Abstract
The health of the intestinal microbiota impacts tolerance at homeostasis and the strength of the inflammation response during acute bloodstream infections. A complete understanding of the feedback loop between systemic inflammation and dysregulation of the gut microbiota is necessary for inflammation management. Here we will review the many ways in which the microbiota can influence the systemic pro-inflammatory response. Short-chain fatty acids, produced through the microbial metabolism of dietary fibers, can suppress inflammation systemically; in the absence of a balanced diet or disruption of the microbiota through antibiotics, there is disrupted metabolite production, leading to systemic inflammation. Dysbiosis or inflammation in the intestines can lead to a breakdown of the sturdy intestinal–epithelial barrier. When this barrier is perturbed, immunogenic lipopolysaccharides or extracellular vesicles enter the bloodstream and induce excessive inflammation. Necessary clinical treatments, such as antifungals or antibacterials, induce microbiota dysregulation and thus increased risk of endotoxemia; though probiotics may aid in improving the microbiota health and have been shown to deflate inflammation during sepsis. Within this complicated relationship: What is in control, the dysbiotic microbiota or the systemic inflammation?
Introduction
Acute systemic inflammatory responses can result from infectious agents – viral, bacterial, or fungal – ultimately resulting in severe conditions, such as cytokine storms and septic shock, which can lead to organ failure and death. Upon suspicion of a bloodstream infection, strong antibiotics or antivirals are administered systemically as source control. Yet the determining factors of what conditions may drive systemic inflammatory responses toward overwhelming cytokine storms and septic shock remains unclear. As the field uncovers more about the far-reaching effects of the intestinal microbiota and the metabolites produced by commensal microbes on systemic immunity, it is becoming clear that the gut microbiota can influence the development and maintenance of systemic inflammation in a myriad of ways. From the production of short-chain fatty acids, which temper inflammatory responses, to serving as a reservoir of the immunogenic lipopolysaccharide (LPS), the gut microbiota may both dampen and drive inflammation at various times.
Bloodstream infections, including bacteremia and sepsis, can kick off overwhelming feed-forward cascades of inflammation driven by cytokine storms, culminating in septic shock. At the eye of this cytokine storm are pro-inflammatory serum cytokines, such as IL-6, TNFα, IL-1β, and other IL-1-receptor family members (Yiu et al. 2012), though disrupting these cytokines by blockade or depletion has failed to lead to successful therapeutics (Chousterman et al. 2017). Still, these easy-to-measure serum cytokines make useful benchmarks of the inflammatory state in the bloodstream, and these factors can be increased in some individuals during chronic disease – without apparent acute infections – suggesting an increased predisposition to systemic inflammation.
An essential indicator of systemic inflammation is the classic fever response. Recent clinical observations connected four fever signatures: no body temperature change, reduced body temperature, high body temperature with a fast resolution, and high body temperature with a slow resolution and temperature-associated taxa, suggesting the composition of an individual’s microbiota could dictate the temperature response during sepsis (Bongers et al. 2023). Yet, germ-free mice had a reduced body temperature change compared to conventional mice, suggesting the temperature response during sepsis may be, in part, a result of the presence of the microbiota. These conflicting results indicate the complicated nature of the microbiota’s contribution to the systemic inflammatory response. It is not so simple as the presence of the microbiota is associated with good outcomes, and lack of a microbiota is associated with poor outcomes. The consideration of a ‘eubiotic’ microbiota, or healthy microbiota, compared to a ‘dysbiotic’ microbiota, or perturbed microbiota, could impact and identify the key ‘good’ and ‘bad’ microbes during systemic inflammation. The presence of a dysbiotic microbial population may be worse for sepsis outcomes than a complete lack of a microbiota, in part due to the excessive activation of an inflammatory pathway and increased clinical outcomes due to the risk of recurrent infections. Here, we review the many ways the microbiota may influence how the inflammatory response is initiated and resolved in the system.
Reduction of systemic inflammation by microbial metabolites
In the past decade, there has been an exponential increase in understanding how a dysbiotic intestinal microbiota can contribute to systemic disease distanced from the gut. Associations with the intestinal microbiota are made with just about every systemic disease: autoimmunity, cancers, asthma and allergies, and neurological disorders (Ho et al. 2015), so it is no surprise that the intestinal microbiota can contribute to acute systemic inflammation (Miller et al. 2021). When considering an association of the intestinal microbiota with sites far from the gut, there is always a question of the mechanism of this action – is there a direct contribution of intestinal microbes to systemic health, or does a dysbiotic intestinal microbiota serve as a bellwether to general systemic health. Metabolites from intestinal microbes that have extensive effects on the systemic tissue and immune components demonstrates one mechanism whereby microbes can directly impact health, as they are the sole source of particular metabolites. Microbial metabolites, including short-chain fatty acids (SCFA), are the focus of interest due to their inflammation-suppressing capabilities and systemic presence (Geuking & Burkhard 2020, Burkhard et al. 2023). The chief SCFAs, derived through the fermentation of dietary carbohydrates, are acetate and propionate – primarily produced by Bacteroidetes – and butyrate – predominantly produced by Firmicutes. SCFAs travel and affect the liver, lungs, and CNS providing nutrition, energy, and influencing the immune compartments (Parada Venegas et al. 2019, Cuna et al. 2021), and have been shown to reduce systemic inflammation (Napier et al. 2019) (Fig. 1).
The systemic influence of the eubiotic microbiome vs. the dysbiotic microbiome. In the eubiotic microbiome, the bacteria produce short-chain fatty acids (SCFAs), which locally promote mucin production. These metabolites cross the intestinal epithelium, disperse systemically, and provide numerous functions in maintaining homeostasis. Many influences can disrupt the microbiota, including systemic inflammation. In the dysbiotic microbiome, there is a lack of bacterial metabolites; this results in decreased tight junctions and the dissemination of extracellular vesicles (EVs) and lipopolysaccharides (LPS), which further promotes systemic inflammation. Figure created with BioRender.
Citation: Microbiota and Host 1, 1; 10.1530/MAH-23-0018
Logically, during sepsis, an excessively inflammatory event, there are reduced SCFAs in the serum of patients (Valdés-Duque et al. 2020, Lou et al. 2022), which was correlated to a reduction of Firmicutes and increased Proteobacteria and Bacteroidetes in the stool, compared to healthy patients (Lou et al. 2022). In mice, either treatment with SCFAs or a fecal microbiota transplant (FMT) from healthy male mice resulted in reduced serum IL-1β during a model of sepsis (Lou et al. 2022). Decreased serum cytokines were connected to a reduction in activation of NLRP3 inflammasome and pyroptosis through both FMT and SCFA treatments (Lou et al. 2022), suggesting SCFAs alone were able to dampen inflammation.
Similarly, during Kawasaki Disease (KD), an acute febrile inflammatory disease affecting the vascular system thought to be related to cytokine release, there was acute loss of Lactobacillus associated with the disease (Takeshita et al. 2002), suggesting the lack of these beneficial, SCFA producing microbes contributes to inflammation. A KD mouse model expanded on this and found probiotic treatment of Clostridium butyricum rescued the reduced SCFA production associated with disease. This rescue correlated with a reduction in systemic inflammation measured by serum IL-1β and IL-6, while antibiotic ablation of these microbes had the opposite effect (Wang et al. 2023).
SCFAs are also disrupted at the dietary level; mice fed a Western diet – defined as high saturated fats and sucrose with low fiber – had increased IL-6 and TNF in the blood (Napier et al. 2019). Along with this baseline inflammation, the Western diet increased sepsis severity, sensitivity, and mortality compared to the standard-fiber chow diet. Interestingly, increased sepsis severity could be predicted by Western diet-induced shifts to body temperature and frequency of circulating neutrophils in the blood, suggesting the Western diet, and potentially lack of SCFAs, reprogrammed the baseline systemic immune components and acute response to sepsis. This reprogramming may involve the NLRP2 inflammasome and IL-1 mechanisms and pathways (Christ et al. 2018). Another dietary shift, introducing a high-fat diet, was also associated with increased sepsis severity in a Staphylococcus aureus model of bloodstream infection (Strandberg et al. 2009). Here, the enhanced sepsis severity was associated with abated immune function through elevated serum IL-10, a suppressive cytokine that dampens inflammation, and decreased phagocytosis and pathogen clearance by macrophages, which had increased migration to excessive fat (Strandberg et al. 2009). Other studies also found a shift in the microbiota following high-fat diet was connected to increased sepsis severity (Las Heras et al. 2019); the mechanism for decreased immune function following this dietary change caused by a shift in the metabolic state (Gomes et al. 2023) and decreased SCFAs (Birkeland et al. 2023).
A predominate role of SCFAs is shifting the broader immune response towards general tolerance or manageable inflammation: notably, SCFAs promote IL-10 production during sepsis via butyrate-induced activation of HCA2 – a G protein-coupled receptor – in macrophages and dendritic cells (DCs) which shift responses away from inflammation (Singh et al. 2014). Butyrate drives the polarization of M2 macrophages, macrophages with an anti-inflammatory phenotype that promote resolution, through promoting oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) metabolism as well as increasing an anti-inflammatory protein, phosphatase MKP-1, expression which lowers macrophage inflammation through dephosphorylation of JNK, ERK1/2, and p38 pathways (Scott et al. 2018, Wang et al. 2023). Besides the active anti-inflammatory role SCFAs induce in immune cells, they also suppress inflammation; SCFAs result in reduced serum IL-1β and IL-6, suppressing inflammation at the level of innate cytokine-producing immune cells, as well as dampening the systemic antibody response by downregulating AID and Blimp1, preventing somatic hypermutation and B cell development (Wang et al. 2017, Sanchez et al. 2020). There is a crucial balance of efficient resolution and damaging inflammation; SCFAs, in mice fed a high-fiber diet, bolster the effector function of CD8 T cells – by elevating the metabolism by acting as a substrate for fatty acid oxidation – while reducing the CXCL1 expression on macrophages leading to less neutrophil infiltration and tissue damage (Trompette et al. 2018).
If SCFAs skew the immune system to anti-inflammatory tolerance, then gnotobiotic, or ‘germ-free’, mice should have a dramatically increased propensity towards systemic inflammation due to the complete lack of serum SCFAs. Yet germ-free mice, when presented with inflammatory stimuli, produce larger quantities of IL-10, the suppressive counterpart to inflammatory cytokines (Fagundes et al. 2012). In a model of Klebsiella pneumoniae bloodstream infection, germ-free mice have an increase in mortality, chiefly attributed to a lack of neutrophil influx compared to conventional mice, which is restored by neutralizing IL-10 (Fagundes et al. 2012). Thus, a complete lack of an intestinal microbiota results in stronger brakes on inflammation, reducing the immune system ability to clear pathogens. Microbial components can also induce efficient pathogen clearance function by the innate immune system, as pretreatment of the germ-free mice with LPS increased survival to pulmonary K. pneumoniae infection (Fagundes et al. 2012). The effectiveness of the pretreatment to increase survival suggests a certain degree of immune system training, or priming, can occur.
Quick pathogen clearance from the bloodstream or in the tissues prior to disseminating to the bloodstream is an effective mechanism to prevent infections from developing into sepsis. The liver, which drains the blood, serves as a primary site of pathogen clearance from the blood. d-lactate, a metabolite produced by commensal bacteria within the intestines able to be used systemically, promotes Kupffer cells – a subset of macrophages located in the vascular space of the liver sinusoids – to capture and clear pathogens from the blood (McDonald et al. 2020). Germ-free mice were unable to clear S. aureus in the liver, as the specific pathogen-free (SPF) mice were able, resulting in bacteremia and increased mortality to infection. d-lactate alone, or colonization with d-lactate-producing commensals, was able to rescue germ-free mice and restore pathogen clearance, preventing sepsis (McDonald et al. 2020).
Bile acids produced by the liver emulsify dietary fats, serve as a food source for microbes, and produce a number of primary and secondary mediators that can affect systemic responses. Specific intestinal microbes may directly increase bile acids: Klebsiella quasipneumoniae, a taxa elevated in the stool of patients with blood-stream infections, increased primary bile acid production in mice following oral administration (Yin et al. 2023). Indeed, sepsis events resulted in increased primary bile acids in the serum; however, this was even more pronounced in patients with severe liver failure with significantly increased bile acids compared to healthy controls with sepsis (Leonhardt et al. 2021). Increased primary bile acids resulted in immunosuppression reducing phagocytosis and production of inflammatory cytokines from macrophages, suggesting patients with liver failure may be at risk for prolonged sepsis due to the decrease in functional innate immunity (Leonhardt et al. 2021, 2023). Alternatively, bile acids released into the circulation can induce activation of NLRP3 inflammasome and macrophage secretion of IL-1β by serving as danger-associated molecular patterns (DAMPS) (Hao et al. 2017). Here, again, increased bile acids in the circulation correlated with worse sepsis outcomes, but through increased cytokine production. Sequestration of bile acids through administration of cholestyramine protected mice in a model of sepsis which was associated with reduced IL-1β in the serum. Finally, bile acids can limit cellular stress and apoptosis, which is correlated to sepsis fatalities. The bile acid tauroursodeoxycholic acid (aka TUDCA) reduced both cellular stress and apoptosis in a mouse model of sepsis, and is independent of inflammatory cytokine levels in the serum (Doerflinger et al. 2016). Similarly, G2, a camptothecin–bile acid conjugate, protected the liver from damage in a mouse model of sepsis and decreased serum levels of inflammatory cytokine through preventing the upregulation of p-P65 and p-IκBα (Xiao et al. 2020). Taken together, multiple systemic components from the liver and microbiota serve to dampen systemic inflammation and boost bacterial clearance (Table 1), reducing the likelihood of disseminating bloodstream infections.
Influences on and from the intestinal microbiota.
| Influencer/Action | Reference |
|---|---|
| Antibiotics and antifungals | |
| Induces dysbiosis causing risk of endotoxemia and sepsis | Lepper et al. (2002), Palleja et al. (2018) |
| Bile acids | |
| Increases levels during adult sepsis | Zöhrer et al. (2016) |
| Leads to reduced phagocytosis and elevated cytokines by macrophages | Leonhardt et al. (2021, 2023) |
| Reduces cellular stress and apoptosis during murine sepsis | Doerflinger et al. (2016) |
| d-Lactate | |
| Promotes phagocytosis of pathogens | McDonald et al. (2020) |
| Extracellular vesicles | |
| Induces symptoms of septic shock when produced by bacteria | Hong et al. (2011), Park et al. (2018) |
| IL-22 | |
| Promotes intestinal barrier function | Abt et al. (2016) |
| Reduces serum and liver inflammation | Shao et al. (2020) |
| LPS | |
| Used to model sepsis | Doi et al. (2009) |
| Increases serum LPS leads to elevated systemic inflammation | Mohammad & Thiemermann (2020) |
| Probiotics | |
| Associates with decreased serum IL-6 and IL-17 levels and increased IL-10 | Guo et al. (2023) |
| Reduces bacteremia burden during sepsis model | Khailova et al. (2013) |
| Short-chain fatty acids | |
| Poses inflammation-suppressing abilities | Geuking & Burkhard (2020), Burkhard et al. (2023) |
| Functions to provide nutrition, energy, and immune influence | Parada Venegas et al. (2019), Cuna et al. (2021) |
| Reduces systemic inflammation, reduced serum IL-6 and TNF | Napier et al. (2019) |
| Promotes IL-10 production during sepsis | Singh et al. (2014) |
| Tollip | |
| Inhibits TLR signaling and increases neutrophil function | Diao et al. (2016) |
The intestine: a culprit or victim of sepsis?
The role of metabolites in dampening inflammation or promoting tolerance is no surprise, given the contribution SCFAs and other metabolites provide in the intestinal tolerance maintenance. Most notably, SCFAs are crucial for the intestinal epithelium barrier: Acetate, butyrate, and propionate maintain gut-epithelial barrier functions as demonstrated by the increased measure of transepithelial electrical resistance compared to no SCFAs present (Suzuki et al. 2008).
Beyond the epithelium, the mucus layer is also necessary for a strong intestinal barrier, and butyrate can stimulate mucin release via MUC2 activation (Hatayama et al. 2007). A well-maintained epithelial barrier is required to restrict the intestinal microbes to the luminal space, as even commensal bacteria from the mucosa entering the bloodstream could be perceived as a threat and initiate inflammation (Burkhard et al. 2023). While bloodstream infections can be the result of direct infection, following surgery or clinical procedures, or from a descending infection from a peripheral organ, such as the lung, the intestinal microbiota can serve as a reservoir of potential pathogenic bacteria that reside in the lumen. Burst appendix or punctured intestines, for example, can result in peritonitis or sepsis from the escape of immunostimulatory microbes from these organs into the body cavity. Outside of appendicitis or acute injury to the gut, dissemination of bacteria from the intestine into the bloodstream is rare, given an intact epithelial barrier and eubiotic microbiota.
Components from the microbiota can be introduced into circulation and quickly activate inflammatory cascades, particularly the immunogenic LPS component from gram-negative microbial membranes, also referred to as ‘endotoxin’. While LPS recognition can promote some desirable pathways, such as pathogen clearance, LPS circulating in the bloodstream can rapidly initiate inflammation. Indeed, intraperitoneal injection of LPS is a well-accepted model of sepsis (Doi et al. 2009). The current hypothesize is that microbial dysbiosis can lead to decreased efficiency of the tight junctions in the gut epithelial barrier, referred to as ‘leaky gut’, which can allow for LPS produced by the microbiota to enter the bloodstream (Horowitz et al. 2023) (Fig. 1). Endotoxemia has long been known as a cause of sepsis (Schweinburg & Fine 1960), and the presence of bacterial components in the bloodstream is a logical consequence of a bacterial bloodstream infection.
However, recent observations have shown that increased metabolic endotoxemia, a result of diet-induced microbial dysbiosis (Cani et al. 2007), can contribute to chronic, sustained inflammation (Page et al. 2022). Indeed, increased serum LPS was associated with worse disease outcomes during the recent coronavirus disease 2019 (COVID-19) pandemic (Kruglikov & Scherer 2021, Khan et al. 2022), suggesting increased serum LPS can contribute to worse systemic inflammation (Mohammad & Thiemermann 2020). The contribution of elevated serum LPS, resulting from metabolic endotoxemia, to worse sepsis outcomes remains unclear. Toll-like receptor 4 (TLR4) recognition of LPS leads to two inflammatory pathways: MyD88-dependent signaling, producing proinflammatory cytokines, and MyD88-independent signaling, inducing type I interferons (Lu et al. 2008). TLR4 is also necessary for the appropriate clearing of bacteria; TLR4 complete, as well as neutrophil and macrophage-specific, knockouts had decreased bacterial clearance after cecal-ligation puncture (CLP) than wildtype (Deng et al. 2013). Therefore, while TLR4 signaling induces inflammation, which could lead to increased cytokine storm in sepsis, it is also necessary for efficient clearance of the infection.
Commensal bacteria also release extracellular vesicles (EVs) (Park et al. 2018). Similar to LPS, EVs derived from E. coli or other gram-negative bacteria alone are capable of induce an inflammatory immune response and symptoms of septic shock; some gram-positive bacteria can also release EVs that will produce a similar overreactive inflammation (Hong et al. 2011, Park et al. 2018). Intraperitoneally injected EVs isolated from stool induced an inflammatory response both locally and systemically – resulting in an increased concentration of TNFα and IL-6 in peritoneal lavage fluids; these effects were minimal or absent when the EVs were from germ-free mouse stool (Park et al. 2018). The requisite of bacterial colonization for inflammatory EVs from the stool suggests the need for bacterial-derived EVs, as opposed to mammalian cell-derived EVs (Park et al. 2018). These bacterial EVs may be sensed by pattern-recognition receptors, such as TLRs, suggesting they contain reactive bacterial ligands; TLR2 and TLR4 were required in mice to produce a strong inflammatory response (Park et al. 2018). Inflammation in the lung, demonstrated by the population of neutrophils, was reduced in TLR4 KO mice during the EV challenge. However, signs of inflammation were seen in the TLR4−/− mice, suggesting additional receptors also sense EVs and induce inflammation (Park et al. 2018).
TLRs recognize danger and driving inflammation; however, they are often balanced by regulatory mechanisms to prevent extensive cytokine production. In mice, activation of TLR9 can create a feedback loop with IL-12 induced IFNγ production, which increases monocyte TLR9 activation (Weaver et al. 2019). During times of inflammation, increased hematopoietic stem cell to monocyte differentiation occurs to fight the infection; however, mice that lack a commensal microbiome (germ-free or antibiotic-treated) have a delayed response as they fail to maintain typical levels of myeloid cells at steady state (Khosravi et al. 2014). Antibiotic-treated mice lose this TLR9 pathway through their defective responses to JAK-activating cytokines; mice receiving JAK1/2 inhibitors have a similar effect (Weaver et al. 2019). The research community routinely uses specific-pathogen free housed mice to represent ‘healthy’ or ‘normal’, even though it is clear this restricted microbiota is not representative of natural microbiotas present in the wild. The use of pet store mice co-housed with SPF mice has been a useful model to observe the differences in immune signaling during exposure to a broader microbiota. When dirty mice were cohoused with SPF mice, the SPF mice had increased their numbers of TLR2 and TLR4 expressing cells compared to non-cohoused (Huggins et al. 2019). Interestingly, the increased TLR2+ monocytes were associated with increased protection from TLR2-mediated systemic inflammation, yet the increased TLR4+ monocytes were associated with poorer outcomes and increased systemic inflammation following LPS-induced sepsis. Tollip (Toll-interacting protein) can reduce pro-inflammatory responses by inhibiting TLR signaling intracellularly, as seen in the increased inflammatory cytokines in the plasma of Tollip-deficient mice during a model of colitis (Diao et al. 2016). Tollip can also induce the expression of FPR2 on neutrophils, which allows for efficient migration and production of NETs (Diao et al. 2016). Thus, the microbial regulation of expression of TLRs and associated proteins must be carefully regulated to balance response to the variety of bacterial ligands.
Beyond bacteria, viral stimulation of TLRs can also be protective of intestinal inflammation: murine norovirus (MNV) is capable of activating TLR7 to increase production of IL-23 and IL-22, promoting barrier integrity (Abt et al. 2016). Other inductors of IL-22, such as diet, can also improve barrier function. When digestible fiber inulin is added to a high-fat diet, the fecal bacterial load loss is resolved and IL-22 levels are elevated – this effect is microbiota dependent (Zou et al. 2018). Benefits of this fiber diet included decreased metabolic syndrome, as well as increased Reg3γ levels preventing the intimate proximity of the microbiota to the intestinal epithelium (Zou et al. 2018). IL-22 is well-recognized as a cytokine able to promote barrier function of the intestinal epithelium by regulating growth and renewal of epithelial cells, and function through cytokine secretion and production of antimicrobial proteins (Keir et al. 2020). While a strong intestinal barrier is associated with reduced risk of sepsis, due to a decreased likelihood of bacterial dissemination, IL-22 may also contribute to reduced inflammation during sepsis. Mice pretreated with recombinant IL-22 had reduced serum levels of IL-6, and IL-6, IL1β, and TNFα in the liver by increasing autophagy (Shao et al. 2020). IL-22 may serve to prevent bacterial translocation from the intestinal lumen and prevent untoward systemic inflammation originating from the liver.
Following intestinal damage or local intestinal inflammation, released cytokines can quickly spread systemically and serve as activators of systemic inflammation. During neonatal sepsis, proinflammatory IL-18, originating from the intestine, is secreted following activation by the inflammasome, contributing to systemic disease severity. Interestingly, premature infants (who have increased severity of sepsis) have elevated levels of IL-18 prior to infection than uninfected adults (Wynn et al. 2016). When IL-18 was genetically removed, there was an increased survival in murine neonatal sepsis, and exogenous IL-18 treatments increased severity while not affecting the function or recruitment of myeloid cells (Wynn et al. 2016). This increased mortality through IL-18 depended on IL-1R1, and not IL1β signaling, mature B cells, or T cells as RAG− /− and IL1β−/− mice still faced the monstrous effect while IL1R1−/− mice were protected (Wynn et al. 2016).
IL-18 from the intestine also contributed to severe acute respiratory syndrome coronavirus 2 severity (Tao et al. 2020). Here, the infection came first, which drove intestinal dysbiosis: COVID-19 was found to result in elevated levels of Streptococcus, Clostridium, Lactobacillus, and Bifidobacterium and lower levels of Bacteroidetes, Roseburia, Faecalibacterium, Coprococcus, and Parabacteroides compared to healthy controls and those with the yearly flu, which leads to elevated cytokines such as IL-18 (Tao et al. 2020). Understanding how systemic inflammation can drive intestinal dysbiosis may help to clarify how the intestine can kick off a positive feedback loop, further perpetuating inflammatory conditions.
There is a need for a prompt and non-inflammatory response is necessary to prevent untoward responses to commensal microbes (Burkhard et al. 2023). Gut-induced IgA is crucial for dampening the systemic and intestinal immune response. In the intestine, sIgA prevents adhesion to the intestinal tissues by binding unspecifically to pathogens and toxins; this avoidance limits the recognition of these threats and lowers intestinal inflammation (Pietrzak et al. 2020). Efficient B cell production of IgA requires adequate levels of IL-17; both IL-17−/− and IgA−/− mice have increased mortality to bacterial challenge (Wilmore et al. 2018, Ramakrishnan et al. 2019). Observing individuals who lack normal levels of IgA showed elevated systemic IgG, hyperactive CD8 T cells, and increased frequency of T follicular helper cells (Conrey et al. 2023).
What comes first – dysbiosis or inflammation?
SCFAs and d-lactate require commensal microbes for their production, and any disruptions to the microbiota could affect their production. LPS is shed from the gram-negative microbes, so any disruptions that promote the growth of gram-negative microbes or increase the leak of LPS across the epithelium could increase the risk for systemic inflammation. If metabolites can regulate systemic inflammation, yet systemic inflammation can trigger microbial dysbiosis – what comes first: the dysbiosis or the systemic inflammation? Certainly, dysbiotic gut microbiota can trigger diseases inducing severe and continuous inflammation, but does this correlation precede inflammation, or is it the result of inflammation (Prescott et al. 2015, Guo et al. 2023)?
Antibiotics given for source control of bacteremia, for control of a separate infection, or preemptively are a massive disruption to the intestinal microbiota. Antibiotic use comes with the risk for endotoxemia (Lepper et al. 2002) and recurrent sepsis episodes in both adults (Baggs et al. 2018) and neonates (Kuppala et al. 2011). Patients in the intensive care unit with septic shock had a distinctive microbiota compared to other microbiomes of patients in the ICU, characterized by elevated Bacteroides and Enterobacteriaceae (Liu et al. 2020). This specific microbial signature could result from massive systemic inflammation and is may currently be the potential marker for clinical outcomes (Nabizadeh et al. 2023, Sun et al. 2023). Yet understanding how sepsis can trigger dysbiosis and how dysbiosis may, in turn, dictate sepsis outcomes may be key to controlling systemic inflammation and restoring homeostasis (Lobo et al. 2016, Miller et al. 2021).
Sepsis-induced dysbiosis is shown when mice were colonized via FMT from sepsis patients prior to CLP-induced sepsis; they experienced increased liver inflammation and injury (Liu et al. 2019). A study of cirrhosis patients was able to correlate the serum levels of various metabolites affecting microbial metabolism to the development of acute-on-chronic liver failure and mortality; these metabolites include bile acids, xenobiotics, and estrogenic metabolites (Bajaj et al. 2020). There was a distinct microbial metabolite signature in both the serum and stool from patients who died within 30 days from acute-on-chronic liver failure, suggesting microbial dysbiosis may precede acute disease and fatality.
Antibiotics can also induce dysbiosis; the richness and Shannon diversity scores of the microbiome of healthy adults treated with antibiotics remained significantly different 42 days post-treatment compared to baseline – the richness score did not recover at six months, suggesting potentially permanent loss of species (Palleja et al. 2018). Antifolate antibiotics, used for urinary tract infections and ear infections, can promote the growth of Staphylococcus aureus small colony variants due to the disruption of thymidine synthesis. These small colony variants can directly increase inflammation through STING activation promoting IFNβ (Tang et al. 2022). Therefore, this dysbiotic microbial population results in the excessive activation of an inflammatory pathway and increased clinical outcomes due to the risk of recurrent infections.
Dysbiosis of the gut is not restricted to bacterial taxa, as the contributions of fungal species, both pathogen and commensal, have been appreciated in recent years. While antifungal treatments are effectively used in clinics to support patients at risk for or with infection of invasive fungal species, there is a risk for these treatments to increase the severity of sepsis when used prophylactically (Sheng et al. 2021), suggesting the role of commensal fungal species in the maintenance of tolerance. When mice receive antifungal treatments, there was decreased survival and increased organ injury to both gram-negative bacteria (Salmonella Typhimurium) and LPS-induced sepsis, which was rescued by supplementation of the drinking water with mannan, a fungal cell wall component (Sheng et al. 2021). Though, similar to bacteria, not all fungal species are equally able to promote tolerance. Noted opportunistic fungus C. albicans induces worse murine sepsis models through excess inflammation (Panpetch et al. 2018, Hiengrach et al. 2022). Similarly, the chemical depletion of macrophages, resulted in a higher ratio of fungi present in the gut, which was associated with increased gut leakage and serum cytokines TNFα and IL-6 (Hiengrach et al. 2022). Thus, a careful understanding of what defines a eubiotic microbiota, both bacterial and fungal species, is required to understand how dysbiosis can promote inflammation.
The dysbiosis of the gut microbiome is a significant contributor to the risk of sepsis, particularly in neonates. In this early stage of life, while the microbiota is still developing dysbiosis is often noted by a prolonged overabundance of proteobacteria which is often present in the weeks just following delivery (Shin et al. 2015, Henrick et al. 2021). When compared to adult or pediatric gastrointestinal and oral samples, the PICU patients had reduced alpha diversity and a unique beta; ICU patients have decreased Firmicutes and Bacteroidetes (commensal) and an increase in Proteobacteria (pathogenic) (Rogers et al. 2016, Liu et al. 2020). This dysregulation can also be seen in bile acids; while adults have increased bile acids during septic events, in early onset neonatal sepsis, both preterm and full-term infants have overall decreased human bile acids compared to age-matched individuals (Zöhrer et al. 2016). Interestingly, the predominate bile acid present in neonates with sepsis was the rare conjugate tauro-omega-muricholic acid (aka TOMCA); the contribution of this rare bile acid during neonatal sepsis remains unclear, though it may be a useful biomarker (Zöhrer et al. 2016, 2018).
Neonates are uniquely susceptible to the dissemination of enteric-originating pathogens causing sepsis, where the overgrowth of a single bacterial species facultative anaerobe family (Enterococcaceae, Staphylococcaceae, or Enterobacteriaceae) can breach the intestinal environment and can gain systemic access (Carl et al. 2014, Singer et al. 2019). In this case, intestinal dysbiosis is due to development and age: both neonatal mice and preterm humans have a delay in the obligate anaerobes, leading to an environment where facultative bacteria can flourish (Singer et al. 2019). Clustering analysis of 16S sequencing from premature infant stool shows a correlation between an overabundant Klebsiella population and inflammation driven by IL-17A, produced by the innate-like γδT cells, which could traffic systemically and induce inflammation in the central nervous system (Seki et al. 2021). Interestingly, blockade of IL-17A increases mortality in murine neonatal sepsis (Wynn et al. 2016), connecting dysbiosis to IL-17A driven inflammation to sepsis severity. The altered colonization from an inherited microbiome can have drastic effects; mice born to dams treated with gentamicin had increased development of sepsis, whereas vancomycin-treated dam’s pups were less susceptible when compared to specific pathogen-free pups (Singer et al. 2019). Antibiotic use in neonates also reduces pathogen-clearing neutrophils from circulation (Kuppala et al. 2011, Deshmukh et al. 2014). Granulocytopenia in neonatal mice resulting from antibiotics was correlated to increased sepsis development by E. coli or K. pneumonia (Deshmukh et al. 2014) and could be rescued through the transfer of healthy neonatal microbiota (Deshmukh et al. 2014). This demonstrates how the colonization that occurs in early life can provide a protective effect against infection and microbial signals can promote a tempered response to systemic inflammation (Singer et al. 2019).
Conclusions
The multifaceted contributions of microbial components in preventing and restraining overwhelming systemic inflammation underscores the importance of a healthy, balanced microbiota. However, given the many environmental insults that can push a microbiota into dysbiosis, systemic inflammation itself, future work will focus on how to restore the dysbiotic microbiota. Preclinical trials with probiotics can reduce decreased serum endotoxin levels and TLR expression (Arno et al. 2018, Liu et al. 2022), though there remains much debate around the choice of probiotic taxa suitable for human trials. Additionally, the use of probiotics in early life may help to prevent early-life sepsis; however, controversy surrounds the use of probiotics in the vulnerable neonatal population (van den Akker et al. 2018). Both Akkermansia muciniphila and Lactobacillus plantarum – a lactic acid bacterium with antibacterial properties – were associated with decreased serum IL-6 and IL-17 levels and increased IL-10, systemically reducing inflammation (Guo et al. 2023). Specifically, Lactobacillus rhamnosus and Bifidobacterium, common probiotic strains, reduced bacteremia burden during CLP-induced sepsis and reduced systemic IL-6 levels and colonic TLR2, TLR4, and MyD88 gene expression (Khailova et al. 2013). The many options for probiotics suggest that the exact taxa are of less concern compared to their physiological function in promoting tolerance. Future work should explore the many strains of probiotics capable of mitigating inflammation and their ability to promote resolution during sepsis events, restore microbially balance following acute inflammation, and prevent recurrent episodes by promotion of a strong intestinal barrier. Treatments are being explored to fight the effects of sepsis on the other side of the reaction. Use of microbial or even metabolite-based therapeutics could represent a new line of care in the maintenance of acute, or chronic, systemic inflammation.
Declaration of interest
The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work was supported by the National Institute of Health (DK134366 (KAK)).
Author contribution statement
JMM and KAK performed the literature review, and conceived and wrote the paper.
References
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