MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection

Abstract

The presentation of protein antigens on the cell surface by major histocompatibility complex (MHC) molecules coordinates vertebrate adaptive immune responses, thereby mediating susceptibility to a variety of autoimmune and infectious diseases. The composition of symbiotic microbial communities (the microbiota) is influenced by host immunity and can have a profound impact on host physiology. Here we use an MHC congenic mouse model to test the hypothesis that genetic variation at MHC genes among individuals mediates susceptibility to disease by controlling microbiota composition. We find that MHC genotype significantly influences antibody responses against commensals in the gut, and that these responses are correlated with the establishment of unique microbial communities. Transplantation experiments in germfree mice indicate that MHC-mediated differences in microbiota composition are sufficient to explain susceptibility to enteric infection. Our findings indicate that MHC polymorphisms contribute to defining an individual's unique microbial fingerprint that influences health.

Protective major histocompatibility complex allele prevents type 1 diabetes by shaping the intestinal microbiota early in ontogeny

“…Eα16/NOD and NOD littermates did not differ in the flow cytometric frequency or mean fluorescence intensity of IgA-coated cecal bacteria (Fig. S3), contrary to previous data demonstrating fluctuations in the proportion of IgA + stool bacteria depending on the host MHC allele (19). In our IgA-sequencing data, direct comparisons between the genotypes revealed no OTUs that had significantly different IgA-coating index (ICI) values for either age group (Fig.…”

“…One possibility is that an additional restriction element, the E complex, could allow immune responses against additional microbial antigens, thereby shaping the developing microbiota. In particular, there could be an effect on the nascent IgA repertoire via presentation of additional microbial antigens, and IgAs are known, in turn, to shape the intestinal microbiota (19,30). We tested the hypothesis that the type of MHC class II allele present would influence the affinity and specificity of the IgA produced in response to the intestinal microbiota of young Eα16/NOD vs. NOD mice.…”

“…Recent results have highlighted a role for the intestinal microbiota in promoting or protecting from several autoimmune diseases, including this one (16,17). Since a few reports have suggested that MHC/HLA complexes can influence microbial colonization of the gut (18,19), although others have appeared to disagree (20), we hypothesized that E-mediated protection from NOD autoimmunity might be an indirect effect, channeled through influences on the intestinal microbiota. Using multiple experimental approaches, we demonstrate this hypothesis to be true.…”

Invasions of Host-Associated Microbiome Networks

“…An experiment in threespined sticklebacks has demonstrated that fish with higher MHC diversity have lower diversity in their gut flora, and that different MHC allele repertoires are associated with shifts in the relative abundance of some bacterial functional groups (Bolnick et al 2014). Recently, Kubinak et al (2015) found that the role of MHC in regulating gut microbial community composition is also applicable to mice, in which specific MHC genotypes reduce the fitness of resident microbiota, favouring systemic infection.…”

Emerging roles for antigen presentation in establishing host–microbiome symbiosis

“…Interestingly, another recent study examined the impact of MHC polymorphisms on the host-commensal bacteria homeostasis and host susceptibility to infection. Here, it was shown that unique host MHC genotypes underlie unique populations of commensal bacteria, with a range of susceptibility to enteric infections among the different commensal populations (103). Although a role for ILC3s was not examined in this context, the primary role of ILC3 MHCII in modulating intestinal homeostasis would suggests that ILC3s may play a causative role in this context.…”