ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Science 2019;365:eaat9351.

As in humans, weight gain in mice leads to fatty liver disease, inflammatory adipose tissue, and insulin resistance. The depletion of the microbiota through antibiotic treatment rescued this weight gain. The cohousing of T-Myd88–/– mice transferred the weight gain to wild-type mice. The major feature of the microbiota formed within T-Myd88–/– mice was a reduction in Clostridia colonization.

The microbiota has emerged as a key regulator of metabolism within the mammalian host, and the composition of the microbiota in obese individuals is sufficient to confer metabolic defects when transferred into mice. Reductions in the gene richness of the microbiota have been reported during the metabolic syndrome including decreased butyrate and methane production, while, some microbiota functions are enhanced, such as hydrogen sulfide and mucus degradation.

Gut immune responses are critical in regulating the composition of the microbiota. Young mice whose T cells have disabled Myd88 signaling (T-Myd88–/– mice) exhibit reduced follicular T cell responses and defective IgA targeting of their gut bacteria. Mice depleted of the innate adaptor molecule T-Myd88 developed many of the metabolic disease comorbidities found in humans, including visible weight gain in middle-age between 5 and 6 months of age.

What is the role of inflammatory responses during obesity? During weight, within the adipose tissue gain macrophage infiltrate and there is a reduction in regulatory T cells. Such suboptimal immune response is associated with the metabolic syndrome and obesity. Obese adults show a decrease in immune response to immunizations, increased incidence of infection, and reduced mucosal IgG levels. The links between defective immune reactions and the metabolic syndrome are unclear. T cell–dependent events are required to prevent disease, and replacement of Clostridia rescued obesity. Inappropriate immunoglobulin A targeting of Clostridia and increased Desulfovibrio antagonized the colonization of beneficial Clostridia.

We now learn that mice defective in T follicular helper cell and gut IgA production develop the metabolic syndrome with age, they gain more weight, accumulate more fat, and show greater insulin resistance compared with controls. Their IgA inaptly targets Clostridia which enhances host lipid absorption by modulating CD36 expression.

In conclusion, gut bacteria can differentially regulate lipid metabolism. Products secreted by Desulfovibrio up-regulate CD36 expression, whereas products produced by Clostridia can down-regulate CD36 expression. Therefore, the loss of organisms that function to temper CD36 expression may lead to the inappropriate absorption of lipids, which accumulate over time, leading to obesity and the metabolic syndrome.