Roux-en-Y gastric bypass surgery decreases intestinal aryl hydrocarbon receptor signaling in male mice

The impact of Roux-en-Y gastric bypass (RYGB) on indole metabolism and AhR signaling is poorly understood. Therefore, we tested the hypothesis that RYGB changes the indole metabolite profile in the gut, leading to changes in AhR signaling. To test this hypothesis, we developed a mouse model of RYGB that recapitulates the human procedure. Given that indole metabolism is influenced by body weight, we included sham-operated control mice that were either fed ad libitum (S-AL) or food restricted to match body weight to RYGB (S-WM). We measured weight- and surgery-dependent changes to glucose metabolism, indole metabolism, and AhR activation. RYGB-operated mice exhibited body weight-independent improvements in glucose tolerance, insulin, and glucagon-like peptide-1 secretion. Plasma levels of indole-3-propionic acid (I3PA) and kynurenic acid (KA) were reduced in RYGB mice compared to S-WM mice, but not S-AL mice. However, the S-WM group exhibited a trend for increased I3PA and KA compared to S-AL. Consistent with the reduction in indoles, RYGB reduced AhR signaling and increased lipocalin-2 expression, a marker of inflammation. These data suggest that indole metabolites do not contribute to the metabolic benefits of RYGB, but their reduction may contribute to increases in gut inflammation after RYGB.