GPR41 deficiency alters the gut microbiota-bile acid axis, reduces ileal expression of Npc1l1, and attenuates hypercholesterolemia in male mice.

Hypercholesterolemia contributes to the development of atherosclerosis and is a major risk factor for cardiovascular diseases (CVD). Dietary fiber can attenuate CVD, at least in part, by serving as a fermentable substrate for gut bacteria, leading to the production of short-chain fatty acids (SCFAs), such as butyrate and propionate, which have been linked to atheroprotective effects. SCFAs are sensed by G-protein coupled receptors including GPR41, GPR43, and GPR109A. To explore the role of these receptors in hypercholesterolemia and CVD, we examined atherosclerosis progression and lipid metabolism in Gpr41-/-, Gpr43-/-, and Gpr109a-/- mice using a proprotein convertase subtilisin/kexin type 9 adeno-associated virus (PCSK9-AAV) model of hypercholesterolemia. Deficiency of any single SCFA receptor did not significantly affect atherosclerotic plaque burden compared with wild-type (WT) littermates. However, male Gpr41-/- mice exhibited decreased gonadal fat, plasma triacylglycerol, and low-density lipoprotein cholesterol levels compared to their WT littermates. GPR41 deficiency in males was also associated with increased cecal propionate levels, reduced ileal expression of nutrient transporters such as Npc1l1 and a trend toward increased gut motility. In addition, male Gpr41-/- mice displayed altered gut microbiota composition and lower levels of microbially generated bile acids relative to their WT counterparts. Together, these findings highlight GPR41 as a key intestinal chemosensor regulating nutrient uptake, lipid storage, and microbiota composition.