Leaky Gut as a Potential Culprit for the Paradoxical Dysglycemic Response to Gastric Bypass-Associated Ileal Microbiota

Abstract

Altered host-intestinal microbiota interactions are increasingly implicated in the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We previously found, however, that RYGB-associated ileal microbiota can paradoxically impair host glycemic control when transferred to germ-free mice. Here we present complementary evidence suggesting that this could be due to the heightened development of systemic endotoxemia. Consistently, application of ileal content from RYGB-treated compared with sham-operated rats onto Caco-2 cell monolayers compromised barrier function and decreased expression of the barrier-stabilizing proteins claudin-4 and desmoglein-2. Our findings raise the possibility that RYGB-associated ileal microbiota produce and release soluble metabolites which locally increase intestinal permeability to promote systemic endotoxemia-induced insulin resistance, with potential implications for the treatment of RYGB patients who eventually relapse onto type 2 diabetes.

Questioning the foundations of the gut microbiota and obesity

“…More recent research has not supported the hypothesis; a transfer of gut microbiota from the caecum of rats following RYGB surgery into germ-free mice failed to produce a difference in percentage body fat gain despite the successful establishment of transplanted microbiota [18]. Another similar study in 2021 transferred colonic microbiota from rats six weeks after RYGB surgery into germ-free mice and reported that body weights were similar between recipient groups [19]. A well-described recent study in 2022 transplanted the faecal microbiota from human patients before and after two different types of gastric weight loss surgery into mice with differences in particular bacterial genera between different groups of recipient mice [20].…”

Novel Insights into the Physiology of Nutrient Sensing and Gut-Brain Communication in Surgical and Experimental Obesity Therapy

“…For example, a study on Zucker fatty rats found that RYGB causes major shifts in the microbiota across the small and large intestine [37]. Interestingly, transplanting ileal microbiota from RYGB-operated rats to germ-free mice worsened oral glucose tolerance [37], likely due to the generation of metabolites that disrupt the intestinal epithelial barrier and trigger systemic endotoxemia [38]. On the other hand, transplanting colonic microbiota of RYGB-operated rats to germ-free mice improved oral glucose tolerance, possibly by stabilizing the intestinal epithelial barrier through increased bile acid receptor FXR signaling via the generation of secondary bile acids [39].…”

Building and breaking the gut barrier with bariatric surgery

“…Reminiscent of the studies of Blanchard et al [6] and Jin et al [8], ileal content of RYGB-treated rats caused the opposite effect of content from the other gut regions. That is, it increased paracellular permeability in Caco-2 cells and heightend endotoxemia in germ-free mice [10]. The former effect was associated with a strong reduction in the tight junction protein claudin-4 and the adherens junction protein desmoglein-2 [10] in Caco-2 cells.…”

“…That is, it increased paracellular permeability in Caco-2 cells and heightend endotoxemia in germ-free mice [10]. The former effect was associated with a strong reduction in the tight junction protein claudin-4 and the adherens junction protein desmoglein-2 [10] in Caco-2 cells. The implications of these findings are unclear, but raise the possiblity that during relapse of type 2 diabetes in the significant proportion of patients after RYGB the barrier-disruptive ileal microbiota expand thereby exerting a dominant (negative) effect on endotoxemia (Figure 1).…”

“…In a subsequent study by Hankir et al [10], content from the remaining section of the gut, i.e. the ileum, of RYGB-treated and sham-operated rats was investigated.…”