Influence of the Gut Microbiome on Immune Development During Early Life

34.1 Introduction

The gastrointestinal tract harbors the largest population of commensal organisms in the human body, whose homeostasis requires immunoregulatory mechanisms to prevent unnecessary activation of the immune system against antigens generated by environmental exposures including host-associated microbes. The establishment of immunological tolerance is a result of proper education of resident and newly immigrated immune populations suggesting a dynamic and active relationship between the nascent and naive immune system and pioneering microbial communities that make up the host-commensal microbiome. Exposure to microbes begins in utero after which opportunistic commensal populations disseminate the gastrointestinal tract, skin, and oral cavities. Metagenomic surveys of fecal matter as a measure of the composition of the commensal population suggest higher levels of diversity in the gut microbiota of newborns that reach relatively stable proportions through early childhood and adolescence. The identity and relative diversity of commensal species are influenced by environmental factors, including the mode of delivery, diet, antibiotic exposure, and infection that affect the access of microbial communities to nutrients and suitable habitat. Given the relative instability of the microbiome during infancy, and particularly during the first year of life, studies suggest external factors, such as diet or exposure to antibiotics, can contribute to the volatility of newly emerging and opportunistic microbial populations. At the same time, recent animal studies have suggested that many regulatory and effector immune subsets are permissive to microbial instruction during a restrictive period of early life, we term the “window of opportunity” that contributes to proper (or improper) immune responses to local and systemic endogenous and environmental stimuli throughout life. In this chapter, we discuss the role of the microbiota during immune development throughout early life and consider how disruption of these interactions alters host susceptibility to disease in later life.

34.2 Microbiota Influences on the Structural Development and Function of the Immune System Within the Gastrointestinal Tract

The establishment of the field of gnotobiology , which is the selective colonization of germ-free (GF) (sterile) animals, supports the notion that there is a dynamic interaction between the host immune system and the microbiota. Initial comparisons between animals raised under GF or specific pathogen-free (SPF) environments revealed that virtually the entire ultra-structural development of the gastrointestinal tract is actively influenced by the presence of bacteria. GF animals harbor an enlarged cecum, principally due to an accumulation of nondegraded mucus and aberrant intestinal epithelial cell (IEC) morphology characterized by longer villi and shorter crypts in comparison to genetically identical animals raised under conventional (SPF) settings. In addition, GF animals exhibit extensive deficiencies in the development of gut-associated lymphoid tissues (GALTs), harbor fewer and smaller Peyer’s patches and mesenteric lymph nodes (mLNs), and exhibit impaired development and maturation of isolated lymphoid follicles (ILFs) versus their SPF counterparts. Significantly, introducing gut bacteria to formerly GF animals normalize many of these associated structural abnormalities. These latter studies not only emphasize the influence of the microbiota on proper lymphoid tissue development, but also intimate that specific microbial communities can interact with the immune system of the gut, particular at the mucosal interface.

34.2.1 A Role for Commensals During Colonization and Infection

GF animals are more susceptible to infection by certain bacterial, viral, and parasitic invaders suggesting a general role for the endogenous microbiota to provide protective immunity against pathogens. One mode of defense against exogenous pathogens by commensals relates to the competition between these two classes of organisms for the same ecological niche within the host, through a phenomenon known collectively as colonization resistance. One strategy that favors the indigenous microbial community is the preferential consumption of nutrients required for growth of competing pathogenic bacteria. Thus, by consuming common limited resources, Escherichia coli ( E. coli ) can outcompete enterohaemmorrhagic E. coli (EHEC) for organic acids, amino acids, and other nutrients. Commensal metabolism can also restrict the virulence of invading pathogens. Production of the short chain fatty acid (SCFA) butyrate by commensals specifically suppresses expression of virulence genes encoding the Type 3 secretion system (T3SS) machinery of Salmonella entera , including Serovar Enteritidis, and Typhimurium. In an analogous fashion, mucin- derived fucose, generated by fucosidase-bearing commensal bacteria, like Bacteroides thetaiotaomicron , modulates the expression of the virulence factor ler limiting the growth of EHEC. Finally, commensals can also produce specific antimicrobial peptides that directly affect pathogen growth or survival; for instance, E. coli produce bacteriocins, proteinaceous toxins that specifically inhibit the grown of the same or similar bacterial species, including EHEC. A consequence of the disruption of commensal-mediated colonization resistance is that susceptibility to enteric infection may increase. Administration of antibiotics to SPF animals or introduction of low-complexity microbiota to GF animals leads to increased accumulation and dissemination of infectious bacteria in the context of infection or during a breach in epithelial barrier function.

34.2.2 Modulation of the Mucosal Immune System by Commensal Microbes Throughout Life

During infancy, microbial communities exist in a volatile state suggesting colonization resistance has not yet been established and as such, the ability of the host to accept pioneering microbes can in part be explained by the relatively poor immune surveillance capacity of the neonatal immune system at birth including the presence of immune cells that promote a characteristic tolererogenic environment within mucosal sites throughout the body. The developing immune system is characterized by low inflammatory cytokine production and the enrichment of immune subsets of T and B cells with regulatory rather than effector capacity. Consistent with this, the neonatal system responds uniquely to conserved microbial-associated molecular patterns (MAMPs) to promote healthy microbial colonization through impaired production of inflammatory mediators, such as radical oxygen species, and elevated production of antiinflammatory cytokines such as interleukin 10 (IL-10) compared to adults. Although the underlying mechanisms responsible for these observations remain elusive, comparisons of GF and SPF animals demonstrate that signals derived from the microbiota can modulate many aspects of immune regulatory and effector function within both the innate and adaptive immune system. Introducing commensals to previously GF animals can restore or enhance many host defense mechanisms ; however, more recent studies suggest that optimal development of the intestinal immune system can only be achieved if the host is exposed and responds to these microbes during a critical and restricted period of time during neonatal development. Failure to “correct” deficiencies associated with appropriate microbial exposure during this “window of opportunity” in early life results in suboptimal maturation of the developing immune system with potentially deleterious ramifications for the host that can extend into adulthood. Below, we discuss specific regulatory and effector cells of the mucosal immune system subject to microbial regulation in the context of intestinal development during health and disease.

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