Short‐chain fatty acid sensing in rat duodenum

  • Yasutada Akiba
    Greater Los Angeles Veterans Affairs Healthcare System, 11301 Wilshire Boulevard Los Angeles CA 90073 USA
  • Takuya Inoue
    Department of Medicine, University of California Los Angeles CA 90095 USA
  • Izumi Kaji
    Department of Medicine, University of California Los Angeles CA 90095 USA
  • Masaaki Higashiyama
    Department of Medicine, University of California Los Angeles CA 90095 USA
  • Kazuyuki Narimatsu
    Department of Medicine, University of California Los Angeles CA 90095 USA
  • Ken‐ichi Iwamoto
    Laboratory of Organic Chemistry School of Pharmaceutical Science 52‐1 Yada, Suruga‐ku Shizuoka 422‐8526 Japan
  • Masahiko Watanabe
    Department of Anatomy Hokkaido University Graduate School of Medicine Kita 15, Nishi 7 Kita‐ku Sapporo 060‐8638 Japan
  • Paul H. Guth
    Greater Los Angeles Veterans Affairs Healthcare System, 11301 Wilshire Boulevard Los Angeles CA 90073 USA
  • Eli Engel
    Department of Anatomy Hokkaido University Graduate School of Medicine Kita 15, Nishi 7 Kita‐ku Sapporo 060‐8638 Japan
  • Atsukazu Kuwahara
    Laboratory of Physiology Institute for Environmental Science University of Shizuoka 52‐1 Yada, Suruga‐ku Shizuoka 422‐8526 Japan
  • Jonathan D Kaunitz
    Greater Los Angeles Veterans Affairs Healthcare System, 11301 Wilshire Boulevard Los Angeles CA 90073 USA

抄録

<jats:sec><jats:title>Key points</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item><jats:p>Luminal lipid in the duodenum modulates gastroduodenal functions via the release of gut hormones and mediators such as cholecystokinin and 5‐HT.</jats:p></jats:list-item> <jats:list-item><jats:p>The effects of luminal short‐chain fatty acids (SCFAs) in the foregut are unknown.</jats:p></jats:list-item> <jats:list-item><jats:p>Free fatty acid receptors (FFARs) for long‐chain fatty acids (LCFAs) and SCFAs are expressed in enteroendocrine cells. SCFA receptors, termed FFA2 and FFA3, are expressed in duodenal enterochromaffin cells and L cells, respectively.</jats:p></jats:list-item> <jats:list-item><jats:p>Activation of LCFA receptor (FFA1) and presumed FFA3 stimulates duodenal HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> secretion via a glucagon‐like peptide (GLP)‐2 pathway, whereas FFA2 activation induces HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> secretion via muscarinic and 5‐HT<jats:sub>4</jats:sub> receptor activation.</jats:p></jats:list-item> <jats:list-item><jats:p>The presence of SCFA sensing in the duodenum with GLP‐2 and 5‐HT signals further supports the hypothesis that luminal SCFA in the foregut may contribute towards the generation of functional symptoms.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec><jats:sec><jats:title>Abstract</jats:title><jats:p>Intraduodenal fatty acids (FA) and bacterial overgrowth, which generate short‐chain FAs (SCFAs), have been implicated in the generation of functional dyspepsia symptoms. We studied the mechanisms by which luminal SCFA perfusion affects duodenal HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> secretion (DBS), a measure of mucosal neurohumoral activation. Free fatty acid receptor (FFAR) 1 (FFA1), which binds long‐chain FA (LCFA), and SCFA receptors FFA2 and FFA3 were immunolocalised to duodenal enteroendocrine cells. FFA3 colocalised with glucagon‐like peptide (GLP)‐1, whereas FFA2 colocalised with 5‐HT. Luminal perfusion of the SCFA acetate or propionate increased DBS, enhanced by dipeptidyl peptidase‐IV (DPPIV) inhibition, at the same time as increasing GLP‐2 portal blood concentrations. Acetate‐induced DBS was partially inhibited by monocarboxylate/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> exchanger inhibition without affecting GLP‐2 release, implicating acetate absorption in the partial mediation of DBS. A selective FFA2 agonist dose‐dependently increased DBS, unaffected by DPPIV inhibition or by cholecystokinin or 5‐HT<jats:sub>3</jats:sub> receptor antagonists, but was inhibited by atropine and a 5‐HT<jats:sub>4</jats:sub> antagonist. By contrast, a selective FFA1 agonist increased DBS accompanied by GLP‐2 release, enhanced by DPPIV inhibition and inhibited by a GLP‐2 receptor antagonist. Activation of FFA1 by LCFA and presumably FFA3 by SCFA increased DBS via GLP‐2 release, whereas FFA2 activation stimulated DBS via muscarinic and 5‐HT<jats:sub>4</jats:sub> receptor activation. SCFA/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> exchange also appears to be present in the duodenum. The presence of duodenal fatty acid sensing receptors that signal hormone release and possibly signal neural activation may be implicated in the pathogenesis of functional dyspepsia.</jats:p></jats:sec>

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