Effects of Chang-Kang-Fang Formula on the Microbiota-Gut-Brain Axis in Rats With Irritable Bowel Syndrome
Chang-Kang-Fang formula (CKF), a multi-herb traditional Chinese medicine, has been used in clinical settings to treat irritable bowel syndrome (IBS). Recent studies show that 5.0 g/kg/d CKF can alleviate the symptoms of IBS rats by modulating the brain-gut axis through the production of brain-gut pe...
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Frontiers Media S.A.
2022-05-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.778032/full |
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| author | Xiwen Ling Siyuan Peng Jingbin Zhong Lirong Guo Yaqin Xu Xiaobao Jin Fujiang Chu |
| author_facet | Xiwen Ling Siyuan Peng Jingbin Zhong Lirong Guo Yaqin Xu Xiaobao Jin Fujiang Chu |
| author_sort | Xiwen Ling |
| collection | DOAJ |
| description | Chang-Kang-Fang formula (CKF), a multi-herb traditional Chinese medicine, has been used in clinical settings to treat irritable bowel syndrome (IBS). Recent studies show that 5.0 g/kg/d CKF can alleviate the symptoms of IBS rats by modulating the brain-gut axis through the production of brain-gut peptides (BGPs), thus relieving pain, and reversing the effects of intestinal propulsion disorders. However, the exact mechanisms underlying the therapeutic effects of CKF in IBS remain unclear. The microbiota-gut-brain axis (MGBA) is central to the pathogenesis of IBS, regulating BGPs, depression-like behaviors, and gut microbiota. Given that CKF ameliorates IBS via the MGBA, we performed metabolomic analyses, evaluated the gut microbiota, and system pharmacology to elucidate the mechanisms of action of CKF. The results of intestinal tract motility, abdominal withdrawal reflex (AWR), sucrose preference test (SPT), and the forced swimming test (FST) showed that the male Sprague–Dawley rats subjected to chronic acute combining stress (CACS) for 22 days exhibited altered intestinal motility, visceral hypersensitivity, and depression-like behaviors. Treatment of IBS rats with CKF normalized dysfunctions of CACS-induced central and peripheral nervous system. CKF regulated BDNF and 5-HT levels in the colon and hippocampus as well as the expressions of the related BGP pathway genes. Moreover, the system pharmacology assays were used to assess the physiological targets involved in the action of CKF, with results suggesting that CKF putatively functioned through the 5-HT-PKA-CREB-BDNF pathway. LC-MS-based metabolomics identified the significantly altered 5-HT pathway-related metabolites in the CKF treatment group, and thus, the CKF-related signaling pathways were further examined. After pyrosequencing-based analysis of bacterial 16S rRNA (V3 + V4 region) using rat feces, the Lefse analysis of gut microbiota suggested that CKF treatment could induce structural changes in the gut microbiota, thereby regulating it by decreasing Clostridiales, and the F-B ratio while increasing the levels of Lactobacillus. Furthermore, the integrated analysis showed a correlation of CKF-associated microbes with metabolites. These findings showed that CKF effectively alleviated IBS, which was associated with the altered features of the metabolite profiles and the gut microbiota through a bidirectional communication along the microbiota-gut-brain axis. |
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| spelling | doaj.art-1933a68735ca4a028283235bb66ef1282022-12-22T00:41:13ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-05-011310.3389/fphar.2022.778032778032Effects of Chang-Kang-Fang Formula on the Microbiota-Gut-Brain Axis in Rats With Irritable Bowel SyndromeXiwen Ling0Siyuan Peng1Jingbin Zhong2Lirong Guo3Yaqin Xu4Xiaobao Jin5Fujiang Chu6Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou Higher Education Mega Center, Guangdong Pharmaceutical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou Higher Education Mega Center, Guangdong Pharmaceutical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou Higher Education Mega Center, Guangdong Pharmaceutical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou Higher Education Mega Center, Guangdong Pharmaceutical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou Higher Education Mega Center, Guangdong Pharmaceutical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou Higher Education Mega Center, Guangdong Pharmaceutical University, Guangzhou, ChinaChang-Kang-Fang formula (CKF), a multi-herb traditional Chinese medicine, has been used in clinical settings to treat irritable bowel syndrome (IBS). Recent studies show that 5.0 g/kg/d CKF can alleviate the symptoms of IBS rats by modulating the brain-gut axis through the production of brain-gut peptides (BGPs), thus relieving pain, and reversing the effects of intestinal propulsion disorders. However, the exact mechanisms underlying the therapeutic effects of CKF in IBS remain unclear. The microbiota-gut-brain axis (MGBA) is central to the pathogenesis of IBS, regulating BGPs, depression-like behaviors, and gut microbiota. Given that CKF ameliorates IBS via the MGBA, we performed metabolomic analyses, evaluated the gut microbiota, and system pharmacology to elucidate the mechanisms of action of CKF. The results of intestinal tract motility, abdominal withdrawal reflex (AWR), sucrose preference test (SPT), and the forced swimming test (FST) showed that the male Sprague–Dawley rats subjected to chronic acute combining stress (CACS) for 22 days exhibited altered intestinal motility, visceral hypersensitivity, and depression-like behaviors. Treatment of IBS rats with CKF normalized dysfunctions of CACS-induced central and peripheral nervous system. CKF regulated BDNF and 5-HT levels in the colon and hippocampus as well as the expressions of the related BGP pathway genes. Moreover, the system pharmacology assays were used to assess the physiological targets involved in the action of CKF, with results suggesting that CKF putatively functioned through the 5-HT-PKA-CREB-BDNF pathway. LC-MS-based metabolomics identified the significantly altered 5-HT pathway-related metabolites in the CKF treatment group, and thus, the CKF-related signaling pathways were further examined. After pyrosequencing-based analysis of bacterial 16S rRNA (V3 + V4 region) using rat feces, the Lefse analysis of gut microbiota suggested that CKF treatment could induce structural changes in the gut microbiota, thereby regulating it by decreasing Clostridiales, and the F-B ratio while increasing the levels of Lactobacillus. Furthermore, the integrated analysis showed a correlation of CKF-associated microbes with metabolites. These findings showed that CKF effectively alleviated IBS, which was associated with the altered features of the metabolite profiles and the gut microbiota through a bidirectional communication along the microbiota-gut-brain axis.https://www.frontiersin.org/articles/10.3389/fphar.2022.778032/fullChang-Kang-Fang formulaMGBAIBSgut microbiotametabonomicsnetwork pharmacology |
| spellingShingle | Xiwen Ling Siyuan Peng Jingbin Zhong Lirong Guo Yaqin Xu Xiaobao Jin Fujiang Chu Effects of Chang-Kang-Fang Formula on the Microbiota-Gut-Brain Axis in Rats With Irritable Bowel Syndrome Frontiers in Pharmacology Chang-Kang-Fang formula MGBA IBS gut microbiota metabonomics network pharmacology |
| title | Effects of Chang-Kang-Fang Formula on the Microbiota-Gut-Brain Axis in Rats With Irritable Bowel Syndrome |
| title_full | Effects of Chang-Kang-Fang Formula on the Microbiota-Gut-Brain Axis in Rats With Irritable Bowel Syndrome |
| title_fullStr | Effects of Chang-Kang-Fang Formula on the Microbiota-Gut-Brain Axis in Rats With Irritable Bowel Syndrome |
| title_full_unstemmed | Effects of Chang-Kang-Fang Formula on the Microbiota-Gut-Brain Axis in Rats With Irritable Bowel Syndrome |
| title_short | Effects of Chang-Kang-Fang Formula on the Microbiota-Gut-Brain Axis in Rats With Irritable Bowel Syndrome |
| title_sort | effects of chang kang fang formula on the microbiota gut brain axis in rats with irritable bowel syndrome |
| topic | Chang-Kang-Fang formula MGBA IBS gut microbiota metabonomics network pharmacology |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.778032/full |
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