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Microbiota‐Derived Metabolites Associated with Metabolic Improvements after Gastric Bypass Surgery and their Effects on Intestinal Cells in vitro
Author(s) -
Jennis Matthew,
Mabus John R,
Cavanaugh Cassandre R.,
Leo Gregory,
Lenhard James,
Hornby Pamela J
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.720.3
Subject(s) - metabolite , medicine , endocrinology , tryptophan , chemistry , intestinal permeability , type 2 diabetes mellitus , barrier function , type 2 diabetes , serotonin , gastric bypass surgery , diabetes mellitus , obesity , pharmacology , biochemistry , biology , gastric bypass , amino acid , weight loss , receptor , microbiology and biotechnology
Gastric Bypass surgery (RYGB) improves glycemic control in obese patients with Type 2 Diabetes (T2DM) by multiple mechanisms, including increased incretins (Reed et al., J Clin Endocrinol Metab 2011). Despite the known RYGB changes in intestinal microbial communities, limited information exists on either the impact of bacterially‐derived metabolites on host metabolism, or their potential mechanisms in T2DM and obesity. To address this, metabolomic data that was generated from the same RYGB study were analyzed by PLS‐DA loadings plot to identify differences in microbial‐related metabolites from lean controls, obese and T2DM obese patients pre‐ and post‐surgery (n ~ 9/group). Next, selected metabolites were incubated with human intestinal T‐84 polarized cell monolayers to determine alterations in permeability/barrier function and gene expression. in addition, monolayers were incubated (24 h) in the presence or absence of stressors to increase permeability (e.g. interferon‐gamma, IFNγ) as an in vitro model of metabolic endotoxemia. Our results demonstrate that bacterially‐derived indoles metabolized from the tryptophan/serotonin pathway (e.g. Indole‐3‐propionic acid, IPA and indoxyl sulphuric acid, ISA) were decreased in obese/T2DM patients, compared to lean, and this was reversed by RYGB. In T‐84 polarized cell monolayers, IFNγ increased intestinal permeability 2–4 fold whereas IPA and serotonin reversed this shift. Serotonin was associated with transcriptional increases (e.g.Muc2, Ocln, Slc10A2, Ccbl1 and glutaminase) and decreases (e.g. Slc2a5, IDO1, and G6PC). In conclusion, microbial‐derived metabolite associations with T2DM and their reversal by RYGB have been identified. Furthermore, these metabolites affect intestinal permeability and gene expression for junctional, glucogenic, glutaminolytic or lipogenic proteins. The results are being confirmed in 3D intestinal organoids for further translation and will identify novel targets within the tryptophan/serotonin pathway for therapeutic assessment in i n vivo animal models of diabetes and obesity.