Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Sep;279(1):70-89.
doi: 10.1111/imr.12567.

Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease

Joseph M Pickard  1 , Melody Y Zeng  1 , Roberta Caruso  1 , Gabriel Núñez  1
Affiliations
Review

Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease

Joseph M Pickard et al. Immunol Rev. 2017 Sep.

Abstract

The intestinal tract of mammals is colonized by a large number of microorganisms including trillions of bacteria that are referred to collectively as the gut microbiota. These indigenous microorganisms have co-evolved with the host in a symbiotic relationship. In addition to metabolic benefits, symbiotic bacteria provide the host with several functions that promote immune homeostasis, immune responses, and protection against pathogen colonization. The ability of symbiotic bacteria to inhibit pathogen colonization is mediated via several mechanisms including direct killing, competition for limited nutrients, and enhancement of immune responses. Pathogens have evolved strategies to promote their replication in the presence of the gut microbiota. Perturbation of the gut microbiota structure by environmental and genetic factors increases the risk of pathogen infection, promotes the overgrowth of harmful pathobionts, and the development of inflammatory disease. Understanding the interaction of the microbiota with pathogens and the immune system will provide critical insight into the pathogenesis of disease and the development of strategies to prevent and treat inflammatory disease.

Keywords: bacterial; colonization resistance; gut microbiota; inflammatory bowel disease; mucosa.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Direct and indirect mechanisms of colonization resistance. Direct mechanisms (left): Symbiotic bacteria scavenge nutrients that would otherwise be available to pathogens (red, with flagella). Bacteriophages, type 6 secretion systems (T6SS), and bacteriocins may target and kill pathogens. Products of bacterial metabolism, such as short-chain fatty acids (SCFAs), can inhibit pathogen growth. Symbiotic bacteria produce enzymes that convert conjugated, primary bile acids to secondary bile acids, which can kill some pathogens. Indirect mechanisms (right): symbionts produce butyrate which can lower oxygen concentration by stimulating host epithelial cell metabolism. Microbe-associate molecular patterns (MAMPs) produced by bacteria and viruses stimulate host innate immunity via TLRs and MyD88, on epithelial cells directly or dendritic cells (DCs). ILC3 and Th17 cells can be activated to produce IL-22, which promotes secretion of AMPs (antimicrobial peptides) such as Reg3g from epithelial cells. B cells produce IgA and IgG antibodies, which can target bacteria in the lumen. Mucus production is stimulated by bacteria, and the mucus is decorated with various glycans. These can be cleaved by bacterial enzymes and the free sugars, such as fucose, can suppress pathogen or pathobiont virulence. The host can also oxidize sugars via reactive nitrogen species produced by inducible nitric oxide synthase (iNOS).
FIGURE 2
FIGURE 2
Effects of the gut microbiota on host immune responses. Through TLRs, molecules from gut symbiotic bacteria promote granulopoiesis of neutrophils in the bone marrow and mobilization of neutrophils upon infection. The presence of gut symbiotic bacteria is important for expression of pro-IL-1 in intestinal macrophages, which can be cleaved to mature IL-1 by selective gut Enterobacterial symbionts via NLRP3 inflammation during gut injury to promote proper inflammatory response. IL-1, IL-23 and IL-6 from intestinal macrophages are important to promote mucosal Th17 cell response, and IL-10 from intestinal macrophages as well as microbial short-chain fatty acids (SCFAs) are involved in the development of Tregs in the gut under homeostatic conditions. The presence of the gut microbiota is critical for induction of both T cell-dependent and independent production of IgA antibodies, most of which are specific for gut symbionts and are transferred to intestinal lumen where they target invading bacteria to prevent them from crossing the epithelial barrier. During enteric Citrobacter rodentium or Clostridium difficile infection, IL-22, mostly produced by ILC3 cells, can act systemically to induce hepatocytes to produce hemopexin and complement C3, respectively, to inhibit growth and clearance of systemically translocated bacteria. Under homeostatic conditions, selective members of Gram-negative gut symbionts induce systemic production of IgG antibodies that can recognize bacterial surface antigens, such as murein lipoprotein (MLP) that are expressed on some Gram-negative pathogens, thereby contributing to host defense against systemic infection by gut symbionts or pathogens.
FIGURE 3
FIGURE 3
Host-immune interactions play a crucial role in the pathogenesis of Inflammatory Bowel Disease. During homeostasis, gut microbiota critically contribute to the development of host intestinal immunity. Beneficial symbionts usually control the expansion of colitogenic pathobionts through the induction of regulatory immune responses, involving regulatory T (Treg) cells, interleukin-10 (IL-10) and regenerating islet-derived protein 3γ (REGIIIγ). In IBD, confluence of environmental and genetics factors may alter the balance between host immune and gut microbial factors triggering intestinal inflammation. Environmental factors, such as diet and antibiotic treatment, can disrupt the gut microbial community structure. Additionally, variants in NOD2, ATG16L1 and IRGM genes may perturb many aspects of immune homeostasis including reduced muramyl-dipeptide sensing in antigen-presenting cells, impaired anti-microbial responses in Paneth cells, and altered intraepithelial autophagy leading to defective barrier function and/or bacterial killing. These alterations can lead to a reduced overall microbial diversity with loss of beneficial symbionts and/or expansion of pathobionts and ultimately result in an enhanced mucosal adherence and translocation of bacteria leading to the development of chronic inflammation involving expansion of T helper 1 (Th1) and Th17 cells. IEC, intestinal epithelial cells, IEL, intraepithelial lymphocyte, DC, dendritic cell, MΦ, macrophage, N, neutrophil, Mo, inflammatory monocyte, ILC, innate lymphoid cell, IgA, immunoglobulin A, sIgA, secretory immunoglobulin A, AMPs, anti-microbial peptides.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Marcobal A, Barboza M, Froehlich JW, et al. Consumption of human milk oligosaccharides by gut-related microbes. J Agric Food Chem. 2010;58:5334–5340. - PMC - PubMed
    1. Kamada N, Seo SU, Chen GY, Nunez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013;13:321–335. - PubMed
    1. Freter R. The fatal enteric cholera infection in the guinea pig, achieved by inhibition of normal enteric flora. The Journal of infectious diseases. 1955;97:57–65. - PubMed
    1. Bohnhoff M, Drake BL, Miller CP. Effect of streptomycin on susceptibility of intestinal tract to experimental Salmonella infection. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine. 1954;86:132–137. - PubMed
    1. Pultz NJ, Stiefel U, Subramanyan S, Helfand MS, Donskey CJ. Mechanisms by which anaerobic microbiota inhibit the establishment in mice of intestinal colonization by vancomycin-resistant Enterococcus. The Journal of infectious diseases. 2005;191:949–956. - PubMed