The serotonin receptor 3E variant is a risk factor for female IBS-D

Abstract

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.

Different regulatory mechanisms of Na+/ glucose transport in mouse ileum and jejunum

“…Rather, we revealed that the 5-HT4R/cAMP/PKA pathway negatively regulated ileal glucose absorption, consistent with previous reports that cAMP/PKA inhibited NHE3 to regulate SGLT1 activity in mouse ileum [37,25,24]. High levels of 5-HT in the gastrointestinal tract are associated with diarrhea-related celiac disease, irritable bowel syndrome, and carcinoid syndrome [7,13]. 5-HT has a propulsive effect on the gastrointestinal tract.…”

Cytolethal distending toxin B inoculation leads to distinct gut microtypes and IBS-D-like microRNA-mediated gene expression changes in a rodent model

“…Moreover, a serotonin receptor 3E variant was recently implicated as a risk factor for female IBS-D subjects who exhibited downregulated transcript levels in the colon. 64 Interestingly, Htr1b – a similar serotonin receptor – was significantly downregulated in the E. coli microtype in this study and was a predicted target of multiple miRNAs, such as miR-29a-3p. Further, tachykinin family members Tac3 and Tac1 (a substance P precursor closely associated with regulation of gastrointestinal motility, secretion, and pain sensitivity), and the miRNAs miR-17-5p, miR-423-5p, miR-324-3p and miR-99a-3p (predicted to interact with pain-associated targets) were dysregulated in both the Desulfovibrio and E. coli microtypes, suggesting that pain-related pathways might be a common signature in both microtypes.…”