The gut peptide Reg3g links the small intestine microbiome to the regulation of energy balance, glucose levels, and gut function

Changing composition of the gut microbiome is an important component of the gut adaptation to various environments, which have been implicated in various metabolic diseases including obesity and type 2 diabetes, but the mechanisms by which the microbiota influence host physiology remain contentious. Here we find that both diets high in the fermentable fiber inulin and vertical sleeve gastrectomy increase intestinal expression and circulating levels of the anti-microbial peptide Reg3g. Moreover, a number of beneficial effects of these manipulations on gut function, energy balance, and glucose regulation are absent in Reg3g knockout mice. Peripheral administration of various preparations of Reg3g improves glucose tolerance, and this effect is dependent on the putative receptor Extl3 in the pancreas. These data suggest Reg3g acts both within the lumen and as a gut hormone to link the intestinal microbiome to various aspects of host physiology that may be leveraged for novel treatment strategies. [Display omitted] •Reg3g is required for metabolic benefits of surgical or dietary interventions•Surgical or dietary intervention improves gut function in a Reg3g-dependent manner•Alteration of microbiome composition can provoke Reg3g in the system•Pharmacological application of Reg3g improves glucose tolerance in DIO mice Shin et al. find that both surgical and dietary gut manipulations increase the gut peptide Reg3g and require Reg3g for their beneficial effects on body weight, glucose levels, and gut function. Reg3g may also act as a gut hormone since systemic administration improves glucose regulation via actions on the pancreas.