Maddux, S. | bioRxiv Science

bioRxiv2022

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

Early life microbiota drive immune system development and influence risk for immune dysfunction later in life, including the development of type 1 diabetes (T1D). Which specific early-life microbes modulate diabetes risk and the timing of these critical interactions are not well understood. To address this gap in knowledge, we screened for microbes that induce systemic IgG1 responses in young NOD mice. We isolated a strain of Akkermansia muciniphila that potently induces systemic IgG1 antibodies and peripheral regulatory T cells (pTregs). Since this mucus-degrading commensal protects NOD mice from T1D and is associated with lower risk of developing T1D in children, we investigated how A. muciniphila impacts early-life host-commensal interactions using gnotobiotic NOD mice colonized with a defined 9-member bacterial consortium that models the early life microbiome. We find that A. muciniphila potently induces pTregs and enhances antibody responses to other commensal microbes. Remarkably, these effects only occur when A. muciniphila colonizes NOD mice prior to weaning, establishing that the specific window of exposure to A. muciniphila shapes adaptive immune system development in diabetes-susceptible NOD mice. This time dependence provides important evidence that early-life exposure may enhance microbiota-based therapies to prevent T1D. One Sentence SummaryAkkermansia muciniphila induces peripheral Tregs and enhances antibody responses to itself and other commensals during an early life window.

immunology↗

bioRxiv2022

Arresting microbiome development limits immune system maturation and resistance to infection.

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. One Sentence SummaryArresting microbiome development stunts immune ontogeny

immunology↗