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. Author manuscript; available in PMC: 2016 Mar 1.
Published in final edited form as: Curr Opin Gastroenterol. 2015 Mar;31(2):118–123. doi: 10.1097/MOG.0000000000000143

Host-microbe interactions in the small bowel

Julie M Davies 1, Maria T Abreu 1
PMCID: PMC4340613  NIHMSID: NIHMS662951  PMID: 25426971

Abstract

Purpose of Review

The intestine, home to a vast microbiome, balances its immune reactivity on a knife’s edge. This review will summarize recent studies examining innate immune signals that shape the microbiota, and how pathogens can usurp protective responses to their advantage.

Recent findings

Innate signaling uses several pathways to maintain epithelial defense. Toll-like receptor signaling through myeloid differentiation factor 88 maintains segregation between bacteria and the epithelium through production of anti-microbial proteins and inflammasome signaling mediates efficient goblet cell release of mucus containing granules. Conversely, negative regulators of TLR signaling help maintain a healthy microbiota resistant to pathogen infection. Methods to evade immune elimination by pathogens associated with human infections and inflammatory bowel disease are described. Emerging evidence that pattern recognition receptors can differentiate between commensals and pathogens will be examined.

Summary

The balance of innate signaling in the intestine is crucial to homeostasis: too little and bacteria can directly contact the epithelium, too much depletes the protective microbiota creating a niche for pathogens. Understanding the dynamic interaction between the immune system and the microbiota in a variety of infection and inflammation models will hopefully translate to new therapies.

Keywords: toll-like receptor, microbiota, intestine, inflammasome, Salmonella enterica serovar Typhimurium

Introduction

Tolerance in the intestinal environment is a precarious balancing act between non-reactivity against commensal symbionts and active inflammation against pathogens. The single cell epithelial layer that forms the barrier to the lumen has a number of capabilities to defend its borders. Subsets of epithelial cells have secretory functions that produce mucus (goblet cells) or secrete anti-microbial peptides (Paneth cells) to constrain the growth of microbes in the epithelial vicinity. Epithelial cells are induced to secrete mucus and anti-microbial peptides in response to innate immune signaling initiated by lamina propria resident immune cells (1). Innate signaling in the intestine is tightly controlled, with anatomical segregation of receptors (2) and increased quantities of negative regulators (3, 4) to prevent inappropriate immune activation. However, how the host is able to maintain homeostasis in the face of the onslaught of pathogen derived molecular patterns that abound in the environment has yet to be fully elucidated.

In this review we will consider recent studies that have investigated the interaction between host defense mechanisms and their effect on the intestinal microbiota. We will consider new evidence that defines the roles for innate signaling in maintenance of the mucus layer and anti-microbial peptide synthesis and secretion. We will also review the evidence that supports the requirement for balanced inflammatory signaling in maintaining a homeostatic relationship with the microbiota. We will examine the evidence showing how some enteric pathogens are able to subvert immune responses to promote their own growth. Finally we will consider an exciting study of a new pattern recognition receptor, and a new purpose for a well-known one, and how they are re-defining our notion of innate recognition of commensals and pathogens.

Innate signaling is required for effective segregation of bacteria from the epithelium

Recognition by innate immune sensors in the intestinal epithelium contribute to maintaining separation of the niche environments of both the host and microbiota. Myeloid differentiation facto 88 (MyD88) functions as an adaptor molecule for signaling initiated by Toll-like receptors (TLRs) and the Interleukin-1R (IL-1R). TLRs recognize conserved pathogen associated molecular patterns (PAMPs) and activate nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-dependent transcription of pro-inflammatory mediators (2). In the epithelium, TLR activation is important in driving production of antimicrobial peptides and mice which lack MyD88 specifically in the epithelium (MyD88ΔIEC ) have decreased production of Muc2 (Mucin), Defa-rs1 (alpha Defensin) and Reg3g (C-type lectin) compared to control MyD88fl/fl mice (5). In normal conditions, the mucus layer prevents luminal bacteria from coming into contact with the epithelium (6). Specific loss of MyD88 in epithelial cells (MyD88ΔIEC) reduces the distance between the bacterial biofilm and the apical border of the epithelium. This allows bacteria to come directly into contact with the epithelium, which doesn’t occur in wild-type mice. The importance of epithelial MyD88 signaling was found to lie in its ability to induce secretion of the anti-microbial peptide RegIIIγ. Loss of RegIIIγ was most important in the small intestine, as RegIIIγ expression is low in the colon (6). Epithelial MyD88 signaling was also important in containing pathogenic microbiota to the lumen, as MyD88ΔIEC mice had increased translocation of Klebsiella pneumonia to the mesenteric lymph nodes (5). In the colon, loss of IEC MyD88 also increased susceptibility to dextran sodium sulfate (DSS)-induced colitis through increased destruction of the epithelial layer and increased inflammatory cell infiltrate despite lower levels of inflammatory cytokines TNF, IL-1β and the chemokine CXCL2 (5). Thus, MyD88 signaling in intestinal epithelial cells impacts both the protective mucus layer and the production of antimicrobial factors that directly control the proximity and survival of the microbiota at the interface of the luminal environment and the host tissues.

Other pattern recognition receptors play a similar role to MyD88 in maintaining segregation of bacteria from the epithelial layer. NOD-like receptor family pyrin domain containing 6 (NLRP6) is a member of the NOD-like receptor family that forms an inflammasome complex in association with apoptosis-associated speck-like protein containing a CARD and Caspase 1. Loss of NLRP6 results in spontaneous hyperplasia and increased inflammatory infiltrate in these mice. These mice also have an altered microbiota that transfers worse colitis risk to co-housed WT mice. Like MyD88ΔIEC mice, NLRP6−/− mice have bacteria in contact with the crypt and epithelium in the colon, and antibiotic treatment decreased the Prevotellacea and TM7 bacterial classes and resulted in better colitis scores. Indicating that the dysbiotic bacteria was driving the inflammation in this model (7). In a follow-up study by the same group, the NLRP6−/− mice were found to have a profound defect in secretion of goblet cell granules to the lumen which impacted the mucus layer, and the luminal secretion of anti-microbial peptides. They found that inflammasome signaling was required for efficient induction of autophagy, which was a requirement for the fusion of goblet cell granules with the plasma membrane for their release into the lumen. Without this fusion, the granules were found intact in the lumen, which was unproductive in creating a mucus layer and preventing bacterial contact with the epithelium and release of the anti-microbial peptides. Mice with defective autophagy (Atg5+/−) also have this goblet cell functional defect, demonstrating the connection between the two pathways (8). These studies have been crucial to understanding the specific defect in goblet cell production of an effective mucus layer in the absence of inflammasome signaling, because these mice produce ample gene transcripts of Muc2 and anti-microbial peptides, but were still unable to generate an effective mucus layer, and control access of the microbiota to the epithelium. Additionally, these studies drive home the inter-connectedness of autophagy and inflammasome activation – defects in both of these pathways are highly significantly associated with the development of inflammatory bowel disease (9). These studies highlight how these two pathways connect to regulate the environmental at the interface of the epthelium.

The above-mentioned studies demonstrate that epithelial innate signaling promotes an effectively anti-microbial mucus layer. Epithelial MyD88 signaling induces RegIIIγ and establishes a protective segregation between bacteria and the epithelium, and NLRP6 inflammasome signaling in combination with autophagy is required for proper goblet cell granule maturation and release.

Loss of regulation of innate signaling breaks the balance with commensal microbiota

Balanced innate signaling is vital to a peaceful co-existence between microbes and the host in the intestine. Too little, and there is ineffective mucus production and antimicrobial peptide production. However, too much is equally perilous to homeostasis. TLR signaling is important to keep bacteria segregated from the epithelium, but negative regulators of TLR signaling are also important in maintaining balance in the intestine. Single Ig IL-1 Related Receptor (SIGIRR) is a membrane inhibitor of TLR and IL-1R signaling (10). Loss of SIGIRR results in increased inflammatory gene expression in response to Citrobacter rodentium infection compared to WT mice, but the inflammation did not reduce bacterial burdens, and actually lead to increased bacterial loads in the cecum at early time points. Loss of SIGIRR increased anti-microbial peptide expression including: RegIIIγ, β-defensin-III, and cathelin-related antimicrobial peptide (CRAMP) (11). How is it that increased anti-microbial peptide production didn’t protect against C. rodentium infection? The authors postulated that increased anti-microbial peptide levels actually decreased the commensal bacteria which were sensitive to their actions, and this opened up a niche that C. rodentium was able to fill. Thus it was the loss of competition from other commensals that allowed the outgrowth of C. rodentium in this model (11). Studies from the same laboratory have investigated the role of SIGIRR in the course of infection with the human pathogen Campylobacter jejuni. In this infection model increased inflammation is driven by TLR4 signaling since double knock outs of SIGIRR and TLR4 have decreased colonic pathology and inflammatory gene expression. Conversely, TLR2 was protective in the same model and SIGIRR−/−TLR2−/− double knock outs were more susceptible to infection, having increased pathology and cytokine secretion than the SIGIRR−/− mice (12).

Loss of another negative regulator of TLR4 signaling Toll-interacting protein (TOLLIP) leads to increased intestinal permeability during DSS colitis compared to WT mice indicating a role for microbial sensing in maintaining tight junctions barriers in the intestine. Bone marrow chimeras suggest that the IEC TOLLIP contribution is most important to increased colitis severity, but there was no baseline inflammation in this model, nor was there a role for the microbiota in driving increased colitis susceptibility (13). Loss of IRAK-M in IL-10−/− mice also increases colitis susceptibility while TLR4−/−IL10−/− double knock outs and MyD88−/−IL-10−/− double knock outs had decreased severity, suggesting that de-regulation of TLR signaling in the absence of the regulatory cytokine IL-10 was driving inflammation in this model (14). IRAK-M was found to be induced in response to the microbiota, as germ-free mice had low levels of IRAK-M expression which was increased following colonization (14).

So, the intestine employs a delicately balanced system in which innate signaling responses in epithelial cells are crucial to host-microbe homeostasis. Innate signaling that alters the mucus layer or production of commensal-modifying anti-microbial peptides has a huge impact on keeping the microbiota constrained to its anatomical niche and out of direct contact with the epithelial layer. But what happens when pathogens learn the rules?

Pathogens out-fox epithelial defenses

There is a point at which the effectiveness of host-derived anti-microbial peptides becomes hazardous. Certain pathogens have evolved to take advantage of the lack of competition that occurs after anti-microbial peptides have cleaned-out the commensal microbiota. They use this opportunity to gain a foothold and take over the niche as evidenced in the above-mentioned studies in SIGIRR−/− mice infected with C. rodentium. Salmonella enterica serovar Typhimurium (S.typh) is one such human pathogen that uses immune responses to its advantage. S.typh is a colonizing human pathogen that induces inflammatory diarrhea and thrives in the inflamed gut. In fact, S.typh requires inflammation in order to colonize (15) S.typh has developed several competitive advantages over the commensal microbiota to survive host defenses (16–18). Infection with S.typh induces a huge increase in IL-22, which acts on epithelial cells to increase anti-microbial gene expression including Lcn2 (lipocalin2), s100A8, s100A9 and Reg3g and oxidative stress proteins Nos2 (inducible nitric oxide synthase 2) and Duox2 (dual oxidase 2) (19) – which are all ineffective against S.typh. S100A8 and S100A9 form a heterodimer called calprotectin which functions to mop up zinc in the lumen; metal chelation is a common anti-microbial strategy to limit bacterial growth. S.typh uses a zinc sequestration protein ZnuABC to grow in the presence of calprotectin (20). Similarly, S.typh is able to use neutrophil-derived oxidation by-products as an energy source. Hydrogen sulfate, normally produced by the microbiota is oxidized to tetrathionate after neutrophil activation of gp91phox in the NADPH pathway and release of oxygen radicals. S.typh can use tetrathionate as an energy source using genes encoded by the ttrSR and ttrBCA gene cluster (15). S.typh can also outcompete iron-dependent bacteria in the presence of lipocalin2 using its iroN siderophore genes (21). IL-22−/− mice are protected from S.typh colonization without any increase in inflammatory cell recruitment. Protection is mediated through changes in the commensal microbiota communities that occur after infection with S.typh. Without IL-22 induced increases in anti-microbial peptides which would normally wipe out members of the Enterobacteriaceae group, these bacteria are able to compete with S.typh for growth (19). These data highlight the potential role of fecal transplants in treating conditions in which normal commensals can compete with pathogens for niche space.

Other pathogenic bacteria have also developed similar immune evasion strategies. Adherent-invasive Esherichia coli (AIEC) is more frequently found in Crohn’s disease patients with ileal disease than in controls, or patients without ileal disease. AIEC strains have been found in the lamina propria of CD patients and can persist and replicate in macrophages and as such are candidate as instigating agents in CD (22). Following phagocytosis, AIECs have been shown to induce the secretion of TNF which is dose dependent on their own proliferation inside of the phagolysosomes (23). The mechanism by which TNF secretion by macrophages allows intracellular proliferation of the bacteria is still unclear. However, treatment of infected macrophages with anti-TNF antibodies decreased their proliferation, and may represent an otherwise unconsidered aspect of the efficacy of anti-TNF treatment in CD and UC patients. That TNF promotes the intracellular proliferation of AIEC is not common to all intracellular pathogens. S. typh was not able to increase its intracellular growth following TNF treatment inside macrophages (23). AIEC strains isolated from CD patients with ileal disease have also been found to have genomic islands that encode genes able to evade anti-microbial peptides including LL-37, two other alpha helical cationic proteins chemotactic protein 10A (CP10A) and CP28 and is also somewhat resistant to alpha and beta defensins. The gene islands allow the AIEC to outcompete other strains lacking parts of the gene island in vivo and also to colonize better over time (24).

Taken together these new studies have provided insight into the way in which the immune system interacts with the commensal microbiota; through modulation of the mucus layer and secretion of proteins that constrain the growth of bacteria. This has a direct impact on the composition of the microbiota – and influences the interactions amongst commensal and pathogenic populations. Broad spectrum immune responses such as those induced by S. typh may limit systemic dissemination of the pathogen (25), but allow it to gain a foothold in the intestinal niche through eradication of its competitors. S. typh has gained the ability to evade host responses, and even use them to their own advantage. It may be of interest for future studies to investigate the types of commensal bacteria that directly compete with S. typh including members of the Enterobacteriacea family to determine if therapies aimed at providing competition for the pathogenic bacteria may be a beneficial treatment strategy.

Emerging pattern recognition receptors discriminate between pathogens and commensals

A central tenet of innate PRRs is that they recognize broad classes of structures present in commensals and pathogens alike and are not sufficiently sensitive to distinguish between the two. This has proved a paradox in the intestine where the large majority of the bacteria are commensal and well tolerated by the immune system, and do not actively induce inflammatory reactions. It has been postulated that this anergy toward commensal microbiota lies in the inability of commensals to breach the epithelial barrier and induce tissue damage, and is maintained through the physical segregation of PRRs to the apical surface of epithelial cells. Lately, several new classes of PRRs have been identified that may be able to do just that - distinguish commensals from pathogens.

Uracil recognition

Initial studies in Drosophila have elucidated a role for reactive oxygen species (ROS) generation in mounting protective responses against gut pathogens which are not activated by commensals. DUOX2 is a member of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family and prouduces ROS to kill invading microbes. Screening studies in Drosophila identified, by NMR structural analysis, the ROS-inducing secreted factor from the gut pathogen Erwinia carotovora subsp. carotovora-15 as uracil. Symbiont bacteria that normally colonize the Drosophia gut were generally found to be low producers of uracil and subsequently unable to induce ROS whereas opportunistic pathogens including Klebsiella pneumoniae, Shigella sonnei and Pseudomonas aeruginosa all produced significant quantities of uracil. Studies in the human Caco2 epithelial cell line also determined that uracil activates ROS generation (26). The induction of ROS by pathogens and not commensals while seemingly at cross-purpose to their survival may prove to be a strategy to deplete competing commensal as we have seen above with S. typh.

Bacterial double-stranded RNA

TLR3 is usually considered a viral double-stranded RNA (dsRNA) sensor however, a recent study has found that heat killed commensal lactic acid bacteria (LAB) have abundant dsRNA available to activate TLR3 whereas pathogens have low levels of dsRNA. Selective RNAse treatment of the heat killed bacteria to reduce dsRNA levels significantly reduced the amount of IFNβ induced by bone marrow-derived dendritic cells, but not other inflammatory cytokines like IL-6 and TNFα which were assumed to be induced by other TLR engagement. LAB strains induced IFNβ but not IFNα. IFNβ has previously been shown to mediate anti-inflammatory reactions in several auto-immune experimental models including collagen-induced arthritis and delayed-type hypersensitivity (27). Mice orally fed with LAB were protected from DSS colitis having less inflammatory infiltrate, lower myeloperoxidase concentrations (measure of neutrophil accumulation), and this protection was lost in TLR3−/− mice. CD11c+ dendritic cells were the probable source of IFNβ. Luminal contents from the ileum were shown to contain the highest quantity of dsRNA even compared to the colon, demonstrating the importance of TLR3 in regulating immune responses in the small intestine (28).

The innate immune system in the intestine may not be as blunt an instrument as previously thought. Subtle differences in the secretion of uracil or the presence of dsRNA may be just enough for the innate immune system to be able to differentiate between commensals and pathogens. Careful studies may yet uncover new recognition systems that are able to discriminate between friend and foe.

Concluding Remarks

The above studies have shown us the tight regulation of immune activation in the intestine. Insufficient innate immune signaling allows the microbiota to contact the epithelium but; over-activation of innate pathways is just as hazardous. Any process that alters production of anti-microbial peptides has the potential to significantly impact the vulnerable microbiota to the advantage of resistant and potentially pathogenic species. Future research in this area should focus on understanding the microbial population changes occurring during infection to determine how input from the immune system alters interactions amongst the microbiota. Finally, ongoing studies of newly identified PRRs that can differentiate between commensal and pathogen may prove an attractive testing model in the drive to discover novel probiotics. There is tremendous potential in the studies that are ongoing in this field for application to human therapies for infection and dysbiosis.

Key Points.

  • Balanced innate signaling in the intestine is required to maintain homeostasis with the microbiota

  • Loss of MyD88 in epithelial cells allow bacteria to contact the epithelium through decreased production of anti-microbial peptides, and loss of inflammasome signaling impairs goblet cell secretory function

  • Pathogens can use the innate immune responses against them to gain a foothold in the intestinal niche

  • Novel pattern recognition receptors have been reported that can differentiate between commensal and pathogen.

  • Understanding how microbial populations change during inflammation and infection may provide new therapeutic options for treating infections and inflammatory bowel disease.

Acknowledgments

The authors would like to acknowledge the support of the members of the Abreu laboratory in the preparation of this review.

Financial Support and Sponsorship

Funding for this review was provided by grants to support the laboratory of MTA (National Institute of Health, National Cancer Institute 5R01CA137869-05, National Institute of Diabetes and Digestive and Kidney Diseases 2R01DK099076-06A1; Crohn’s and Colitis Foundation of America Senior Investigator Award).

Footnotes

Conflict of Interest

MTA serves as a consultant and scientific board member of AbbVie Laboratories, GI Health Foundations and Asana Medical Inc, and consults for Hospira, Takeda, Merck, Pfizer, Sanofi Aventis, Janssen, Prometheus, Mucosal Health Board, Focus Medical Communications, Shire Pharmaceuticals, GSK Holding Americas Inc. and UCB. JMD declares no conflict of interest.

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