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Intestinal epithelial adaptations to vertical sleeve gastrectomy defined at single-cell resolution

ABSTRACT: The gut plays a key role in regulating metabolic health. Dietary factors disrupt intestinal physiology and contribute to obesity and diabetes, whereas bariatric procedures such as vertical sleeve gastrectomy (VSG) cause gut adaptations that induce robust metabolic improvements. However, our understanding of these adaptations at the cellular and molecular levels remains limited. In a validated murine model, we leverage single-cell transcriptomics to determine how VSG impacts different cell lineages of the small intestinal epithelium. We define cell type-specific genes and pathways that VSG rescues from high-fat diet perturbation and characterize additional rescue-independent changes brought about by VSG. We show that Paneth cells have increased expression of the gut peptide Reg3g after VSG. We also find that VSG restores pathways pertaining to mitochondrial respiration and cellular metabolism, especially within crypt-based cells. Overall, our study provides unprecedented molecular resolution of VSG’s therapeutic effects on the gut epithelium.

ORGANISM(S): Mus musculus

PROVIDER: GSE234189 | GEO | 2024/03/27

REPOSITORIES: GEO

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Project description:Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective long-term metabolic improvements in individuals with obesity and/or Type 2 diabetes. These powerful effects of manipulating the gastrointestinal tract point to an important role of gastrointestinal signals in regulating both energy balance and metabolism. To that end, we have used mouse models of VSG to identify key gut signals that mediate these beneficial effects. Previous data from our rodent model of VSG led us to hypothesize a potential role for the hormone Fibroblast-Growth Factor15/19 (mouse/human ortholog) which pharmacologically can regulate many aspects of energy homeostasis and glucose handling. FGF15 is expressed in ileal enterocytes of the small intestine and is released postprandially. Like many other gut hormones, postprandial plasma concentrations of the human ortholog FGF19 and ileal FGF15 expression in mice increase after VSG. We generated intestinal-specific FGF15 knock out (VilCreERT2; Fgf15f/f) mice and controls, which were maintained on 60% high-fat diet. VSG resulted in increased plasma bile acid levels. However, intestinal-specific FGF15 knock out mice had considerably higher levels of circulating total and hydrophobic bile acids after VSG. Unlike what we had predicted, intestinal-specific FGF15 knock out mice lost more weight after VSG as a result of increased lean tissue loss compared to control mice. Further, the loss of bone mineral density and bone marrow adipose tissue observed after VSG in control mice was even greater in intestinal-specific FGF15 knock out mice, perhaps secondary to anemia and elevated erythropoietin/FGF23. Finally the effect of VSG to improve glucose tolerance and to reduce hepatic cholesterol was also absent in intestinal-specific FGF15 knock out mice. These data point to an important role for intestinal FGF15 to protect the organism from deleterious effects of bile acid toxicity after VSG.

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Intestinal epithelial adaptations to vertical sleeve gastrectomy defined at single-cell resolution

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