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The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

ABSTRACT: Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

SUBMITTER: Mohr S

PROVIDER: S-EPMC8358858 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

Mohr Sandra S Fritz Nikola N Hammer Christian C Martínez Cristina C Martínez Cristina C Berens Sabrina S Schmitteckert Stefanie S Wahl Verena V Schmidt Malin M Houghton Lesley A LA Goebel-Stengel Miriam M Kabisch Maria M Götze Dorothea D Milovač Irina I D'Amato Mauro M Zheng Tenghao T Röth Ralph R Mönnikes Hubert H Engel Felicitas F Gauss Annika A Tesarz Jonas J Raithel Martin M Andresen Viola V Frieling Thomas T Keller Jutta J Pehl Christian C Stein-Thöringer Christoph C Clarke Gerard G Kennedy Paul J PJ Cryan John F JF Dinan Timothy G TG Quigley Eamonn M M EMM Spiller Robin R Beltrán Caroll C Madrid Ana María AM Torres Verónica V Pérez de Arce Edith E Herzog Wolfgang W Mayer Emeran A EA Sayuk Gregory G Gazouli Maria M Karamanolis George G Kapur-Pojskič Lejla L Bustamante Mariona M Rabionet Raquel R Estivil Xavier X Franke André A Lieb Wolfgang W Boeckxstaens Guy G Wouters Mira M MM Simrén Magnus M Rappold Gudrun A GA Vicario Maria M Santos Javier J Schaefert Rainer R Lorenzo-Bermejo Justo J Niesler Beate B

Journal of cellular and molecular medicine 20210624 16

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and ...[more]

PMID: 34165249

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Project description:Background & aimsIncreased colonic serotonin (5-HT) level and decreased serotonin reuptake transporter (SERT) expression in irritable bowel syndrome (IBS) may contribute to diarrhea and visceral hypersensitivity. We investigated whether mucosal SERT is modulated by gut microbiota via a mast cell-prostaglandin E2 (PGE2) pathway.MethodsC57Bl/6 mice received intracolonic infusion of fecal supernatant (FS) from healthy controls or patients with diarrhea-predominant irritable bowel syndrome (IBS-D). The role of mast cells was studied in mast cell-deficient mice. Colonic organoids and/or mast cells were used for in vitro experiments. SERT expression was measured by quantitative polymerase chain reaction and Western blot. Visceromotor responses to colorectal distension and colonic transit were assessed.ResultsIntracolonic infusion of IBS-D FS in mice caused an increase in mucosal 5-HT compared with healthy control FS, accompanied by ∼50% reduction in SERT expression. Mast cell stabilizers, cyclooxygenase-2 inhibitors, and PGE2 receptor antagonist prevented SERT downregulation. Intracolonic infusion of IBS-D FS failed to reduce SERT expression in mast cell-deficient (W/Wv) mice. This response was restored by mast cell reconstitution. The downregulation of SERT expression evoked by IBS FS was prevented by lipopolysaccharide (LPS) antagonist LPS from Rhodobacter sphaeroides and a bacterial trypsin inhibitor. In vitro LPS treatment caused increased cyclooxygenase-2 expression and PGE2 release from cultured mouse mast cells. Intracolonic infusion of IBS-D FS in mice reduced colonic transit, increased fecal water content, and increased visceromotor responses to colorectal distension. Ondansetron prevented these changes.ConclusionsFecal LPS acting in concert with trypsin in patients with IBS-D stimulates mucosal mast cells to release PGE2, which downregulates mucosal SERT, resulting in increased mucosal 5-HT. This may contribute to diarrhea and abdominal pain common in IBS.

Dataset Information

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

Publications

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

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