Research Article: Does MHC heterozygosity influence microbiota form and function?

Date Published: May 16, 2019

Publisher: Public Library of Science

Author(s): M. A. Wadud Khan, W. Zac Stephens, Ahmed Dawood Mohammed, June Louise Round, Jason Lee Kubinak, Brenda A Wilson.


MHC molecules are essential for the adaptive immune response, and they are the most polymorphic genetic loci in vertebrates. Extreme genetic variation at these loci is paradoxical given their central importance to host health. Classic models of MHC gene evolution center on antagonistic host-pathogen interactions to promote gene diversification and allelic diversity in host populations. However, all multicellular organisms are persistently colonized by their microbiota that perform essential metabolic functions for their host and protect from infection. Here, we provide data to support the hypothesis that MHC heterozygote advantage (a main force of selection thought to drive MHC gene evolution), may operate by enhancing fitness advantages conferred by the host’s microbiome. We utilized fecal 16S rRNA gene sequences and their predicted metagenome datasets collected from multiple MHC congenic homozygote and heterozygote mouse strains to describe the influence of MHC heterozygosity on microbiome form and function. We find that in contrast to homozygosity at MHC loci, MHC heterozygosity promotes functional diversification of the microbiome, enhances microbial network connectivity, and results in enrichment for a variety of microbial functions that are positively associated with host fitness. We demonstrate that taxonomic and functional diversity of the microbiome is positively correlated in MHC heterozygote but not homozygote animals, suggesting that heterozygote microbiomes are more functionally adaptive under similar environmental conditions than homozygote microbiomes. Our data complement previous observations on the role of MHC polymorphism in sculpting microbiota composition, but also provide functional insights into how MHC heterozygosity may enhance host health by modulating microbiome form and function. We also provide evidence to support that MHC heterozygosity limits functional redundancy among commensal microbes and may enhance the metabolic versatility of their microbiome. Results from our analyses yield multiple testable predictions regarding the role of MHC heterozygosity on the microbiome that will help guide future research in the area of MHC-microbiome interactions.

Partial Text

MHC molecules display protein antigens (peptides) on the surface of cells and are central to the development of the vertebrate adaptive immune response. They are also important signaling molecules that coordinate immune cell development and effector function[1–6]. MHC genes are the most polymorphic loci known in vertebrates, and much of this polymorphism lies in the exons encoding the peptide-binding cleft of MHC molecules or the promoter regions of MHC genes[7–10]. MHC class I molecules are expressed on all nucleated cells and present intracellularly-derived peptide antigens to circulating cytotoxic T cells. These molecules are central to anti-viral and anti-tumor immunity. MHC class II molecules (MHCII) have more restricted expression and present extracellularly-derived peptides to circulating helper T cells. These molecules are central to humoral (i.e. antibody-mediated) immunity against extracellular microbes (primarily bacteria).

Several major observations from our sequencing study support the hypothesis that MHC heterozygosity significantly influences microbiome form and function. First, MHC heterozygotes have a unique taxonomic composition of their gut microbiota compared to that of MHC homozygotes. Second, while the microbiomes of MHC heterozygotes have similar numbers of total gene functions compared to MHC homozygotes, heterozygosity results in significant differential enrichment for certain functions relevant to host health; notably within the core microbiome that is hypothesized to be particularly important to host fitness. In particular, the core microbiomes of MHC heterozygotes appear to be enriched for beneficial functions and deficient in functions that have been associated with a variety of gastrointestinal diseases. MHC heterozygosity also results in greater individual variation in taxonomic and functional composition of the microbiome, which could be linked to selection favoring the addition of species that perform novel functions. All else being equal, novel functions are more likely to come from more phylogenetically distinct species. Interestingly, we also found that the core microbiome of MHC heterozygotes tends to reflect a more integrated network of species.