{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:57:12Z","timestamp":1792051032157,"version":"4.4.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T00:00:00Z","timestamp":1721174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Constipation is a prevalent gastrointestinal disorder affecting approximately 15% of the global population, leading to significant healthcare burdens. Emerging evidence suggests that gut microbiota plays a pivotal role in the pathogenesis of constipation, although causality remains uncertain due to potential confounding factors in observational studies. This study aims to clarify the causal relationships between gut microbiota and constipation using a bidirectional Mendelian Randomization (MR) approach, which helps to overcome confounding issues and reverse causality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Utilizing data from genome-wide association studies (GWAS) from the MiBioGen consortium and other sources, we identified genetic variants as instrumental variables (IVs) for 196 bacterial traits and constipation. These IVs were rigorously selected based on their association with the traits and absence of linkage with confounding factors. We applied several MR methods, including Inverse Variance Weighted (IVW), MR Egger, and MR-PRESSO, to examine the causal effects in both directions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analysis revealed a significant causal relationship where specific bacterial taxa such as <jats:italic>Coprococcus1<\/jats:italic> (OR\u2009=\u20090.798, 95%CI: 0.711\u20130.896, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001), <jats:italic>Coprococcus3<\/jats:italic> (OR\u2009=\u20090.851, 95%CI: 0.740\u20130.979, <jats:italic>p<\/jats:italic>\u2009=\u20090.024), <jats:italic>Desulfovibrio<\/jats:italic> (OR\u2009=\u20090.902, 95%CI: 0.817\u20130.996, <jats:italic>p<\/jats:italic>\u2009=\u20090.041), <jats:italic>Flavonifracto<\/jats:italic>r (OR\u2009=\u20090.823, 95%CI: 0.708\u20130.957, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001), and <jats:italic>Lachnospiraceae UCG004<\/jats:italic>, whereas others including <jats:italic>Ruminococcaceae UCG005<\/jats:italic> (OR\u2009=\u20091.127, 95%CI: 1.008\u20131.261, <jats:italic>p<\/jats:italic>\u2009=\u20090.036), <jats:italic>Eubacterium nodatum group<\/jats:italic> (OR\u2009=\u20091.080, 95%CI: 1.018\u20131.145, <jats:italic>p<\/jats:italic>\u2009=\u20090.025), <jats:italic>Butyricimonas<\/jats:italic> (OR\u2009=\u20091.118, 95%CI: 1.014\u20131.233, <jats:italic>p<\/jats:italic>\u2009=\u20090.002), and <jats:italic>Bacteroidetes<\/jats:italic> (OR\u2009=\u20091.274, 95%CI: 1.014\u20131.233, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001) increase constipation risk. In the reverse MR analysis, constipation was found to influence the abundance of certain taxa, including <jats:italic>Family XIII<\/jats:italic>, <jats:italic>Porphyromonadaceae<\/jats:italic>, <jats:italic>Proteobacteria<\/jats:italic>, <jats:italic>Lentisphaeria<\/jats:italic>, <jats:italic>Veillonellaceae<\/jats:italic>, <jats:italic>Victivallaceae<\/jats:italic>, <jats:italic>Catenibacterium<\/jats:italic>, <jats:italic>Sellimonas<\/jats:italic>, and <jats:italic>Victivallales<\/jats:italic>, indicating a bidirectional relationship. Sensitivity analyses confirmed the robustness of these findings, with no evidence of heterogeneity or horizontal pleiotropy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The relationship between our study gut microbiota and constipation interacts at the genetic level, which gut microbiota can influence the onset of constipation, and constipation can alter the gut microbiota. <jats:italic>Coprococcus1<\/jats:italic>, <jats:italic>Coprococcus3<\/jats:italic>, <jats:italic>Desulfovibrio<\/jats:italic>, <jats:italic>Flavonifractor<\/jats:italic> and <jats:italic>Lachnospiraceae UCG004<\/jats:italic> play a protective role against constipation, while <jats:italic>Ruminococcaceae UCG005<\/jats:italic>, <jats:italic>Eubacterium nodatum group<\/jats:italic>, <jats:italic>Butyricimonas<\/jats:italic>, and <jats:italic>Bacteroidetes<\/jats:italic> are associated with an increased risk. In addition, constipation correlates positively with the abundance of <jats:italic>Family XIII<\/jats:italic>, <jats:italic>Porphyromonadaceae<\/jats:italic> and <jats:italic>Proteobacteria<\/jats:italic>, while negatively with <jats:italic>Lentisphaeria<\/jats:italic>, <jats:italic>Veillonellaceae<\/jats:italic>, <jats:italic>Victivallaceae<\/jats:italic>, <jats:italic>Catenibacterium<\/jats:italic>, <jats:italic>Sellimonas<\/jats:italic>, and <jats:italic>Victivallales<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmicb.2024.1438778","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T04:59:36Z","timestamp":1721192376000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Causal relationship between gut microbiota and constipation: a bidirectional Mendelian randomization study"],"prefix":"10.3389","volume":"15","author":[{"given":"Cuncheng","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanzhuang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqi","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1007\/s00018-018-2943-4","article-title":"An insight into gut microbiota and its functionalities","volume":"76","author":"Adak","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"261","DOI":"10.15386\/mpr-1222","article-title":"The economic burden of constipation therapy","volume":"92","author":"Albu","year":"2019","journal-title":"Med. Pharm. Rep."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2560","DOI":"10.1111\/j.1572-0241.2005.00230.x","article-title":"Interactions between commensal bacteria and gut sensorimotor function in health and disease","volume":"100","author":"Barbara","year":"2005","journal-title":"Am. J. Gastroenterol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1053\/j.gastro.2019.12.034","article-title":"Mechanisms, evaluation, and management of chronic constipation","volume":"158","author":"Bharucha","year":"2020","journal-title":"Gastroenterology"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.chom.2018.05.004","article-title":"Gut microbiota-produced tryptamine activates an epithelial G-protein-coupled receptor to increase colonic secretion","volume":"23","author":"Bhattarai","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"14302","DOI":"10.1101\/cshperspect.a041302","article-title":"Mendelian randomization","volume":"12","author":"Birney","year":"2022","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1177\/0962280215597579","article-title":"A review of instrumental variable estimators for Mendelian randomization","volume":"26","author":"Burgess","year":"2017","journal-title":"Stat. Methods Med. Res."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1111\/j.1365-2036.2012.05007.x","article-title":"Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome","volume":"35","author":"Chassard","year":"2012","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1007\/s00394-021-02649-2","article-title":"Dietary inflammatory index and its relationship with gut microbiota in individuals with intestinal constipation: a cross-sectional study","volume":"61","author":"Costa","year":"2022","journal-title":"Eur. J. Nutr."},{"key":"ref10","author":"Diaz","year":"2024"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"484","DOI":"10.3945\/an.116.014407","article-title":"Mechanisms of action of probiotics and the gastrointestinal microbiota on gut motility and constipation","volume":"8","author":"Dimidi","year":"2017","journal-title":"Adv. Nutr."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1007\/s00248-021-01796-7","article-title":"Bacteria and methanogens in the human microbiome: a review of syntrophic interactions","volume":"83","author":"Djemai","year":"2022","journal-title":"Microb. Ecol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"16568","DOI":"10.1021\/acs.jafc.3c04150","article-title":"Broccoli-derived exosome-like nanoparticles alleviate Loperamide-induced constipation, in correlation with regulation on gut microbiota and tryptophan metabolism","volume":"71","author":"Duan","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"956528","DOI":"10.3389\/fcimb.2022.956528","article-title":"Abnormal bile acid metabolism is an important feature of gut microbiota and fecal metabolites in patients with slow transit constipation","volume":"12","author":"Fan","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"6484","DOI":"10.1080\/21655979.2021.1973356","article-title":"The mechanism of intestinal flora dysregulation mediated by intestinal bacterial biofilm to induce constipation","volume":"12","author":"Fu","year":"2021","journal-title":"Bioengineered"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"367","DOI":"10.5056\/jnm18071","article-title":"Role of gut microbiota-gut hormone Axis in the pathophysiology of functional gastrointestinal disorders","volume":"24","author":"Fukui","year":"2018","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"105","DOI":"10.12938\/bmfh.2020-073","article-title":"Efficacy of Bifidobacterium bifidum G9-1 in improving quality of life in patients with chronic constipation: a prospective intervention study","volume":"40","author":"Fuyuki","year":"2021","journal-title":"Biosci. Microbiota Food Health"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1007\/s12664-018-0901-6","article-title":"A randomized double-blind placebo-controlled trial showing rifaximin to improve constipation by reducing methane production and accelerating colon transit: a pilot study","volume":"37","author":"Ghoshal","year":"2018","journal-title":"Indian J. Gastroenterol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"163","DOI":"10.2217\/fmb-2019-0283","article-title":"The composition of intestinal microbiota and its association with functional constipation of the elderly patients","volume":"15","author":"Guo","year":"2020","journal-title":"Future Microbiol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.14309\/ajg.0000000000001708","article-title":"Burden of constipation: looking beyond bowel movements","volume":"117","author":"Harris","year":"2022","journal-title":"Am. J. Gastroenterol."},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.2867-23","article-title":"Management of chronic constipation: a comprehensive review","author":"Hojo","year":"2023","journal-title":"Intern. Med."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1126\/science.291.5505.881","article-title":"Molecular analysis of commensal host-microbial relationships in the intestine","volume":"291","author":"Hooper","year":"2001","journal-title":"Science"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"8850","DOI":"10.1039\/D1FO01125A","article-title":"Fruits and their impact on the gut microbiota, gut motility and constipation","volume":"12","author":"Katsirma","year":"2021","journal-title":"Food Funct."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"111","DOI":"10.5056\/jnm14048","article-title":"Change of fecal flora and effectiveness of the short-term VSL#3 probiotic treatment in patients with functional constipation","volume":"21","author":"Kim","year":"2015","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s41588-020-00763-1","article-title":"Large-scale association analyses identify host factors influencing human gut microbiome composition","volume":"53","author":"Kurilshikov","year":"2021","journal-title":"Nat. Genet."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"2197837","DOI":"10.1080\/19490976.2023.2197837","article-title":"Effects of dietary fibers or probiotics on functional constipation symptoms and roles of gut microbiota: a double-blinded randomized placebo trial","volume":"15","author":"Lai","year":"2023","journal-title":"Gut Microbes"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"9879","DOI":"10.1038\/s41598-017-10663-w","article-title":"Unveiling the gut microbiota composition and functionality associated with constipation through metagenomic analyses","volume":"7","author":"Mancabelli","year":"2017","journal-title":"Sci. Rep."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"755","DOI":"10.18553\/jmcp.2013.19.9.755","article-title":"A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation","volume":"19","author":"Nellesen","year":"2013","journal-title":"J. Manag. Care Pharm."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1111\/j.1469-7793.1999.0533t.x","article-title":"Characteristics of mucosally projecting myenteric neurones in the guinea-pig proximal colon","volume":"517","author":"Neunlist","year":"1999","journal-title":"J. Physiol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"581","DOI":"10.3390\/healthcare9050581","article-title":"Association between anticholinergic burden and constipation: a systematic review","volume":"9","author":"Rodriguez-Ramallo","year":"2021","journal-title":"Healthcare (Basel)"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"3253","DOI":"10.1681\/ASN.2016010098","article-title":"Mendelian randomization as an approach to assess causality using observational data","volume":"27","author":"Sekula","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1177\/1756283X11417483","article-title":"The LUCK study: laxative usage in patients with GP-diagnosed constipation in the UK, within the general population and in pregnancy. An epidemiological study using the general practice research database (GPRD)","volume":"4","author":"Shafe","year":"2011","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/0306-9877(89)90016-9","article-title":"Primary constipation: an underlying mechanism","volume":"28","author":"Sikirov","year":"1989","journal-title":"Med. Hypotheses"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1080\/19490976.2018.1546522","article-title":"Hydrogen cross-feeders of the human gastrointestinal tract","volume":"10","author":"Smith","year":"2019","journal-title":"Gut Microbes"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"777961","DOI":"10.3389\/fmed.2021.777961","article-title":"Gut metagenome as a potential diagnostic and predictive biomarker in slow transit constipation","volume":"8","author":"Tian","year":"2021","journal-title":"Front. Med. (Lausanne)"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"2055","DOI":"10.14309\/ajg.0000000000001997","article-title":"Methanogens and hydrogen sulfide producing bacteria guide distinct gut microbe profiles and irritable bowel syndrome subtypes","volume":"117","author":"Villanueva-Millan","year":"2022","journal-title":"Am. J. Gastroenterol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1111\/j.1365-2036.2007.03376.x","article-title":"The burden of constipation on quality of life: results of a multinational survey","volume":"26","author":"Wald","year":"2007","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1117905","DOI":"10.3389\/fmicb.2023.1117905","article-title":"Enteric nervous system damage caused by abnormal intestinal butyrate metabolism may lead to functional constipation","volume":"14","author":"Wang","year":"2023","journal-title":"Front. Microbiol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1152435","DOI":"10.3389\/fpsyt.2023.1152435","article-title":"Association between constipation and major depression in adult Americans: evidence from NHANES 2005-2010","volume":"14","author":"Wang","year":"2023","journal-title":"Front. Psychiatry"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.1039\/D1FO03896F","article-title":"A randomised, double-blind, placebo-controlled trial of Bifidobacterium bifidum CCFM16 for manipulation of the gut microbiota and relief from chronic constipation","volume":"13","author":"Wang","year":"2022","journal-title":"Food Funct."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3390\/nu15071779","article-title":"Characteristics of the gut microbiome and serum metabolome in patients with functional constipation","volume":"15","author":"Wang","year":"2023","journal-title":"Nutrients"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"6899","DOI":"10.1007\/s00253-022-12197-2","article-title":"Gut microbiota: a new avenue to reveal pathological mechanisms of constipation","volume":"106","author":"Yang","year":"2022","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e0235985","DOI":"10.1371\/journal.pone.0235985","article-title":"Characterization of gut contractility and microbiota in patients with severe chronic constipation","volume":"15","author":"Yarullina","year":"2020","journal-title":"PLoS One"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"102371","DOI":"10.1016\/j.eclinm.2023.102371","article-title":"Constipation preceding depression: a population-based cohort study","volume":"67","author":"Yun","year":"2024","journal-title":"EClinicalMedicine"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1093\/gastro\/goab035","article-title":"Role of gut microbiota in functional constipation","volume":"9","author":"Zhang","year":"2021","journal-title":"Gastroenterol. Rep. 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