{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:17:30Z","timestamp":1787725050338,"version":"build-2784847793"},"reference-count":40,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI Grants-in-Aid for Scientific Research","award":["21K14808"],"award-info":[{"award-number":["21K14808"]}]},{"name":"JSPS KAKENHI Grants-in-Aid for Scientific Research","award":["20K22881"],"award-info":[{"award-number":["20K22881"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Western-type diets (WDs) damage the intestinal barrier by disrupting the gut microbiota composition and causing inflammation, leading to the development of obesity, type 2 diabetes, and non-alcoholic fatty liver disease. Short-chain fatty acids (SCFAs) are produced by the gut microbiota and found in fermented foods and can stimulate the anti-inflammatory action of type 3 innate lymphoid cells (ILCS3s) in the intestine. This study hypothesised that supplementing miso, a Japanese fermented food, to a WD could increase the levels of SCFAs and thus stimulate ILC3s, decreasing inflammation in the intestine and protecting intestinal barrier integrity. Methods: Mice with ROR\u03b3t total (KI\/KI) or partial (KI\/w) knockout were fed a high-fat high-sugar diet (HFHSD) for eight weeks as a model of WD. Half of the mice received miso supplementation in addition to the HFHSD. Weight gain, glucose tolerance and insulin resistance, intestinal barrier integrity, intestinal immunity, and liver condition were assessed. Results: Miso supplementation increased SCFA levels in the small intestine, which stimulated ILC3 function in KI\/w mice. Glucose tolerance was improved, intestinal barrier integrity was ameliorated, and mucus production was increased. The level of IL-22 was increased, while pro-inflammatory ILC1s, M1 macrophages, TNF-\u03b1, and IL-1\u03b2 were decreased. Liver condition was not affected. Conclusions: This study demonstrated that miso supplementation influenced several factors involved in inflammation and intestinal barrier integrity by stimulating ILC3s in ROR\u03b3t heterozygous mice. Moreover, it showed that the number of ILC3s is not the key factor in immune regulation, but rather the ability of ILC3 to produce IL-22 and employ it to control the immune response in the small intestine.<\/jats:p>","DOI":"10.3390\/nu16213743","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T12:31:32Z","timestamp":1730377892000},"page":"3743","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Supplementation of Miso to a Western-Type Diet Stimulates ILC3s and Decreases Inflammation in the Small Intestine"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9076-6112","authenticated-orcid":false,"given":"River","family":"Budau","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7269-1697","authenticated-orcid":false,"given":"Takuro","family":"Okamura","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3435-6868","authenticated-orcid":false,"given":"Yuka","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8651-4445","authenticated-orcid":false,"given":"Masahide","family":"Hamaguchi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0903-1797","authenticated-orcid":false,"given":"Michiaki","family":"Fukui","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Malesza, I.J., Malesza, M., Walkowiak, J., Mussin, N., Walkowiak, D., Aringazina, R., Bartkowiak-Wieczorek, J., and M\u0105dry, E. (2021). High-Fat, Western-Style Diet, Systemic Inflammation, and Gut Microbiota: A Narrative Review. Cells, 10.","DOI":"10.3390\/cells10113164"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Croci, S., D\u2019Apolito, L.I., Gasperi, V., Catani, M.V., and Savini, I. (2021). Dietary Strategies for Management of Metabolic Syndrome: Role of Gut Microbiota Metabolites. Nutrients, 13.","DOI":"10.3390\/nu13051389"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.immuni.2019.09.020","article-title":"Western Diet and the Immune System: An Inflammatory Connection","volume":"51","author":"Christ","year":"2019","journal-title":"Immunity"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.2147\/DMSO.S216791","article-title":"How Western Diet and Lifestyle Drive The Pandemic of Obesity and Civilization Diseases","volume":"12","author":"Kopp","year":"2019","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Moszak, M., Szuli\u0144ska, M., and Bogda\u0144ski, P. (2020). You Are What You Eat-The Relationship between Diet, Microbiota, and Metabolic Disorders-A Review. Nutrients, 12.","DOI":"10.3390\/nu12041096"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Singh, R.B., Fedacko, J., Fatima, G., Magomedova, A., Watanabe, S., and Elkilany, G. (2022). Why and How the Indo-Mediterranean Diet May Be Superior to Other Diets: The Role of Antioxidants in the Diet. Nutrients, 14.","DOI":"10.20944\/preprints202201.0373.v1"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kinashi, Y., and Hase, K. (2021). Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.673708"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Paray, B.A., Albeshr, M.F., Jan, A.T., and Rather, I.A. (2020). Leaky Gut and Autoimmunity: An Intricate Balance in Individuals Health and the Diseased State. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249770"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"108273","DOI":"10.1016\/j.pharmthera.2022.108273","article-title":"Short-chain fatty acid receptors and gut microbiota as therapeutic targets in metabolic, immune, and neurological diseases","volume":"239","author":"Ikeda","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.foodchem.2018.07.158","article-title":"An insight into the health benefits of fermented soy products","volume":"271","author":"Jayachandran","year":"2019","journal-title":"Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Binienda, A., Twardowska, A., Makaro, A., and Salaga, M. (2020). Dietary Carbohydrates and Lipids in the Pathogenesis of Leaky Gut Syndrome: An Overview. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218368"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nri.2017.7","article-title":"Dysbiosis and the immune system","volume":"17","author":"Levy","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Leeuwendaal, N.K., Stanton, C., O\u2019Toole, P.W., and Beresford, T.P. (2022). Fermented Foods, Health and the Gut Microbiome. Nutrients, 14.","DOI":"10.3390\/nu14071527"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.biotechadv.2018.12.001","article-title":"Bioactivity of soy-based fermented foods: A review","volume":"37","author":"Cao","year":"2019","journal-title":"Biotechnol. Adv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110922","DOI":"10.1016\/j.foodres.2021.110922","article-title":"Current perspectives on the anti-inflammatory potential of fermented soy foods","volume":"152","author":"Das","year":"2022","journal-title":"Food Res. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"663","DOI":"10.4162\/nrp.2024.18.5.663","article-title":"Consumption of poly-\u03b3-glutamate-vitamin B6 supplement and urinary microbiota profiles in Korean healthy adults: A randomized, double-blinded, placebo-controlled intervention study","volume":"18","author":"Park","year":"2024","journal-title":"Nutr. Res. Pract."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Annunziata, G., Arnone, A., Ciampaglia, R., Tenore, G.C., and Novellino, E. (2020). Fermentation of Foods and Beverages as a Tool for Increasing Availability of Bioactive Compounds. Focus on Short-Chain Fatty Acids. Foods, 9.","DOI":"10.3390\/foods9080999"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8579","DOI":"10.1111\/jcmm.16856","article-title":"Innate lymphoid cells are double-edged swords under the mucosal barrier","volume":"25","author":"Duan","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41419-019-1540-2","article-title":"ILC3 function as a double-edged sword in inflammatory bowel diseases","volume":"10","author":"Zeng","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.immuni.2019.09.014","article-title":"Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity","volume":"51","author":"Chun","year":"2019","journal-title":"Immunity"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2006.07.035","article-title":"The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells","volume":"126","author":"Ivanov","year":"2006","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/ni1022","article-title":"An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells","volume":"5","author":"Eberl","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hamaguchi, M., Okamura, T., Fukuda, T., Nishida, K., Yoshimura, Y., Hashimoto, Y., Ushigome, E., Nakanishi, N., Majima, S., and Asano, M. (2021). Group 3 Innate Lymphoid Cells Protect Steatohepatitis From High-Fat Diet Induced Toxicity. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.648754"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hashimoto, Y., Okamura, T., Bamba, R., Yoshimura, Y., Munekawa, C., Kaji, A., Miki, A., Majima, S., Senmaru, T., and Ushigome, E. (2024). Miso, fermented soybean paste, suppresses high-fat\/high-sucrose diet-induced muscle atrophy in mice. J. Clin. Biochem. Nutr., 74.","DOI":"10.3164\/jcbn.23-36"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1538\/expanim.60.481","article-title":"Effect of three types of mixed anesthetic agents alternate to ketamine in mice","volume":"60","author":"Kawai","year":"2011","journal-title":"Exp. Anim."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"27006","DOI":"10.1289\/EHP11072","article-title":"Oral Exposure to Polystyrene Microplastics of Mice on a Normal or High-Fat Diet and Intestinal and Metabolic Outcomes","volume":"131","author":"Okamura","year":"2023","journal-title":"Environ. Health Perspect."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/clpt.2012.108","article-title":"Alanine aminotransferase: A clinical and regulatory tool for detecting liver injury-past, present, and future","volume":"92","author":"Senior","year":"2012","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1097\/MED.0000000000000530","article-title":"Triglycerides and residual risk","volume":"27","author":"Corral","year":"2020","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s00125-017-4534-6","article-title":"Association of NEFA composition with insulin sensitivity and beta cell function in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort","volume":"61","author":"Johnston","year":"2018","journal-title":"Diabetologia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.bpj.2021.01.003","article-title":"Intestinal villus structure contributes to even shedding of epithelial cells","volume":"120","author":"Kai","year":"2021","journal-title":"Biophys. J."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bonis, V., Rossell, C., and Gehart, H. (2021). The Intestinal Epithelium\u2014Fluid Fate and Rigid Structure From Crypt Bottom to Villus Tip. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.661931"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.2147\/DDDT.S151725","article-title":"Regulation profile of the intestinal peptide transporter 1 (PepT1)","volume":"11","author":"Wang","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1517\/14728222.2016.1168808","article-title":"Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus","volume":"20","author":"Song","year":"2016","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1111\/1750-3841.15773","article-title":"Fermentation and the microbial community of Japanese koji and miso: A review","volume":"86","author":"Allwood","year":"2021","journal-title":"J. Food Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Takahashi, F., Hashimoto, Y., Kaji, A., Sakai, R., Miki, A., Okamura, T., Kitagawa, N., Okada, H., Nakanishi, N., and Majima, S. (2021). Habitual Miso (Fermented Soybean Paste) Consumption Is Associated with Glycemic Variability in Patients with Type 2 Diabetes: A Cross-Sectional Study. Nutrients, 13.","DOI":"10.3390\/nu13051488"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Okouchi, R., Sakanoi, Y., and Tsuduki, T. (2019). Miso (Fermented Soybean Paste) Suppresses Visceral Fat Accumulation in Mice, Especially in Combination with Exercise. Nutrients, 11.","DOI":"10.3390\/nu11030560"},{"key":"ref_38","unstructured":"The Jackson Laboratory (2024, May 11). B6.129P2-Rorctm1Litt\/J. Available online: https:\/\/www.jax.org\/strain\/007571."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kotake, K., Kumazawa, T., Nakamura, K., Shimizu, Y., Ayabe, T., and Adachi, T. (2022). Ingestion of miso regulates immunological robustness in mice. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0261680"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1042\/CS20210778","article-title":"Gut microbiota-derived butyrate regulates gut mucus barrier repair by activating the macrophage\/WNT\/ERK signaling pathway","volume":"136","author":"Liang","year":"2022","journal-title":"Clin. Sci."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/21\/3743\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:25:47Z","timestamp":1760113547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/21\/3743"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,31]]},"references-count":40,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["nu16213743"],"URL":"https:\/\/doi.org\/10.3390\/nu16213743","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,31]]}}}