A Weaning Reaction to Microbiota Is Required for Resistance to Immunopathologies in the Adult

From time to time, these GEITP pages have covered articles on the gut microbiome. It is now appreciated that — if our entire body were examined for total DNA content — more than 90% of all DNA would be found to be derived from the bacteria that live on and in us! This remarkable bacterial community participates in metabolism of food and the production of essential compounds [including vitamins, short-chain fatty acids (SCFAs), and secondary bile acids], as well as playing a role in the immune response and host-mediated defense against pathogens. It has been proposed that the intestinal microbiota behaves like an organ, producing microbial components and metabolites that are involved in many processes of the animal host; this includes influencing the metabolism of drugs and other environmental toxicants.

Shortly after birth, the colonizing microbiota is known to be shaped — by the dietary and immunological components of the milk, which includes maternal-derived immunoglobulin A (IgA), and follows a developmental process characterized by the presence of age-specific

bacterial species. During weaning, introduction of solid foods into the infant’s diet leads to a new phase in the development of the microbiota — characterized by a large increase in bacterial numbers, and evolution toward the composition (profile) that will be associated with adult individuals, and further influenced by ethnicity, gender, diet, drugs (especially antibiotics) being taken, climate, and individual genetic architecture of related family members.

The period between birth and weaning also witnesses important changes in the intestinal immune system. Populations of fetus-derived T cells, innate lymphoid cells (ILCs), and myeloid cells are progressively replaced by cells generated in the bone marrow and thymus after birth. Moreover, the colonizing microbiota induces the generation and expansion of effector and regulatory T cells (Tregs) and ILCs, as well as formation of isolated lymphoid follicles that produce antimicrobial IgA (i.e. important changes in the intestine occur after birth and during weaning, changes that link the development of the microbiota with the development of the immune system).

Authors [see attached article] examined the reactivity of the mouse intestinal immune system during the first weeks after birth, and into adulthood. At weaning, the intestinal microbiota induced a vigorous immune response — a ‘‘weaning reaction’’ — that was programmed in time. Inhibition of the weaning reaction led to pathological imprinting and increased susceptibility to colitis, allergic inflammation, and cancer later in life. Prevention of this pathological imprinting was associated with the generation of RORgt+ regulatory T cells, which required bacterial and dietary metabolites — short-chain fatty acids and retinoic acid. Therefore, the weaning reaction to microbiota is required for immune ontogeny, perturbation of which leads to increased susceptibility to immunopathologies later in life. Wow. Although these studies were performed in mice, it is likely that very similar events occur in the human.


Immunity 21 May 2o19; 50: 1-13

This entry was posted in Center for Environmental Genetics. Bookmark the permalink.