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      Lactobacillus rhamnosus Strains Relieve Loperamide-Induced Constipation via Different Pathways Independent of Short-Chain Fatty Acids

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          Abstract

          Increasing researches have confirmed the relationship between slow-transit constipation and gut microbiota dysbiosis. Many population and animal experiments have identified probiotics as effectors for the relief of constipation symptoms, but the specific mechanism remains unclear. In this intervention study, Lactobacillus rhamnosus strains isolated from five different sources were administered to mice with loperamide-induced constipation, and the impacts of these strains on constipation-related indicators were evaluated. All five strains of L. rhamnosus were found to improve constipation to various degrees. However, contrary to previous studies, the abilities of L. rhamnosus strains to improve constipation symptoms were not associated with the levels of short-chain fatty acids (SCFAs) in the colon. The effects of different strains of L. rhamnosus on constipation relief were associated with different aspects of the GI tract, including gastrointestinal regulatory peptides, neurotransmitters, neurotrophic factors, and gut microbiota. The findings of this study demonstrate that L. rhamnosus strains can alleviate constipation-related symptoms via different pathways independent of SCFAs regulation. This study yields a new perspective for clinical use of probiotics to better improve constipation symptoms, by combining strains with different mechanisms for alleviation of constipation.

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          Most cited references29

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          Meta-analyses of human gut microbes associated with obesity and IBD.

          Recent studies have linked human gut microbes to obesity and inflammatory bowel disease, but consistent signals have been difficult to identify. Here we test for indicator taxa and general features of the microbiota that are generally consistent across studies of obesity and of IBD, focusing on studies involving high-throughput sequencing of the 16S rRNA gene (which we could process using a common computational pipeline). We find that IBD has a consistent signature across studies and allows high classification accuracy of IBD from non-IBD subjects, but that although subjects can be classified as lean or obese within each individual study with statistically significant accuracy, consistent with the ability of the microbiota to experimentally transfer this phenotype, signatures of obesity are not consistent between studies even when the data are analyzed with consistent methods. The results suggest that correlations between microbes and clinical conditions with different effect sizes (e.g. the large effect size of IBD versus the small effect size of obesity) may require different cohort selection and analysis strategies.
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            Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion

            Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the physiologic effect of tryptamine in the gastrointestinal (GI) tract remains unknown. Here, we show that the biological effects of tryptamine are mediated through the 5-HT4 receptor (5-HT4R), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium. Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, consistent with increased intestinal secretion. The secretory effect of tryptamine is dependent on 5-HT4R activation and is blocked by 5-HT4R antagonist and absent in 5-HT4R-/- mice. GF mice colonized by Bacteroides thetaiotaomicron engineered to produce tryptamine exhibit accelerated GI transit. Our study demonstrates an aspect of host physiology under control of a bacterial metabolite that can be exploited as a therapeutic modality. VIDEO ABSTRACT.
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              Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats.

              We studied whether physiological concentration of short-chain fatty acids (SCFAs) affects colonic transit and colonic motility in conscious rats. Intraluminal administration of SCFAs (100-200 mM) into the proximal colon significantly accelerated colonic transit. The stimulatory effect of SCFAs on colonic transit was abolished by perivagal capsaicin treatment, atropine, hexamethonium, and vagotomy, but not by guanethidine. The stimulatory effect of SCFAs on colonic transit was also abolished by intraluminal pretreatment with lidocaine and a 5-hydroxytryptamine (HT)(3) receptor antagonist. Intraluminal administration of SCFAs provoked contractions at the proximal colon, which migrated to the mid- and distal colon. SCFAs caused a significant increase in the luminal concentration of 5-HT of the vascularly isolated and luminally perfused rat colon ex vivo. It is suggested that the release of 5-HT from enterochromaffin cells in response to SCFAs stimulates 5-HT(3) receptors located on the vagal sensory fibers. The sensory information is transferred to the vagal efferent and stimulates the release of acetylcholine from the colonic myenteric plexus, resulting in muscle contraction.
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                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                19 August 2020
                2020
                : 10
                : 423
                Affiliations
                [1] 1State Key Laboratory of Food Science and Technology, Jiangnan University , Wuxi, China
                [2] 2School of Food Science and Technology, Jiangnan University , Wuxi, China
                [3] 3Department of Gastroenterology, The Affiliated Wuxi Second People's Hospital of Nanjing Medical University , Wuxi, China
                [4] 4International Joint Research Laboratory for Probiotics, Jiangnan University , Wuxi, China
                [5] 5(Yangzhou) Institute of Food Biotechnology, Jiangnan University , Yangzhou, China
                [6] 6National Engineering Research Center for Functional Food, Jiangnan University , Wuxi, China
                [7] 7Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch , Wuxi, China
                [8] 8Beijing Innovation Centre of Food Nutrition and Human Health, Beijing Technology and Business University , Beijing, China
                Author notes

                Edited by: Nicholas Zachos, Johns Hopkins University, United States

                Reviewed by: Kristina Marie Feye, University of Arkansas, United States; David R. Brown, University of Minnesota Twin Cities, United States

                *Correspondence: Gaojue Wu wugaojue@ 123456aliyun.com

                This article was submitted to Microbiome in Health and Disease, a section of the journal Frontiers in Cellular and Infection Microbiology

                Article
                10.3389/fcimb.2020.00423
                7466723
                32974216
                a6b76464-94bb-484d-af22-b4198ebf0b44
                Copyright © 2020 Wang, Yang, Sun, Si, Wang, Zhang, Wu, Zhao, Zhang and Chen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 October 2019
                : 10 July 2020
                Page count
                Figures: 7, Tables: 1, Equations: 1, References: 40, Pages: 14, Words: 7898
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 31530056
                Award ID: 31671839
                Funded by: Fundamental Research Funds for the Central Universities 10.13039/501100012226
                Award ID: JUSRP51501
                Funded by: Natural Science Foundation of Jiangsu Province 10.13039/501100004608
                Award ID: BK20180613
                Funded by: Postdoctoral Science Foundation of Jiangsu Province 10.13039/501100010246
                Award ID: 2018K090C
                Categories
                Cellular and Infection Microbiology
                Original Research

                Infectious disease & Microbiology
                slow transit constipation,lactobacillus rhamnosus,serotonin,neurotrophic factor,short-chain fatty acids,gut microbiota

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