{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:06:55Z","timestamp":1791270415219,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,14]],"date-time":"2021-11-14T00:00:00Z","timestamp":1636848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Although high-fat diet (HFD)-related dysbiosis is involved in the development of steatohepatitis, its pathophysiology especially in the small intestine remains unclear. We comprehensively investigated not only the liver pathology but also the microbiome profile, mucosal integrity and luminal environment in the small intestine of mice with HFD-induced obesity. C57BL\/6J mice were fed either a normal diet or an HFD, and their small-intestinal contents were subjected to microbial 16S rDNA analysis. Intestinal mucosal permeability was evaluated by FITC-dextran assay. The levels of bile acids in the small-intestinal contents were measured by liquid chromatography\/mass spectrometry. The expression of tight junction molecules, antimicrobial peptides, lipopolysaccharide and macrophage marker F4\/80 in the small intestine and\/or liver was examined by real-time RT-PCR and immunohistochemistry. The abundance of Lactobacillus was markedly increased and that of Clostridium was drastically decreased in the small intestine of mice fed the HFD. The level of conjugated taurocholic acid was significantly increased and those of deconjugated cholic acid\/secondary bile acids were conversely decreased in the small-intestinal contents. The expression of occludin, antimicrobial Reg III\u03b2\/\u03b3 and IL-22 was significantly decreased in the small intestine of HFD-fed mice, and the intestinal permeability was significantly accelerated. Infiltration of lipopolysaccharide was significantly increased in not only the small-intestinal mucosa but also the liver of HFD-fed mice, and fat drops were apparently accumulated in the liver. Pathophysiological alteration of the luminal environment in the small intestine resulting from a HFD is closely associated with minimal inflammation involving the gut-liver axis through disturbance of small-intestinal mucosal integrity.<\/jats:p>","DOI":"10.3390\/cells10113168","type":"journal-article","created":{"date-parts":[[2021,11,14]],"date-time":"2021-11-14T20:48:36Z","timestamp":1636922916000},"page":"3168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Effect of a High-Fat Diet on the Small-Intestinal Environment and Mucosal Integrity in the Gut-Liver Axis"],"prefix":"10.3390","volume":"10","author":[{"given":"Takashi","family":"Nakanishi","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Fukui","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2126-3013","authenticated-orcid":false,"given":"Shin","family":"Nishiumi","sequence":"additional","affiliation":[{"name":"Department of Omics Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Yokota","sequence":"additional","affiliation":[{"name":"R&D Center, Biofermin Pharmaceutical Co., Ltd., Kobe 651-2242, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Makizaki","sequence":"additional","affiliation":[{"name":"R&D Center, Biofermin Pharmaceutical Co., Ltd., Kobe 651-2242, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"R&D Center, Biofermin Pharmaceutical Co., Ltd., Kobe 651-2242, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Ohno","sequence":"additional","affiliation":[{"name":"R&D Center, Biofermin Pharmaceutical Co., Ltd., Kobe 651-2242, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1283-9009","authenticated-orcid":false,"given":"Toshihiko","family":"Tomita","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6949-932X","authenticated-orcid":false,"given":"Tadayuki","family":"Oshima","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroto","family":"Miwa","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1038\/ismej.2013.80","article-title":"Dysbiosis in inflammatory bowel diseases: The oxygen hypothesis","volume":"7","year":"2013","journal-title":"ISME J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137rv6","DOI":"10.1126\/scitranslmed.3004244","article-title":"Therapeutic modulation of microbiota\u2013host metabolic interactions","volume":"4","author":"Holmes","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1172\/JCI76738","article-title":"Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease","volume":"125","author":"Jiang","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20858","DOI":"10.1073\/pnas.0808723105","article-title":"Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface","volume":"105","author":"Vaishnava","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/nm1663","article-title":"TLR4 enhances TGF-beta signaling and hepatic fibrosis","volume":"13","author":"Seki","year":"2007","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8500","DOI":"10.1038\/s41598-019-44994-7","article-title":"Effects of different diets on microbiota in the small intestine mucus and weight regulation in rats","volume":"9","author":"Meng","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1053\/j.gastro.2009.08.042","article-title":"High-fat diet determines the composition of the murine gut microbiome independently of obesity","volume":"137","author":"Hildebrandt","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"G367","DOI":"10.1152\/ajpgi.00232.2016","article-title":"Involvement of gut microbiota in association between GLP-1\/GLP-1 receptor expression and gastrointestinal motility","volume":"312","author":"Yang","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ran, Y., Fukui, H., Xu, X., Wang, X., Ebisutani, N., Tanaka, Y., Maeda, A., Makizaki, Y., Ohno, H., and Kondo, T. (2020). Alteration of colonic mucosal permeability during antibiotic-induced dysbiosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176108"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/bjc.2014.336","article-title":"IL-22 produced by cancer-associated fibroblasts promotes gastric cancer cell invasion via STAT3 and ERK signaling","volume":"111","author":"Fukui","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12384","DOI":"10.1038\/s41598-018-30943-3","article-title":"Effect of probiotic Bifidobacterium bifidum G9-1 on the relationship between gut microbiota profile and stress sensitivity in maternally separated rats","volume":"8","author":"Fukui","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1128\/AEM.70.1.167-173.2004","article-title":"Quantitative PCR with 16S rRNA-gene-targeted species-specific primers for analysis of human intestinal bifidobacteria","volume":"70","author":"Matsuki","year":"2004","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kawahara, T., Makizaki, Y., Oikawa, Y., Tanaka, Y., Maeda, A., Shimakawa, M., Komoto, S., Moriguchi, K., Ohno, H., and Taniguchi, K. (2017). Oral administration of Bifidobacterium bifidum G9-1 alleviates rotavirus gastroenteritis through regulation of intestinal homeostasis by inducing mucosal protective factors. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173979"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4381","DOI":"10.1038\/s41598-019-40978-9","article-title":"Alteration of GLP-1\/GPR43 expression and gastrointestinal motility in dysbiotic mice treated with vancomycin","volume":"9","author":"Xu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.12938\/bmfh.19-023","article-title":"Interaction of the microbiota with the human body in health and diseases","volume":"39","author":"Yildiz","year":"2020","journal-title":"Biosci. Microbiota Food Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nmeth.f.303","article-title":"QIIME allows analysis of high-throughput community sequencing data","volume":"7","author":"Caporaso","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.trsl.2016.03.007","article-title":"Role of regenerating gene I in claudin expression and barrier function in the small intestine","volume":"173","author":"Kitayama","year":"2016","journal-title":"Transl. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cmet.2013.03.013","article-title":"Pleiotropic roles of bile acids in metabolism","volume":"17","author":"Tarling","year":"2013","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1080\/19490976.2015.1127483","article-title":"Consequences of bile salt biotransformations by intestinal bacteria","volume":"7","author":"Ridlon","year":"2016","journal-title":"Gut Microbes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.2337\/db07-1403","article-title":"Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice","volume":"57","author":"Cani","year":"2008","journal-title":"Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1136\/gutjnl-2011-301012","article-title":"Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota","volume":"61","author":"Serino","year":"2012","journal-title":"Gut"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11710","DOI":"10.1021\/acs.jafc.0c02570","article-title":"High-fat proteins drive dynamic changes in gut microbiota, hepatic metabolome, and endotoxemia-TLR-4-NF-\u03baB-mediated inflammation in mice","volume":"68","author":"Ahmad","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/nyas.13360","article-title":"Intestinal epithelial claudins: Expression and regulation in homeostasis and inflammation","volume":"1397","author":"Quiros","year":"2017","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jo, J.K., Seo, S.H., Park, S.E., Kim, H.W., Kim, E.J., Kim, J.S., Pyo, J.Y., Cho, K.M., Kwon, S.J., and Park, D.H. (2021). Gut microbiome and metabolome profiles associated with high-fat diet in mice. Metabolites, 11.","DOI":"10.3390\/metabo11080482"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"110893","DOI":"10.1016\/j.nut.2020.110893","article-title":"Abundance of the species Clostridium butyricum in the gut microbiota contributes to differences in obesity phenotype in outbred Sprague-Dawley CD rats","volume":"78","author":"Obanda","year":"2020","journal-title":"Nutrition"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"152","DOI":"10.4109\/jslab.19.152","article-title":"Taxonomy and atypical characteristics of the genus Lactobacillus","volume":"19","author":"Endo","year":"2008","journal-title":"Jpn. J. Lactic Acid Bact."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2264737","DOI":"10.1155\/2021\/2264737","article-title":"Probiotics alleviated nonalcoholic fatty liver disease in high-fat diet-fed rats via gut microbiota\/FXR\/FGF15 signaling pathway","volume":"2021","author":"Luo","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Vu, V., Muthuramalingam, K., Singh, V., Hyun, C., Kim, Y.M., Unno, T., and Cho, M. (2021). Effects of \u03b2-glucan, probiotics, and synbiotics on obesity-associated colitis and hepatic manifestations in C57BL\/6J mice. Eur. J. Nutr., in press.","DOI":"10.1007\/s00394-021-02668-z"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1152\/physrev.00045.2009","article-title":"Gut microbiota in health and disease","volume":"90","author":"Sekirov","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/nature05414","article-title":"An obesity-associated gut microbiome with increased capacity for energy harvest","volume":"444","author":"Turnbaugh","year":"2006","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1128\/aem.33.1.15-18.1977","article-title":"Deconjugation of bile acids by intestinal lactobacilli","volume":"33","author":"Gilliland","year":"1977","journal-title":"Appl. Environ. Micobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13580","DOI":"10.1073\/pnas.0804437105","article-title":"Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome","volume":"105","author":"Jones","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1194\/jlr.R500013-JLR200","article-title":"Bile salt biotransformations by human intestinal bacteria","volume":"47","author":"Ridlon","year":"2006","journal-title":"J. Lipid Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13099-016-0087-3","article-title":"Whole genome sequencing of \u201cFaecalibaculum rodentium\u201d ALO17, isolated from C57BL\/6J laboratory mouse feces","volume":"8","author":"Lim","year":"2016","journal-title":"Gut Pathog."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/s41564-019-0649-5","article-title":"Endogenous murine microbiota member Faecalibaculum rodentium and its human homologue protect from intestinal tumour growth","volume":"5","author":"Zagato","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cmet.2016.05.005","article-title":"Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism","volume":"24","author":"Sayin","year":"2016","journal-title":"Cell Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1096\/fasebj.10.11.8836041","article-title":"Paneth cell defensins: Endogenous peptide components of intestinal hos defense","volume":"10","author":"Ouellette","year":"1996","journal-title":"FASEB J."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Karlsson, J., P\u00fctsep, K., Chu, H., Kays, R.J., Bevins, C.L., and Anderson, M. (2008). Regional variations in Paneth cell antimicrobial peptide expression along the mouse intestinal tract. BMC Immunol., 9.","DOI":"10.1186\/1471-2172-9-37"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/mnfr.201500406","article-title":"Talking microbes: When gut bacteria interact with diet and host organs","volume":"60","author":"Cani","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9474896","DOI":"10.1155\/2017\/9474896","article-title":"High fat diet alters gut microbiota and the expression of paneth cell-antimicrobial peptides preceding changes of circulating inflammatory cytokines","volume":"2017","author":"Guo","year":"2017","journal-title":"Mediators Inflamm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1126\/science.1127119","article-title":"Symbiotic bacteria direct expression of an intestinal bactericidal lectin","volume":"313","author":"Cash","year":"2006","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.cmet.2012.05.012","article-title":"Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling","volume":"16","author":"Imajo","year":"2012","journal-title":"Cell Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nrmicro2546","article-title":"Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis","volume":"9","author":"Bevins","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/ni.2025","article-title":"Border patrol: Regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22","volume":"12","author":"Sonnenberg","year":"2011","journal-title":"Nat. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3168\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:30:09Z","timestamp":1760167809000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,14]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cells10113168"],"URL":"https:\/\/doi.org\/10.3390\/cells10113168","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,14]]}}}