The gut microbiome shapes intestinal immune responses during health and disease

Immunologic dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. Here we discuss findings which indicate that developmental aspects of the adaptive immune system are influenced by intestinal bacterial colonization. We also highlight the molecular pathways that mediate host–symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support an emerging concept whereby disturbances in the bacterial microbiota result in immunological dysregulation that may underlie disorders such as inflammatory bowel disease. Perhaps the mammalian immune system which appears designed to control microbes is, in fact, controlled by the microbes themselves. Humans represent a scaffold upon which diverse microbial ecosystems are established. Immediately after birth, all mammals are initiated into a life-long process of colonization by foreign microorganisms that inhabit most environmentally exposed surfaces (such as the skin, mouth, gut and vagina)1,2. Shaped by millennia of evolution, some host–bacterial associations have developed into beneficial relationships creating an environment for mutualism. A key example of such an environment is provided by the vast numbers and diversity of bacteria that are harboured by the lower gastrointestinal tract of mammals3,4,1,5. By young adulthood, both humans and other mammals support one of the most complex microbial ecosystems on the planet, with over 100 trillion bacteria comprised of potentially many thousands of microbial species in the distal gut6,7. Symbiotic bacteria of the mammalian gut have long been appreciated for the benefits they provide to the host: through provision of essential nutrients, metabolism of indigestible compounds, defence against colonization by opportunistic pathogens and even contribution to the development of the intestinal architecture8. Moreover, it seems that certain basic developmental features and functions of the mammalian immune system depend on interactions with the human microbiome9. Unlike opportunistic pathogens, which elicit immune responses that result in tissue damage during infection, some symbiotic bacterial species have been shown to prevent inflammatory disease during colonization (see below). Surprisingly, the ‘normal’ microbiota also contains microorganisms that have been shown to induce inflammation under particular conditions. Therefore, the microbiota has the potential to exert both proCorrespondence to S.K. M. sarkis@caltech.edu. NIH Public Access Author Manuscript Nat Rev Immunol. Author manuscript; available in PMC 2014 July 14. Published in final edited form as: Nat Rev Immunol. 2009 May ; 9(5): 313–323. doi:10.1038/nri2515. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript and anti-inflammatory responses, and balances in the community structure of gut bacteria may be intimately linked to the proper function of the immune system. By virtue of its responsibility to recognize, respond and adapt to countless foreign and self molecules, the immune system is central to the processes of health and disease. While the classical view of the immune system is that it evolved to protect organisms from infection by microbial pathogens, we peacefully co-exist with our vast and complex microbiota. In fact, the magnitude of the molecular interactions between the microbiota and the host immune system appear to be extensive. Here, we discuss recent evidence that suggests a beneficial partnership has evolved between symbiotic bacteria and the immune system. These molecular interactions seem to direct the development of immune responses, and in turn, the immune system shapes the composition of the microbiota. We highlight seminal examples of microorganisms that have a role in preventing inflammatory bowel diseases (IBD), and the beneficial immune responses they elicit during protection. Furthermore, technological advances now allow a more detailed understanding of the alterations of the microbial population of the gut during IBD. If some bacteria are actively shaping a healthy immune system, does the absence of these organisms lead to disease? It has recently been proposed that the mammalian genome does not encode the information (i.e., molecules) capable of carrying out all functions required for health, and that products of our microbiome (the collective genomes of the microbiota) are crucial for protection from various diseases10. It is possible that alterations in the development or composition of the microbiota (known as dysbiosis) disturb the partnership between the microbiota and the human immune system, ultimately leading to altered immune responses that may underlie various inflammatory disorders in humans. Insights gained from germ-free mice Developmental defects in germ-free mice Several important effects of the microbiota on the host immune system have been determined by studies of gnotobiology, which is the selective colonization of germ-free (sterile) animals. Immune responses in germ-free animals can be considered naïve to the ‘education’ provided by molecules of both pathogenic and beneficial microorganisms. Germ-free animals show extensive deficits in the development of the gut-associated lymphoid tissues (GALT)9,11. In addition to numerous defects in antibody production (Box 1), germ-free animals have relatively fewer and smaller Peyer's patches and mesenteric lymph nodes (MLNs) compared to animals housed under specific pathogen free (SPF) conditions (Table 1). A recent report has shown that germ-free animals display impaired development and maturation of isolated lymphoid follicles (ILFs)12. These inducible structures seem to form normally following the introduction of gut bacteria, suggesting a dynamic relationship between the immune system and the microbiota. Together with various morphological tissue defects observed in the intestines of germ-free animals, it appears that the entire ultrastructural development of the gut is intimately connected to intestinal bacteria. For example, intestinal epithelial cells (IECs), which line the gut and form a physical barrier between luminal contents (including the microbiota) and the underlying cells of the immune system, have altered patterns of microvilli formation and decreased Round and Mazmanian Page 2 Nat Rev Immunol. Author manuscript; available in PMC 2014 July 14. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript rates of cell turnover in germ-free animals compared with wild-type animals13. Gut bacteria have been shown to direct the glycosylation of lumenally-exposed surface proteins of the epithelium14. IECs have many immunological functions (Table 1): they can secrete and respond to various cytokines and express molecules (such as major histocompatibility molecules) that directly interact with lymphocytes. Expression and localization of patternrecognition receptors (e.g., Toll-like receptors; TLRs) by the epithelium is influenced by bacterial colonization of the gut, and expression of defensins and other antimicrobial proteins are deficient in germ-free animals (Table 1). Consistent with this notion, the Gramnegative commensal organism Bacteroides thetaiotaomicron, but not the Gram-positive microbe, Bifidobacterium longum, induces the expression of the antimicrobial peptide, RegIIIγ, by specialized IECs known as Paneth cells15, 16. Intriguingly, the specificity of RegIIIγ is directed toward specific Gram-positive bacteria. It is therefore tempting to speculate that symbiotic bacteria direct innate immune responses of the gut in an effort to protect their environment. Collectively, these observations of developmental defects in germ-free mice at the tissue, cellular and molecular levels suggest that ‘normal’ immune function may be impaired in the absence of the microbiota. Deficiencies in immune responses in germ-free mice Germ-free animals are more susceptible to infection by certain bacterial, viral and parasitic pathogens. When challenged with the Gram-negative enteric pathogen Shigella flexneri, germ-free animals showed decreased immune resistance to infection and increased mortality compared with conventionally colonized animals17. Prior colonization with specific commensal bacteria antagonized S. flexneri infections, whereas colonization with control species such as E.coli did not, implying that some members of the microbiota provide protection against intestinal bacterial pathogens18. Infection by the Gram-positive intracellular pathogen Listeria monocytogenes results in decreased bacterial clearance in germ-free compared with colonized animals19.The mechanism for this increased susceptibility has been attributed to a T cell trafficking defect in germ-free animals to the site of Listeria infection. L-selectin and CD44 are known to be involved in homing of lymphocytes to sites of inflammation. Listeria infected germ-free mice have decreased accumulation of CD44+L-selectin+ T cells resulting in increased bacterial burden compared to SPF animals20. Salmonella typhimurium is known to cause a more severe acute gastroenteritis in germ-free animals21, however the reasons for this remain unclear. Establishing an infection requires the initial task of colonizing the host. For intestinal pathogens this can pose a difficult problem as all mammals are stably colonized by a consortium of bacteria that can act as a barrier to infection (“colonization resistance”). Recent studies suggest that inflammation induced in response to S. typhimurium changes the composition of the microbiota and suppresses its regrowth. Moreover, S. typhimurium exploits this deficiency in “colonization resistance” to establish infection and cause disease22. While important for maintaining a barrier to the colonization of