576)

  • Goodenough DA, Goliger JA & & Paul DL 1996 Connexins, connexons, and intercellular communication. Annual Review of Biochemistry 65 475502. (https://doi.org/10.1146/annurev.bi.65.070196.002355)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Grau-Perez M, Kuo CC, Gribble MO, et al.2017 Association of low-moderate arsenic exposure and arsenic metabolism with incident diabetes and insulin resistance in the strong heart family study. Environmental Health Perspectives 125 127004. (https://doi.org/10.1289/EHP2566)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Green KJ & & Simpson CL 2007 Desmosomes: new perspectives on a classic. Journal of Investigative Dermatology 127 24992515. (https://doi.org/10.1038/sj.jid.5701015)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guan Q 2019 A comprehensive review and update on the pathogenesis of inflammatory bowel disease. Journal of Immunology Research 2019 7247238. (https://doi.org/10.1155/2019/7247238)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guha Mazumder D & & Dasgupta UB 2011 Chronic arsenic toxicity: studies in West Bengal, India. Kaohsiung Journal of Medical Sciences 27 360370. (https://doi.org/10.1016/j.kjms.2011.05.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gumbiner BM 1996 Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 84 345357. (https://doi.org/10.1016/s0092-8674(0081279-9)

  • Günzel D & & Yu AS 2013 Claudins and the modulation of tight junction permeability. Physiological Reviews 93 525569. (https://doi.org/10.1152/physrev.00019.2012)

  • Halbleib JM & & Nelson WJ 2006 Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes and Development 20 31993214. (https://doi.org/10.1101/gad.1486806)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hao W, Hao C, Wu C, et al.2022 Aluminum induced intestinal dysfunction via mechanical, immune, chemical and biological barriers. Chemosphere 288 132556. (https://doi.org/10.1016/j.chemosphere.2021.132556)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hartsock A & & Nelson WJ 2008 Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochimica et Biophysica Acta 1778 660669. (https://doi.org/10.1016/j.bbamem.2007.07.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hayes CL, Dong J, Galipeau HJ, et al.2018 Commensal microbiota induces colonic barrier structure and functions that contribute to homeostasis. Scientific Reports 8 14184. (https://doi.org/10.1038/s41598-018-32366-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hernández-Chirlaque C, Aranda CJ, Ocón B, et al.2016 Germ-free and antibiotic-treated mice are highly susceptible to epithelial injury in DSS colitis. Journal of Crohn’s and Colitis 10 13241335. (https://doi.org/10.1093/ecco-jcc/jjw096)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hong YS, Song KH & & Chung JY 2014 Health effects of chronic arsenic exposure. Journal of Preventive Medicine and Public Health 47 245252. (https://doi.org/10.3961/jpmph.14.035)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hunt KM, Srivastava RK, Elmets CA, et al.2014 The mechanistic basis of arsenicosis: pathogenesis of skin cancer. Cancer Letters 354 211219. (https://doi.org/10.1016/j.canlet.2014.08.016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • IARC 2012. Special report: policy, A review of Human Carcinogens—part C: metals, arsenic, Dusts, and Fibres IARC Monogr Eval Carcinog Risks Hum 100 11465.

  • Jandhyala SM, Talukdar R, Subramanyam C, et al.2015 Role of the normal gut microbiota. World Journal of Gastroenterology 21 87878803. (https://doi.org/10.3748/wjg.v21.i29.8787)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jiang X, Gu S, Liu D, et al.2018 Lactobacillus brevis 23017 relieves mercury toxicity in the colon by modulation of oxidative stress and inflammation through the interplay of MAPK and NF-kappaB signaling cascades. Frontiers in Microbiology 9 2425. (https://doi.org/10.3389/fmicb.2018.02425)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Johansson ME, Sjövall H & & Hansson GC 2013 The gastrointestinal mucus system in health and disease. Nature Reviews. Gastroenterology and Hepatology 10 352361. (https://doi.org/10.1038/nrgastro.2013.35)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Johansson ME, Jakobsson HE, Holmen-Larsson J, et al.2015 Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host and Microbe 18 582592. (https://doi.org/10.1016/j.chom.2015.10.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jomova K, Jenisova Z, Feszterova M, et al.2011 Arsenic: toxicity, oxidative stress and human disease. Journal of Applied Toxicology 31 95107. (https://doi.org/10.1002/jat.1649)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kayama H & & Takeda K 2020 Manipulation of epithelial integrity and mucosal immunity by host and microbiota-derived metabolites. European Journal of Immunology 50 921931. (https://doi.org/10.1002/eji.201948478)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kim YS & & Ho SB 2010 Intestinal goblet cells and mucins in health and disease: recent insights and progress. Current Gastroenterology Reports 12 319330. (https://doi.org/10.1007/s11894-010-0131-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Konieczna P, Ferstl R, Ziegler M, et al.2013 Immunomodulation by Bifidobacterium infantis 35624 in the murine lamina propria requires retinoic acid-dependent and independent mechanisms. PLoS One 8 e62617. (https://doi.org/10.1371/journal.pone.0062617)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kruger MC, Bertin PN, Heipieper HJ, et al.2013 Bacterial metabolism of environmental arsenic--mechanisms and biotechnological applications. Applied Microbiology and Biotechnology 97 38273841. (https://doi.org/10.1007/s00253-013-4838-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kucharzik T, Lügering A, Lügering N, et al.2000a Characterization of M cell development during indomethacin-induced ileitis in rats. Alimentary Pharmacology and Therapeutics 14 247256. (https://doi.org/10.1046/j.1365-2036.2000.00688.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kucharzik T, Lügering N, Rautenberg K, et al.2000b Role of M cells in intestinal barrier function. Annals of the New York Academy of Sciences 915 171183. (https://doi.org/10.1111/j.1749-6632.2000.tb05240.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lanphear BP, Rauch S, Auinger P, et al.2018 Low-level lead exposure and mortality in US adults: a population-based cohort study. Lancet Public Health 3 e177e184. (https://doi.org/10.1016/S2468-2667(1830025-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Leal J, Smyth HDC & & Ghosh D 2017 Physicochemical properties of mucus and their impact on transmucosal drug delivery. International Journal of Pharmaceutics 532 555572. (https://doi.org/10.1016/j.ijpharm.2017.09.018)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lee JS, Tato CM, Joyce-Shaikh B, et al.2015 Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43 727738. (https://doi.org/10.1016/j.immuni.2015.09.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li X, Brejnrod AD, Ernst M, et al.2019 Heavy metal exposure causes changes in the metabolic health-associated gut microbiome and metabolites. Environment International 126 454467. (https://doi.org/10.1016/j.envint.2019.02.048)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li X, Liu L, Cao Z, et al.2020 Gut microbiota as an “invisible organ” that modulates the function of drugs. Biomedicine and Pharmacotherapy 121 109653. (https://doi.org/10.1016/j.biopha.2019.109653)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li A, Ding J, Shen T, et al.2021 Environmental hexavalent chromium exposure induces gut microbial dysbiosis in chickens. Ecotoxicology and Environmental Safety 227 112871. (https://doi.org/10.1016/j.ecoenv.2021.112871)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li A, Wang Y, Hao J, et al.2022 Long-term hexavalent chromium exposure disturbs the gut microbial homeostasis of chickens. Ecotoxicology and Environmental Safety 237 113532. (https://doi.org/10.1016/j.ecoenv.2022.113532)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lindell AE, Zimmermann-Kogadeeva M & & Patil KR 2022 Multimodal interactions of drugs, natural compounds and pollutants with the gut microbiota. Nature Reviews. Microbiology 20 431443. (https://doi.org/10.1038/s41579-022-00681-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu Y, Li Y, Liu K, et al.2014 Exposing to cadmium stress cause profound toxic effect on microbiota of the mice intestinal tract. PLoS One 9 e85323. (https://doi.org/10.1371/journal.pone.0085323)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu Y, Li Y, Xia Y, et al.2020a The dysbiosis of gut microbiota caused by low-dose cadmium aggravate the injury of mice liver through increasing intestinal permeability. Microorganisms 8. (https://doi.org/10.3390/microorganisms8020211)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu Y, Wu J, Xiao Y, et al.2020b Relief of cadmium-induced intestinal motility disorder in mice by Lactobacillus plantarum CCFM8610. Frontiers in Immunology 11 619574. (https://doi.org/10.3389/fimmu.2020.619574)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu W, Feng H, Zheng S, et al.2021 Pb toxicity on gut physiology and microbiota. Frontiers in Physiology 12 574913. (https://doi.org/10.3389/fphys.2021.574913)

  • Liu S, Kang W, Mao X, et al.2022a Melatonin mitigates aflatoxin b1-induced liver injury via modulation of gut microbiota/intestinal FXR/liver TLR4 signaling axis in mice. Journal of Pineal Research 73 e12812. (https://doi.org/10.1111/jpi.12812)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu X, Wang J, Deng H, et al.2022b In situ analysis of variations of arsenicals, microbiome and transcriptome profiles along murine intestinal tract. Journal of Hazardous Materials 427 127899. (https://doi.org/10.1016/j.jhazmat.2021.127899)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu Y, Kang W, Liu S, et al.2022c Gut microbiota-bile acid-intestinal farnesoid X receptor signaling axis orchestrates cadmium-induced liver injury. Science of the Total Environment 849 157861. (https://doi.org/10.1016/j.scitotenv.2022.157861)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lu K, Cable PH, Abo RP, et al.2013 Gut microbiome perturbations induced by bacterial infection affect arsenic biotransformation. Chemical Research in Toxicology 26 18931903. (https://doi.org/10.1021/tx4002868)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lu K, Mahbub R, Cable PH, et al.2014 Gut microbiome phenotypes driven by host genetics affect arsenic metabolism. Chemical Research in Toxicology 27 172174. (https://doi.org/10.1021/tx400454z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lueschow SR & & McClroy SJ 2020 The Paneth cell: the curator and defender of the immature small intestine. Frontiers in Immunology 11 587. (https://doi.org/10.3389/fimmu.2020.00587)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lueschow SR, Stumphy J, Gong H, et al.2018 Loss of murine Paneth cell function alters the immature intestinal microbiome and mimics changes seen in neonatal necrotizing enterocolitis. PLoS One 13 e0204967. (https://doi.org/10.1371/journal.pone.0204967)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Madden KB, Whitman L, Sullivan C, et al.2002 Role of STAT6 and mast cells in IL-4- and IL-13-induced alterations in murine intestinal epithelial cell function. Journal of Immunology 169 44174422. (https://doi.org/10.4049/jimmunol.169.8.4417)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Martini E, Krug SM, Siegmund B, et al.2017 Mend your fences: the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cellular and Molecular Gastroenterology and Hepatology 4 3346. (https://doi.org/10.1016/j.jcmgh.2017.03.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mazmanian SK, Liu CH, Tzianabos AO, et al.2005 An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122 107118. (https://doi.org/10.1016/j.cell.2005.05.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • McElroy SJ, Underwood MA & & Sherman MP 2013 Paneth cells and necrotizing enterocolitis: a novel hypothesis for disease pathogenesis. Neonatology 103 1020. (https://doi.org/10.1159/000342340)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mehta S, Nijhuis A, Kumagai T, et al.2015 Defects in the adherens junction complex (E-cadherin/ beta-catenin) in inflammatory bowel disease. Cell and Tissue Research 360 749760. (https://doi.org/10.1007/s00441-014-1994-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mir H, Meena AS, Chaudhry KK, et al.2016 Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice. Biochimica et Biophysica Acta 1860 765774. (https://doi.org/10.1016/j.bbagen.2015.12.013)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mitamura Y, Ogulur I, Pat Y, et al.2021 Dysregulation of the epithelial barrier by environmental and other exogenous factors. Contact Dermatitis 85 615626. (https://doi.org/10.1111/cod.13959)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moon K, Guallar E & & Navas-Acien A 2012 Arsenic exposure and cardiovascular disease: an updated systematic review. Current Atherosclerosis Reports 14 542555. (https://doi.org/10.1007/s11883-012-0280-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moon KA, Oberoi S, Barchowsky A, et al.2018 A dose-response meta-analysis of chronic arsenic exposure and incident cardiovascular disease. International Journal of Epidemiology 47 1013. (https://doi.org/10.1093/ije/dyy073)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Morita K, Furuse M, Fujimoto K, et al.1999 Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. PNAS 96 511516. (https://doi.org/10.1073/pnas.96.2.511)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Motta CM, Califano E, Scudiero R, et al.2022 Effects of cadmium exposure on gut villi in Danio rerio. International Journal of Molecular Sciences 23. (https://doi.org/10.3390/ijms23041927)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Naujokas MF, Anderson B, Ahsan H, et al.2013 The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environmental Health Perspectives 121 295302. (https://doi.org/10.1289/ehp.1205875)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Navas-Acien A, Silbergeld EK, Pastor-Barriuso R, et al.2008 Arsenic exposure and prevalence of type 2 diabetes in US adults. JAMA 300 814822. (https://doi.org/10.1001/jama.300.7.814)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nekrasova O & & Green KJ 2013 Desmosome assembly and dynamics. Trends in Cell Biology 23 537546. (https://doi.org/10.1016/j.tcb.2013.06.004)

  • Ninkov M, Popov Aleksandrov A, Demenesku J, et al.2015 Toxicity of oral cadmium intake: impact on gut immunity. Toxicology Letters 237 8999. (https://doi.org/10.1016/j.toxlet.2015.06.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Odenwald MA & & Turner JR 2013 Intestinal permeability defects: is it time to treat? Clinical Gastroenterology and Hepatology 11 10751083. (https://doi.org/10.1016/j.cgh.2013.07.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Okumura R & & Takeda K 2017 Roles of intestinal epithelial cells in the maintenance of gut homeostasis. Experimental and Molecular Medicine 49 e338e338. (https://doi.org/10.1038/emm.2017.20)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Palmer C, Bik EM, Digiulio DB, et al.2007 Development of the human infant intestinal microbiota. PLoS Biology 5 e177. (https://doi.org/10.1371/journal.pbio.0050177)

  • Parker A, Lawson MAE, Vaux L, et al.2018 Host-microbe interaction in the gastrointestinal tract. Environmental Microbiology 20 23372353. (https://doi.org/10.1111/1462-2920.13926)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pelaseyed T, Bergström JH, Gustafsson JK, et al.2014 The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunological Reviews 260 820. (https://doi.org/10.1111/imr.12182)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Perez-Moreno M & & Fuchs E 2006 Catenins: keeping cells from getting their signals crossed. Developmental Cell 11 601612. (https://doi.org/10.1016/j.devcel.2006.10.010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Perez-Moreno M, Jamora C & & Fuchs E 2003 Sticky business: orchestrating cellular signals at adherens junctions. Cell 112 535548. (https://doi.org/10.1016/s0092-8674(0300108-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Peterson LW & & Artis D 2014 Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nature Reviews. Immunology 14 141153. (https://doi.org/10.1038/nri3608)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pinto DV, Raposo RS, Matos GA, et al.2020 Methylmercury interactions with gut microbiota and potential modulation of neurogenic niches in the brain. Frontiers in Neuroscience 14 576543. (https://doi.org/10.3389/fnins.2020.576543)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Podgorski J & & Berg M 2020 Global threat of arsenic in groundwater. Science 368 845850. (https://doi.org/10.1126/science.aba1510)

  • Pynn L 2013 Harvard study concludes elevated rates of Colitis/Crohn’s in Northport [Online]. Available at: https://northportproject.com/2013/11/29/northport-the-town-that-could-help-cure-ibd-2/

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rafati Rahimzadeh M, Rafati Rahimzadeh M, Kazemi S, et al.2017 Cadmium toxicity and treatment: an update. Caspian Journal of Internal Medicine 8 135145. (https://doi.org/10.22088/cjim.8.3.135)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rao R 2008 Oxidative stress-induced disruption of epithelial and endothelial tight junctions. Frontiers in Bioscience 13 72107226. (https://doi.org/10.2741/3223)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rao RK, Basuroy S, Rao VU, et al.2002 Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress. Biochemical Journal 368 471481. (https://doi.org/10.1042/BJ20011804)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rice KM, Walker EM, Wu M, et al.2014 Environmental mercury and its toxic effects. Journal of Preventive Medicine and Public Health 47 7483. (https://doi.org/10.3961/jpmph.2014.47.2.74)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rusanov AL, Smirnova AV, Poromov AA, et al.2015 Effects of cadmium chloride on the functional state of human intestinal cells. Toxicology in Vitro 29 10061011. (https://doi.org/10.1016/j.tiv.2015.03.018)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sampath V, Bhandari V, Berger J, et al.2017 A functional ATG16L1 (T300A) variant is associated with necrotizing enterocolitis in premature infants. Pediatric Research 81 582588. (https://doi.org/10.1038/pr.2016.260)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schmidt TSB, Raes J & & Bork P 2018 The human gut microbiome: from association to modulation. Cell 172 11981215. (https://doi.org/10.1016/j.cell.2018.02.044)

  • Schrezenmeir J & & de Vrese M 2001 Probiotics, prebiotics, and Synbiotics--approaching a definition. American Journal of Clinical Nutrition 73(Supplement) 361S364S. (https://doi.org/10.1093/ajcn/73.2.361s)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Seki N, Akiyama M, Yamakawa H, et al.2021 Adverse effects of methylmercury on gut bacteria and accelerated accumulation of mercury in organs due to disruption of gut microbiota. Journal of Toxicological Sciences 46 9197. (https://doi.org/10.2131/jts.46.91)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shao M & & Zhu Y 2020 Long-term metal exposure changes gut microbiota of residents surrounding a mining and smelting area. Scientific Reports 10 4453. (https://doi.org/10.1038/s41598-020-61143-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sharma P, Bihari V, Agarwal SK, et al.2012 Groundwater contaminated with hexavalent chromium [Cr (VI)]: a health survey and clinical examination of community inhabitants (Kanpur, India). PLoS One 7 e47877. (https://doi.org/10.1371/journal.pone.0047877)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shen L, Black ED, Witkowski ED, et al.2006 Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure. Journal of Cell Science 119 20952106. (https://doi.org/10.1242/jcs.02915)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shrivastava R, Kannan A, Upreti RK, et al.2005 Effects of chromium on the resident gut bacteria of rat. Toxicology Mechanisms and Methods 15 211218. (https://doi.org/10.1080/15376520590945630)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Snoeck V, Goddeeris B & & Cox E 2005 The role of enterocytes in the intestinal barrier function and antigen uptake. Microbes and Infection 7 9971004. (https://doi.org/10.1016/j.micinf.2005.04.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Spindler V, Meir M, Vigh B, et al.2015 Loss of desmoglein 2 contributes to the pathogenesis of Crohn's disease. Inflammatory Bowel Diseases 21 23492359. (https://doi.org/10.1097/MIB.0000000000000486)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stern M & & Walker WA 1984 Food proteins and gut mucosal barrier I. Binding and uptake of cow's milk proteins by adult rat jejunum in vitro. American Journal of Physiology 246 G556G562. (https://doi.org/10.1152/ajpgi.1984.246.5.G556)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Summers AO, Wireman J, Vimy MJ, et al.1993 Mercury released from dental "silver" fillings provokes an increase in mercury- and antibiotic-resistant bacteria in oral and intestinal floras of primates. Antimicrobial Agents and Chemotherapy 37 825834. (https://doi.org/10.1128/AAC.37.4.825)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tan S, Xu X, Cheng H, et al.2022 The alteration of gut microbiome community play an important role in mercury biotransformation in largemouth bass. Environmental Research 204 112026. (https://doi.org/10.1016/j.envres.2021.112026)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tang R, Li X, Mo Y, et al.2019 Toxic responses of metabolites, organelles and gut microorganisms of Eisenia fetida in a soil with chromium contamination. Environmental Pollution 251 910920. (https://doi.org/10.1016/j.envpol.2019.05.069)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tchounwou PB, Yedjou CG, Patlolla AK, et al.2012 Heavy metal toxicity and the environment. Molecular, Clinical and Environmental Toxicology 101 133164. (https://doi.org/10.1007/978-3-7643-8340-4_6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tellez-Plaza M, Navas-Acien A, Menke A, et al.2012 Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. Environmental Health Perspectives 120 10171022. (https://doi.org/10.1289/ehp.1104352)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thompson CM, Proctor DM, Suh M, et al.2013 Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans. Critical Reviews in Toxicology 43 244274. (https://doi.org/10.3109/10408444.2013.768596)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thornton DJ & & Sheehan JK 2004 From mucins to mucus: toward a more coherent understanding of this essential barrier. PNAS 1 5461. (https://doi.org/10.1513/pats.2306016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thursby E & & Juge N 2017 Introduction to the human gut microbiota. Biochemical Journal 474 18231836. (https://doi.org/10.1042/BCJ20160510)

  • Ting HA & & von Moltke J 2019 The immune function of tuft cells at gut mucosal surfaces and beyond. Journal of Immunology 202 13211329. (https://doi.org/10.4049/jimmunol.1801069)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tinkov AA, Filippini T, Ajsuvakova OP, et al.2017 The role of cadmium in obesity and diabetes. Science of the Total Environment 601–602 741755. (https://doi.org/10.1016/j.scitotenv.2017.05.224)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tinkov AA, Gritsenko VA, Skalnaya MG, et al.2018 Gut as a target for cadmium toxicity. Environmental Pollution 235 429434. (https://doi.org/10.1016/j.envpol.2017.12.114)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tsai SL, Singh S & & Chen W 2009 Arsenic metabolism by microbes in nature and the impact on arsenic remediation. Current Opinion in Biotechnology 20 659667. (https://doi.org/10.1016/j.copbio.2009.09.013)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Turner JR 2000 Show me the pathway! Regulation of paracellular permeability by Na(+)-glucose cotransport. Advanced Drug Delivery Reviews 41 265281. (https://doi.org/10.1016/s0169-409x(0000046-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Turner JR 2009 Intestinal mucosal barrier function in health and disease. Nature Reviews. Immunology 9 799809. (https://doi.org/10.1038/nri2653)

  • Underwood MA 2012 Paneth cells and necrotizing enterocolitis. Gut Microbes 3 562565. (https://doi.org/10.4161/gmic.21738)

  • Ungewiss H, Vielmuth F, Suzuki ST, et al.2017 Desmoglein 2 regulates the intestinal epithelial barrier via p38 mitogen-activated protein kinase. Scientific Reports 7 6329. (https://doi.org/10.1038/s41598-017-06713-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Upreti RK, Sinha V, Mishra R, et al.2011 In vitro development of resistance to arsenite and chromium-VI in Lactobacilli strains as perspective attenuation of gastrointestinal disorder. Journal of Environmental Biology 32 325332.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ursell LK, Clemente JC, Rideout JR, et al.2012 The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. Journal of Allergy and Clinical Immunology 129 12041208. (https://doi.org/10.1016/j.jaci.2012.03.010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vaishnava S, Behrendt CL, Ismail AS, et al.2008 Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. PNAS 105 2085820863. (https://doi.org/10.1073/pnas.0808723105)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Van Itallie CM & & Anderson JM 2006 Claudins and epithelial paracellular transport. Annual Review of Physiology 68 403429. (https://doi.org/10.1146/annurev.physiol.68.040104.131404)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Van Itallie CM & & Anderson JM 2014 Architecture of tight junctions and principles of molecular composition. Seminars in Cell and Developmental Biology 36 157165. (https://doi.org/10.1016/j.semcdb.2014.08.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vanuytsel T, Tack J & & Farre R 2021 The role of intestinal permeability in gastrointestinal disorders and current methods of evaluation. Frontiers in Nutrition 8 717925. (https://doi.org/10.3389/fnut.2021.717925)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vazquez M, Velez D & & Devesa V 2014 In vitro evaluation of inorganic mercury and methylmercury effects on the intestinal epithelium permeability. Food and Chemical Toxicology 74 349359. (https://doi.org/10.1016/j.fct.2014.10.022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vermette D, Hu P, Canarie MF, et al.2018 Tight junction structure, function, and assessment in the critically ill: a systematic review. Intensive Care Medicine Experimental 6 37. (https://doi.org/10.1186/s40635-018-0203-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vignal C, Desreumaux P & & Body-Malapel M 2016 Gut: an underestimated target organ for aluminum. Morphologie 100 7584. (https://doi.org/10.1016/j.morpho.2016.01.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • von Moltke J, Ji M, Liang HE, et al.2016 Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit. Nature 529 221225. (https://doi.org/10.1038/nature16161)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang R, Moniruzzaman M, Wong KY, et al.2021 Gut microbiota shape the inflammatory response in mice with an epithelial defect. Gut Microbes 13 118. (https://doi.org/10.1080/19490976.2021.1887720)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang B, Wu C, Cui L, et al.2022a Dietary aluminium intake disrupts the overall structure of gut microbiota in Wistar rats. Food Science and Nutrition 10 35743584. (https://doi.org/10.1002/fsn3.2955)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang G, Li X, Zhou Y, et al.2022b Effects of dietary chromium picolinate on gut microbiota, gastrointestinal peptides, glucose homeostasis, and performance of heat-stressed broilers. Animals (Basel) 12. (https://doi.org/10.3390/ani12070844)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Watson SE, Mckinney MA, Pindo M, et al.2021 Diet-driven mercury contamination is associated with polar bear gut microbiota. Scientific Reports 11 23372. (https://doi.org/10.1038/s41598-021-02657-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu J, Wen XW, Faulk C, et al.2016 Perinatal lead exposure alters gut microbiota composition and results in sex-specific bodyweight increases in adult mice. Toxicological Sciences 151 324333. (https://doi.org/10.1093/toxsci/kfw046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu G, Xiao X, Feng P, et al.2017 Gut remediation: a potential approach to reducing chromium accumulation using Lactobacillus plantarum TW1-1. Scientific Reports 7 15000. (https://doi.org/10.1038/s41598-017-15216-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xia J, Jin C, Pan Z, et al.2018 Chronic exposure to low concentrations of lead induces metabolic disorder and dysbiosis of the gut microbiota in mice. Science of the Total Environment 631–632 439448. (https://doi.org/10.1016/j.scitotenv.2018.03.053)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xing C, Yang F, Lin Y, et al.2022 Hexavalent chromium exposure induces intestinal barrier damage via activation of the NF-kappaB signaling pathway and NLRP3 inflammasome in ducks. Frontiers in Immunology 13 952639. (https://doi.org/10.3389/fimmu.2022.952639)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yang J, Chen W, Sun Y, et al.2021a Effects of cadmium on organ function, gut microbiota and its metabolomics profile in adolescent rats. Ecotoxicology and Environmental Safety 222 112501. (https://doi.org/10.1016/j.ecoenv.2021.112501)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yang TT, Liu Y, Tan S, et al.2021b The role of intestinal microbiota of the marine fish (Acanthopagrus latus) in mercury biotransformation. Environmental Pollution 277 116768. (https://doi.org/10.1016/j.envpol.2021.116768)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yin N, Cai X, Wang P, et al.2022 Predictive capabilities of in vitro colon bioaccessibility for estimating in vivo relative bioavailability of arsenic from contaminated soils: arsenic speciation and gut microbiota considerations. Science of the Total Environment 818 151804. (https://doi.org/10.1016/j.scitotenv.2021.151804)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Young JL, Cai L & & States JC 2018 Impact of prenatal arsenic exposure on chronic adult diseases. Systems Biology in Reproductive Medicine 64 469483. (https://doi.org/10.1080/19396368.2018.1480076)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu Y, Yang W, Li Y, et al.2019 Enteroendocrine cells: sensing gut microbiota and regulating inflammatory bowel diseases. Inflammatory Bowel Diseases 26 1120. (https://doi.org/10.1093/ibd/izz217)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu L, Duan H, Kellingray L, et al.2021a Lactobacillus plantarum-mediated regulation of dietary aluminum induces changes in the human gut microbiota: an in vitro colonic fermentation study. Probiotics and Antimicrobial Proteins 13 398412. (https://doi.org/10.1007/s12602-020-09677-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu L, Yu Y, Xiao Y, et al.2021b Lead-induced gut injuries and the dietary protective strategies: a review. Journal of Functional Foods 83 104528.

  • Zhai Q, Tian F, Zhao J, et al.2016 Oral administration of probiotics inhibits absorption of the heavy metal cadmium by protecting the intestinal barrier. Applied and Environmental Microbiology 82 44294440. (https://doi.org/10.1128/AEM.00695-16)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhai Q, Li T, Yu L, et al.2017 Effects of subchronic oral toxic metal exposure on the intestinal microbiota of mice. Science Bulletin 62 831840. (https://doi.org/10.1016/j.scib.2017.01.031)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhai Q, Qu D, Feng S, et al.2019a Oral supplementation of lead-intolerant intestinal microbes protects against lead (Pb) toxicity in mice. Frontiers in Microbiology 10 3161. (https://doi.org/10.3389/fmicb.2019.03161)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhai Q, Wang J, Cen S, et al.2019b Modulation of the gut microbiota by a galactooligosaccharide protects against heavy metal lead accumulation in mice. Food and Function 10 37683781. (https://doi.org/10.1039/c9fo00587k)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang Z, Cao H, Song N, et al.2020 Long-term hexavalent chromium exposure facilitates colorectal cancer in mice associated with changes in gut microbiota composition. Food and Chemical Toxicology 138 111237. (https://doi.org/10.1016/j.fct.2020.111237)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang A, Matsushita M, Zhang L, et al.2021 Cadmium exposure modulates the gut-liver axis in an Alzheimer's disease mouse model. Communications Biology 4 1398. (https://doi.org/10.1038/s42003-021-02898-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhao Y, Su JQ, Ye J, et al.2019 AsChip: a high-throughput qPCR chip for comprehensive profiling of genes linked to microbial cycling of arsenic. Environmental Science and Technology 53 798807. (https://doi.org/10.1021/acs.est.8b03798)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhao Y, Zhou C, Wu C, et al.2020 Subchronic oral mercury caused intestinal injury and changed gut microbiota in mice. Science of the Total Environment 721 137639. (https://doi.org/10.1016/j.scitotenv.2020.137639)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zihni C, Mills C, Matter K, et al.2016 Tight junctions: from simple barriers to multifunctional molecular gates. Nature Reviews. Molecular Cell Biology 17 564580. (https://doi.org/10.1038/nrm.2016.80)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zolotarevsky Y, Hecht G, Koutsouris A, et al.2002 A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterology 123 163172. (https://doi.org/10.1053/gast.2002.34235)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zuo L, Kuo WT & & Turner JR 2020 Tight junctions as targets and effectors of mucosal immune homeostasis. Cellular and Molecular Gastroenterology and Hepatology 10 327340. (https://doi.org/10.1016/j.jcmgh.2020.04.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • Figure 1

    Effects of heavy metals on gut. Heavy metals such as arsenic (As), lead (Pb), mercury (Hg), cadmium (Cd), and chromium (Cr) lead to increased oxidative stress, altered gut microbial composition, and inflammation, potentially leading to gut leakiness and gut barrier dysfunction.