Long-chain unsaturated free fatty acids control gut motility via nitrergic ganglia of the enteric nervous system
Abstract
Although mechanical tension from luminal distension is a primary regulator of gut motility, we reveal a parallel chemosensory pathway wherein long-chain unsaturated free fatty acids (LUFFAs) from dietary or enterobacterial sources directly modulate gastrointestinal motor function. Using ex vivo and in vivo contractility assays in human and murine intestinal tissues, we found that LUFFAs, particularly Omega-3 fatty acids, suppressed spontaneous contractions and delayed intestinal transit in a double bond-dependent manner. Mechanistically, selective activation of free fatty acid receptor 1/4 (FFAR1/4) on nitrergic myenteric ganglia triggered a rise in intracellular calcium and nitric oxide release, inducing smooth muscle relaxation independent of epithelial signaling. Genetic ablation of Ffar4 in enteric neurons or defect in enteric nitrergic ganglia abolished LUFFAs-mediated motility suppression and ameliorated colonic dysmotility induced by pathologically elevated LUFFAs levels. Our findings establish nitrergic ganglia as critical chemosensors translating dietary or enterobacterial lipid signals into gut motor responses.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Jun-Hao Zhang
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Zhi-Hui Jiang
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Ji Xuan
Research Institute of General Surgery and Department of Gastroenterology, Jinling Hospital, Medical School of Nanjing University
Yang Liao
Center for Water and Ecology, State Key Laboratory of Regional Environment and Sustainability, School of Environment
Peng-Peng Li
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Ye Wang
Han Wang
Tian-Tian Qiu
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Ze-Xu Chen
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Ke-Hui Qiu
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Yu-Wei Zhou
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Jing-Xin Ye
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Jian-Feng Gong
Research Institute of General Surgery and Department of Gastroenterology, Jinling Hospital, Medical School of Nanjing University
Jun Jiang
State Key Laboratory of Precision and Intelligent Chemistry, Hefei National Research Center for Physical Sciences at the Microscale, School of Chemistry and Materials Science
Ling Ni
Research Institute of General Surgery and Department of Gastroenterology, Jinling Hospital, Medical School of Nanjing University
Hong-Feng Ma
Department of Rehabilitation Medicine, Huzhou Rehabilitation Hospital
Xue-Na Zhang
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Hua-Qun Chen
Life Science School of Nanjing Normal University
Min-Sheng Zhu
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory for Molecular Medicine and Department of Neurology of Nanjing Drum Tower Hospital, Medical School of Nanjing University
Xin Chen