{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:25:17Z","timestamp":1787505917066,"version":"build-2736575974"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"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. Immunol."],"abstract":"<jats:p>\n                    Growing evidence suggests a link between the gut microbiome and papillary thyroid carcinoma (PTC), but the causal relationships and the impact on the tumor immune microenvironment (TME) are poorly understood. This study aimed to elucidate the causal role of specific gut microbes in PTC and uncover the underlying immunological and molecular mechanisms. We employed a multi-stage design, beginning with a two-sample Mendelian randomization (MR) analysis using large-scale GWAS data to infer causality. Findings were then validated in 450 PTC patients from The Cancer Genome Atlas (TCGA) by analyzing correlations between microbial abundance, gene expression, immune cell infiltration, and survival. Finally, the core mechanism was confirmed through extensive\n                    <jats:italic>in vitro<\/jats:italic>\n                    experiments with PTC cell lines. Our MR analysis identified a causal association between a genetically predicted higher abundance of the genus\n                    <jats:italic>Terrisporobacter<\/jats:italic>\n                    and an increased risk of PTC (Odds Ratio [OR] = 2.06, 95% Confidence Interval [CI]: 1.34-3.16). In the TCGA cohort, higher intratumoral signals of\n                    <jats:italic>Terrisporobacter<\/jats:italic>\n                    was significantly correlated with an immunosuppressive TME, characterized by increased infiltration of M2 macrophages (\u03c1 = 0.25, p &amp;lt; 0.001) and decreased CD8+ T cells (\u03c1 = -0.19, p = 0.008). Mechanistically,\n                    <jats:italic>Terrisporobacter<\/jats:italic>\n                    abundance was also strongly associated with the upregulation of the oncogene\n                    <jats:italic>NTRK1<\/jats:italic>\n                    (\u03c1 = 0.35, p &amp;lt; 0.001), which independently predicted poorer overall survival (Hazard Ratio [HR] = 2.15, p = 0.004).\n                    <jats:italic>In vitro<\/jats:italic>\n                    experiments confirmed that supernatant from\n                    <jats:italic>Terrisporobacter<\/jats:italic>\n                    culture not only upregulated\n                    <jats:italic>NTRK1<\/jats:italic>\n                    expression and promoted PTC cell proliferation but also enhanced invasion and induced cell de-differentiation. Importantly, pharmacological inhibition of TRK signaling reversed the bacteria-induced aggressive phenotype. Our integrated analysis provides robust, multi-layered evidence for a causal role of\n                    <jats:italic>Terrisporobacter<\/jats:italic>\n                    in promoting PTC progression. We define a novel gut-thyroid axis where\n                    <jats:italic>Terrisporobacter<\/jats:italic>\n                    contributes to PTC development by upregulating the\n                    <jats:italic>NTRK1<\/jats:italic>\n                    oncogene and shaping a pro-tumorigenic, immunosuppressive microenvironment. These findings reveal a new dimension of host-microbe interaction in thyroid cancer and highlight the TME as a key downstream target of microbial influence.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1740257","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:54:35Z","timestamp":1774421675000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Gut microbe Terrisporobacter promotes papillary thyroid carcinoma progression by upregulating the NTRK1 oncogene and fostering an immunosuppressive tumor microenvironment"],"prefix":"10.3389","volume":"17","author":[{"given":"Jia","family":"Li","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine, Tianjin First Central Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Tianjin First Central Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Tianjin First Central Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enci","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Tianjin First Central Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Tianjin First Central Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00020-X","article-title":"Thyroid cancer","volume":"401","author":"Chen","year":"2023","journal-title":"Lancet (London England)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2022.1553","article-title":"Update from the 2022 world health organization classification of thyroid tumors: A standardized diagnostic approach","volume":"37","author":"Jung","year":"2022","journal-title":"Endocrinol Metab (Seoul Korea)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ecl.2018.10.002","article-title":"Evolving understanding of the epidemiology of thyroid cancer","volume":"48","author":"Seib","year":"2019","journal-title":"Endocrinol Metab Clin North Am"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.26348","article-title":"Thyroid cancer: A review","volume":"331","author":"Boucai","year":"2024","journal-title":"Jama"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.571421","article-title":"Early diagnosis of low-risk papillary thyroid cancer results rather in overtreatment than a better survival","volume":"11","author":"Krajewska","year":"2020","journal-title":"Front Endocrinol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA: Cancer J Clin"},{"key":"B7","doi-asserted-by":"publisher","first-page":"105085","DOI":"10.1016\/j.oraloncology.2020.105085","article-title":"Obesity and the prevention of thyroid cancer: Impact of body mass index and weight change on developing thyroid cancer - Pooled results of 24 million cohorts","volume":"112","author":"Youssef","year":"2021","journal-title":"Oral Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.3390\/ijerph19031116","article-title":"Obesity and thyroid cancer risk: an update","volume":"19","author":"Franchini","year":"2022","journal-title":"Int J Environ Res Public Health"},{"key":"B9","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1177\/1099800420941606","article-title":"The oral and gut bacterial microbiomes: similarities, differences, and connections","volume":"23","author":"Maki","year":"2021","journal-title":"Biol Res Nurs"},{"key":"B10","doi-asserted-by":"publisher","first-page":"S17","DOI":"10.1093\/advances\/nmy078","article-title":"Diet, gut microbiota, and obesity: links with host genetics and epigenetics and potential applications","volume":"10","author":"Cuevas-Sierra","year":"2019","journal-title":"Adv Nutr (Bethesda Md)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3390\/microorganisms7010014","article-title":"What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases","volume":"7","author":"Rinninella","year":"2019","journal-title":"Microorganisms"},{"key":"B12","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.chom.2022.02.004","article-title":"Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis","volume":"30","author":"Cai","year":"2022","journal-title":"Cell Host Microbe"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s12865-016-0187-3","article-title":"Role of intestinal microbiota and metabolites on gut homeostasis and human diseases","volume":"18","author":"Lin","year":"2017","journal-title":"BMC Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-22-0724","article-title":"Exploring the complex relationship between gut microbiota and risk of colorectal neoplasia using bidirectional mendelian randomization analysis","volume":"32","author":"Li","year":"2023","journal-title":"Cancer epidemiology Biomarkers prevention: Publ Am Assoc Cancer Research cosponsored by Am Soc Prev Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12916-023-02761-6","article-title":"Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study","volume":"21","author":"Long","year":"2023","journal-title":"BMC Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/jrsm.1346","article-title":"Meta-analysis and Mendelian randomization: A review","volume":"10","author":"Bowden","year":"2019","journal-title":"Res Synth Methods"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2023.1087622","article-title":"Assessment of causal associations among gut microbiota, metabolites, and celiac disease: a bidirectional Mendelian randomization study","volume":"14","author":"Li","year":"2023","journal-title":"Front Microbiol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/nxab025","article-title":"Mendelian randomization analysis reveals causal effects of the human gut microbiota on abdominal obesity","volume":"151","author":"Xu","year":"2021","journal-title":"J Nutr"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyt179","article-title":"Calculating statistical power in Mendelian randomization studies","volume":"42","author":"Brion","year":"2013","journal-title":"Int J Epidemiol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"B21","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s12967-023-04835-8","article-title":"Causal effects of gut microbiota on sepsis and sepsis-related death: insights from genome-wide Mendelian randomization, single-cell RNA, bulk RNA sequencing, and network pharmacology","volume":"22","author":"Yang","year":"2024","journal-title":"J Trans Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32007","article-title":"Alterations in the gut microbiota and metabolite profiles of thyroid carcinoma patients","volume":"144","author":"Feng","year":"2019","journal-title":"Int J Cancer"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2155018","DOI":"10.1080\/19490976.2022.2155018","article-title":"Alterations in gut microbiome and metabolomics in chronic hepatitis B infection-associated liver disease and their impact on peripheral immune response","volume":"15","author":"Shen","year":"2023","journal-title":"Gut Microbes"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05728-y","article-title":"Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer","volume":"615","author":"Tintelnot","year":"2023","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0458-7","article-title":"Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer","volume":"25","author":"Yachida","year":"2019","journal-title":"Nat Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0152126","article-title":"Fecal microbiota, fecal metabolome, and colorectal cancer interrelations","volume":"11","author":"Sinha","year":"2016","journal-title":"PloS One"},{"key":"B27","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1186\/s40168-020-00923-9","article-title":"The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for complex human diseases","volume":"8","author":"Xu","year":"2020","journal-title":"Microbiome"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5313","DOI":"10.1038\/s41467-022-32960-3","article-title":"CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic Malignancies","volume":"13","author":"Hu","year":"2022","journal-title":"Nat Commun"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15466","article-title":"Association of gut microbiome and primary liver cancer: A two-sample Mendelian randomization and case-control study","volume":"43","author":"Ma","year":"2023","journal-title":"Liver international: Off J Int Assoc Study Liver"},{"key":"B30","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s00432-023-05535-y","article-title":"Exploring reciprocal causation: bidirectional mendelian randomization study of gut microbiota composition and thyroid cancer","volume":"150","author":"Zhou","year":"2024","journal-title":"J Cancer Res Clin Oncol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2149019","DOI":"10.1080\/19490976.2022.2149019","article-title":"Predicting butyrate- and propionate-forming bacteria of gut microbiota from sequencing data","volume":"14","author":"Kircher","year":"2022","journal-title":"Gut Microbes"},{"key":"B32","doi-asserted-by":"publisher","first-page":"105420","DOI":"10.1016\/j.phrs.2021.105420","article-title":"The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis","volume":"165","author":"Liu","year":"2021","journal-title":"Pharmacol Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg effect: the metabolic requirements of cell proliferation","volume":"324","author":"Vander Heiden","year":"2009","journal-title":"Sci (New York NY)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-018-1659-0","article-title":"Targeting glutaminase-mediated glutamine dependence in papillary thyroid cancer","volume":"96","author":"Yu","year":"2018","journal-title":"J Mol Med (Berlin Germany)"},{"key":"B35","doi-asserted-by":"publisher","first-page":"355","DOI":"10.3390\/jcm8030355","article-title":"Multiomics analysis reveals that GLS and GLS2 differentially modulate the clinical outcomes of cancer","volume":"8","author":"Saha","year":"2019","journal-title":"J Clin Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0113-0","article-title":"NTRK fusion-positive cancers and TRK inhibitor therapy","volume":"15","author":"Cocco","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30691-6","article-title":"Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1\u20132 trials","volume":"21","author":"Doebele","year":"2020","journal-title":"Lancet Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.28555","article-title":"Neurotrophic-tyrosine receptor kinase gene fusion in papillary thyroid cancer: A clinicogenomic biobank and record linkage study from Finland","volume":"15","author":"Zhang","year":"2024","journal-title":"Oncotarget"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00815-y","article-title":"Phosphodiesterase 4D contributes to angiotensin II-induced abdominal aortic aneurysm through smooth muscle cell apoptosis","volume":"54","author":"Gao","year":"2022","journal-title":"Exp Mol Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"a003996","DOI":"10.1101\/cshperspect.a003996","article-title":"Ryanodine receptors: structure, expression, molecular details, and function in calcium release","volume":"2","author":"Lanner","year":"2010","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1108773","article-title":"Identification of calcium metabolism related score associated with the poor outcome in papillary thyroid carcinoma","volume":"13","author":"Hu","year":"2023","journal-title":"Front Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1740257\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:54:36Z","timestamp":1774421676000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1740257\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2026.1740257"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1740257","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]},"article-number":"1740257"}}