Acarbose Primarily Targets Intracellular GH97 Enzymes in Bacteroides to Impair Their Growth

ABSTRACT: The type 2 diabetes drug acarbose inhibits starch breakdown into glucose by host gluco(amylases) in the upper gastrointestinal tract. Acarbose is poorly absorbed by host tissue and transits to the large intestine with undigested starch. Numerous gut species in the Bacteroides genus break down starch but decrease in relative abundance in acarbose treated individuals. To mechanistically explain this observation, we used two model Bacteroides, Bacteroides ovatus (Bo) and Bacteroides thetaiotaomicron (Bt). Bt growth is severely impaired by acarbose whereas Bo growth is not. The Bacteroides use a starch utilization system (Sus) to grow on starch. We hypothesized that Bo and Bt Sus enzymes are differentially inhibited by acarbose and identified the periplasmic enzymes BoGH97CSus and SusB as the primer acarbose phenotype drivers. But, they do not explain the differential growth inhibition in Bo and Bt. Instead, acarbose affects starch processing at multiple points by competing for transport through the Sus beta-barrel proteins and binding to the Sus transcriptional regulators. Bo expresses a non-Sus GH97, BoGH97D, when grown in starch with acarbose. The Bt homolog, BtGH97H, is not expressed in the same conditions. Bt, however, does not benefit from overexpressing BoGH97D when exposed to acarbose. Though we predicted that acarbose exerts its effects on Bacteroides via enzyme inhibition, the drug interferes with multiple components of Sus to likely decrease bacterial fitness in the human gut. This work informs how acarbose exerts its beneficial effects on the microbiota and can be used to predict microbiota responsiveness to the drug.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Bacteroides Ovatus Atcc 8483

SUBMITTER: Nicole Koropatkin  

LAB HEAD: Nicole Koropatkin

PROVIDER: PXD052070 | Pride | 2024-10-18

REPOSITORIES: Pride