Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB120

Poster Communications

Taurodeoxycholate inhibits ion secretion via basolateral TGR5 receptors on L-cells in mouse ileal and colonic mucosae.

H. Cox1, I. R. Tough1

1. Wolfson CARD, King's College London, London, United Kingdom.


Bile acids (BAs) are released into the duodenum to facilitate absorption of dietary fat and reabsorbed via the enterocyte apical bile salt transporter, ASBT, primarily in the ileum but also in the colon. The BAs cell-surface receptor, TGR5 is expressed by L cells that are found throughout the intestinal tract and release postprandially the satiety and incretin hormones peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), respectively (1). PYY and GLP-1 are released following intrarectal infusion of taurocholate in diabetic patients (2) and by taurodeoxycholate (TDCL) stimulation of isolated L cells (3), thus TGR5 is a putative target for antiobesity and type 2 diabetes agents. Recently we observed antisecretory responses to apically (ap) or basolaterally (bl) added TGR5 agonist in mouse colon mucosa, similar to glucose-dependent, PYY-mediated, GPR119 responses (4). However, unlike GPR119, a latency in ap responses was noted. Here we investigated the effect of TDLC on ion secretion in muscle-stripped terminal ileum or distal colon mucosa from C57Bl6/129Sv mice (>10 weeks, male and female), voltage-clamped in Ussing chambers as described previously (4). Mucosae were prestimulated with vasoactive intestinal polypeptide (10 nM) prior to ap or bl additions of TDLC (10 µM -1 mM), with responses measured as changes in short-circuit current (Isc). Values were pooled from mucosal responses in different animals and expressed as means±1S.E.M., compared using Student's t test or ANOVA. TDCL (ap) responses were monophasic and reduced Isc whereas bl responses were biphasic, with primary increases followed by decreases in Isc. ASBT1 blockade with 10 µM GSK2330672 (5) blunted ap TDCL (100 µM) responses from -13.4±1.0 µA.cm-2 to -3.5±1.0 µA.cm-2 (n=4; p<0.001) in terminal ileum and from -21.0±1.7 µA.cm-2 to -8.3±2.4 µA.cm-2 (n=5; p<0.01) in distal colon. TDLC antisecretory responses were concentration-dependent in distal colon (ap and bl pEC50 values: 4.0±0.1 and 4.1±0.1, with maximal Isc reductions of -32.2±1.7 µA.cm-2 and -49.1±1.7 µA.cm-2, respectively), whereas no maximum response was reached for bl secretory responses. Additionally, bl responses were unaffected by TTX (100 nM) pretreatment; however, the PYY Y1 receptor blocker BIBO3304 (300 nM) potentiated the secretory phase (from 12.7±4.7 to 38.1±5.8 µA.cm-2; n=5, p<0.01) and abolished the secondary phase (from -36.9±7.2 to -2.0±0.9 µA.cm-2; n=5, p<0.001). Furthermore, replacement of apical glucose with mannitol attenuated the bl antisecretory phase (from -36.1±1.6 to -11.1±3.7 µA.cm-2; n=5, p<0.001) in distal colon. We conclude that in the mouse intestine, ap transported BAs stimulate TGR5 on the bl membranes of L cells to cause glucose-dependent release of PYY, which subsequently has a paracrine antisecretory action via Y1 receptors.

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