The intestinal microbiota have been proposed as one of the causally contributing factors to the current obesity pandemic. A dearth of safe and effective approaches to the therapy of obesity points to the need for clearer definition of the mechanisms underlying the development of obesity and its clinically significant sequelae. The role of the intestinal microbiota in the development of obesity (and its sequelae) is an area of research that is particularly marked by a lack of mechanistic insight. We sought to more clearly define the mechanistic contribution of the intestinal microbiota to the development and maintenance of obesity and its sequelae, by examining its mediate effects on the immune system.
In particular, we addressed the role of Segmented Filamentous Bacteria (SFB), a specific constituent of the intestinal microbiota with defined immunostimulatory properties, in the development and maintenance of obesity and in the progression of a particular sequelum of obesity, non-alcoholic steatohepatitis. Our data indicate that SFB provides modest protection from the development and maintenance of obesity, but this was mostly evident only in the setting of severe monogenic obesity. Colonization with SFB also exacerbated the progression from benign non-alcoholic steatosis to non-alcoholic steatohepatitis, with attendant hepatocellular damage. Further, SFB colonization additively contributed to elevations in the serum level of IL-17A, a cytokine that exacerbates the progression to non-alcoholic steatohepatitis.
Parallel investigation of an endogenous negative regulator of the response to pro-inflammatory bacterial products provided a means to address the role of microbiota-mediated immune modulation in a less specific context. Data presented here indicate that RP105, an endogenous negative regulator of TLR signaling, also regulated the development of diet-induced obesity (DIO) and its sequelae. When subjected to high fat diet (HFD) stress, RP105-/- mice gained significantly less weight and were thereby protected from the metabolic and end-organ sequelae of obesity. Phenotypic characterization of this response revealed that this effect was mediated via increased adaptive thermogenesis. At the cellular level, RP105 regulated the recruitment of thermogenic capacity in brown adipose tissue (BAT). Surprisingly, the critical locus mediating such regulation by RP105 was neither its expression by hematopoietic cells nor cell-autonomous expression in thermogenic tissues. These findings led us to BAFF, a “B-cell” cytokine that is predominately derived from non-hematopoietic sources during homeostasis. RP105-/- mice exhibit augmented BAFF expression. Such BAFF overexpression was also found to be associated with protection from obesity in several additional models, including B-cell deficient (μMT) mice, BAFF-transgenic mice and TACI-deficient mice, with an approximate log-linear dose response in terms of the effect of serum BAFF concentration on weight gain. Converging lines of evidence suggest that RP105 deletion and BAFF overexpression regulate energy metabolism by modulating adaptive thermogenesis.
Taken together, these studies help to define the contribution of microbiota-mediated modulation of the immune system to the development of obesity and its sequelae.