Arresting microbiome development limits immune system maturation and resistance to infection

Abstract

Disruptions to the intestinal microbiome during weaning lead to long-term negative effects on host immune function. However, the critical host-microbe interactions occurring during weaning required for healthy immune system development remain poorly understood. We find that restricting microbiome maturation during weaning leads to stunted immune system development and increased susceptibility to enteric infection. We developed a gnotobiotic mouse model of the early-life microbiome designated as Pediatric Community (PedsCom). This nine-member consortium of microbes derived from intestinal microbiomes of preweaning mice stably colonized germfree adult mice and was efficiently transmitted to offspring for multiple generations. Unexpectedly, the relative abundance of PedsCom microbes were largely unaffected by the transition from a milk-based to a fiber rich solid food diet. PedsCom mice developed less peripheral regulatory T cells and Immunoglobulin A, hallmarks of microbiota-driven immune system development. Consistent with defects in maturation, adult PedsCom mice retain high susceptibility to salmonella infection characteristic of young mice and humans. Altogether, our work illustrates how the post-weaning transition in intestinal microbiome composition contributes to normal immune maturation and protection from enteric infection. Accurate modelling of the pre-weaning microbiome provides a window into the microbial requirements of healthy immune development and suggests an opportunity to design microbial interventions at weaning to improve immune system development in human infants.

Modulation of adaptive immune responses by Akkermansia muciniphila is restricted to an early life window in NOD mice

“…Importantly, A. muciniphila was associated with lower risk of progression to T1D in the TEDDY trial 4 and murine studies implicated this microbe in decreasing T1D rates in NOD mice 15,16 ; however, the specific mechanisms by which it functions in NOD mice remain poorly understood. We determined that the ability of A. muciniphila to enhance RORγ + Foxp3 + Treg induction and commensal-targeting systemic antibody production are age restricted in NOD mice, with preweaning exposure to A. muciniphila being necessary for the microbe to modulate these immune responses in the context of a defined set of 9 bacteria that models the early-life microbiome 46 . Additionally, we demonstrated that the presence of A. muciniphila enhances antibody responses to Staphylococcus species in NOD mice colonized with PedsCom.…”

“…The isolators were independently tested for contamination quarterly by Charles River Laboratories (NJ, USA). PedsCom NOD and C57BL/6J mice were generated as previously described 46 . Gnotobiotic mice were transferred sterilely to autoclaved cages containing the same bedding and food as isolator cages and housed outside isolators during experiments that required colonizing with A. muciniphila .…”

“…Gnotobiotic models, which allow microbial communities to be rationally designed, are valuable tools for studying the impact of individual microbes on the host 17 and examining the dynamics between specific microbes [42][43][44][45] . Since A. muciniphila colonizes well in early life when the immune system is most malleable, we introduced A. muciniphila into a pediatric microbiota model developed by our laboratory called Pediatric Community or PedsCom 46 . This model is comprised of 9 microbes (Table S1) that represent over 90% of the bacterial reads in pre-weaning mice in our specific pathogen free (SPF) NOD colony.…”

Using the canine microbiome to bridge translation of cancer immunotherapy from pre-clinical murine models to human clinical trials

“…However, this germ-free environment also leads to significant impairment of immune system development and responses. For example, mice raised in sterile conditions develop higher levels of IgE and fail to induce the same levels of immune reactivity seen during the "weaning period" of wild-type mice (20)(21)(22)(23). This results in susceptibility to certain bacteria and increased risk of immunopathologies, complications which are not resolved with instillation of an "adult" or "wild-type" microbiome (21,22,24).…”

“…For example, mice raised in sterile conditions develop higher levels of IgE and fail to induce the same levels of immune reactivity seen during the "weaning period" of wild-type mice (20)(21)(22)(23). This results in susceptibility to certain bacteria and increased risk of immunopathologies, complications which are not resolved with instillation of an "adult" or "wild-type" microbiome (21,22,24). Additionally, mouse studies of the microbiome show a large genetic influence which is distinct from humans where <10% of taxa are thought to be heritable (24-28).…”