Natural microbiota confer life-long protection against obesity via an early-life, immune-mediated effect on brown adipocytes.

Obesity, a major risk factor for metabolic disease, has increased in industrialized nations alongside a reduction in gut microbiota diversity. Reconstituting laboratory mice with complex, natural microbiota and commensals from wild mice resulted in protection against diet-induced obesity. These natural microbiota reduced weight gain in both male and female mice of different genetic backgrounds throughout their life and increased energy expenditure. Single-nuclei RNA sequencing identified a dominant adipocyte population in brown adipose tissue (BAT) with a transcriptional signature of increased thermogenic activity, while white adipose tissue mass and beiging were reduced. Protection against diet-induced obesity was transferable to adult germ-free mice via exposure to natural microbiota, indicating an association with the timing of immune response induction rather than BAT developmental programming. However, protection against diet-induced obesity did not require type 2 immune signaling, as shown in STAT6 knockout mice. Rather, it was associated with increased levels of chemokines and monocytes in BAT in early life, pointing to a role of infiltrating myeloid cells. Indeed, CCR2-deficient mice with natural microbiota lacked the BAT transcriptional signature of increased thermogenic activity, increased energy expenditure, and protection against diet-induced obesity that wild-type mice with natural microbiota exhibited. The latter was restored upon injection with wild-type bone marrow. Taken together, these findings identify a novel microbiota‒immune‒adipose tissue axis that results in increased BAT thermogenesis and improved energy balance throughout life.