VISCERAL SENSITIVITY, CORTISOL LEVEL, AND THEIR ASSOCIATION WITH GUT MICROBIOTA CHANGES IN PATIENTS WITH HYPOTHYROIDISM AND DISORDERED BOWEL HABITS
DOI:
https://doi.org/10.11603/1811-2471.2025.v.i4.15777Keywords:
hypothyroidism, visceral sensitivity, cortisol, gut microbiota, dysbiosis, irritable bowel syndromeAbstract
SUMMARY. Intestinal dysfunction frequently accompanies hypothyroidism and co-occurs with dysbiosis and heightened visceral sensitivity; however, causal mechanisms within this cluster remain insufficiently clarified.
The aim – to determine visceral sensitivity, serum cortisol, and alterations of the proximal small-intestinal and colonic microbiota in patients with hypothyroidism and disordered bowel function, and to assess their potential interrelationships.
Material and Methods. We examined 42 patients with hypothyroidism (constipation, n=28; diarrhea, n=14), 28 patients with irritable bowel syndrome (14 with constipation, 14 with diarrhea), and 18 apparently healthy controls. Thyroid hormones were measured using standard immunoassays; cortisol was quantified by solid-phase ELISA; visceral sensitivity was assessed with the validated Visceral Sensitivity Index (VSI). Culture-based analysis was performed on the mucosa-associated colonic microbiota and the luminal flora of the proximal small intestine. Statistical processing applied parametric and nonparametric tests and correlation analysis (p<0.05).
Results. In hypothyroid patients with constipation, marked reductions in Bifidobacterium and Lactobacillus were observed alongside increases in Clostridia, Escherichia coli (including lactose-negative strains), Klebsiella spp., Enterobacter cloacae, and Candida yeasts (p<0.01). These shifts coincided with elevated cortisol (307.6±8.0 nmol/L) and higher VSI scores (75.1±2.4 points). Positive correlations were identified between Clostridia, Klebsiella, E. coli and cortisol concentration (r=0.58–0.74; p<0.05). In the diarrhea subgroup, features of small-intestinal bacterial overgrowth were documented and were accompanied by lower cortisol levels.
Conclusions. In hypothyroidism, intestinal dysbiosis is closely linked to increased cortisol and visceral sensitivity, reflecting activation of the hypothalamic–pituitary–adrenal axis and amplification of neuroendocrine stress mechanisms. The findings support the concept of a “microbiota–thyroid–stress axis” and justify an integrated therapeutic approach that combines optimization of thyroid function, normalization of gut microbiota, and control of stress hormones.
References
Vargas-Uricoechea H. Autoimmune thyroid disease and differentiated thyroid carcinoma: a review of the mechanisms that explain an intriguing and exciting relationship. World J Oncol. 2024 Feb;15(1):14-27. DOI: 10.14740/wjon1728 DOI: https://doi.org/10.14740/wjon1728
Alanazi MS, Alanazi AS, Alruwaili AA, Alshalan MJ, Alanazi WA, Alanazi FS. Prevalence of thyroid disorders among the diabetic population in Arar, Saudi Arabia. Saudi Med J. 2024 Jun;45(6):591-7. DOI: 10.15537/smj.2024.45.6. 20240144. DOI: https://doi.org/10.15537/smj.2024.45.6.20240144
Zhu X, Zhang C, Feng S, He R, Zhang S. Intestinal microbiota regulates the gut-thyroid axis: the new dawn of improving Hashimoto thyroiditis. Cancer Chemother Pharmacol. 2024 Feb 21. DOI: 10.1007/s10238-024-01304-4. PMID:38386169; PMCID:PMC10884059. DOI: https://doi.org/10.1007/s10238-024-01304-4
Kocełak P, Mossakowska M, Puzianowska-Kuźnicka M, Sworczak K, Wyszomirski A, Handzlik G, et al. Prevalence and risk factors of untreated thyroid dysfunctions in the older Caucasian adults: results of PolSenior 2 survey. PLoS One. 2022 Aug 22;17(8):e0272045. DOI: 10.1371/journal.pone.0272045. DOI: https://doi.org/10.1371/journal.pone.0272045
Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM, Okosieme OE. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018 May;14(5):301-16. DOI: 10.1038/nrendo.2018.18. DOI: https://doi.org/10.1038/nrendo.2018.18
Bargiel P, Szczuko M, Stachowska L, Prowans P, Czapla N, Markowska M, Petriczko J, Kledzik J, Jędrzejczyk-Kledzik A, Palma J, Zabielska P, Maciejewska-Markiewicz D. Microbiome Metabolites and Thyroid Dysfunction. Journal of Clinical Medicine. 2021;10(16):3609. DOI: 10.3390/jcm10163609
Stramazzo I, Colaiori I, Ralli M, Latini G, Gatta A, Angeletti D, Fiore M, Minni A, Ciofalo A, Polimeni A, Artico M, Lambiase A, De Vincentiis M, Greco A. Microbiota and thyroid disease: an updated systematic review. Int J Mol Sci. 2023 Mar 17;24(6):5795. DOI: 10.3390/ijms24065795. PMID:36971966; PMCID:PMC10047262. DOI: https://doi.org/10.3390/ijms24065795
Xu GM, Hu MX, Li SY, Ran X, Zhang H, Ding XF. Thyroid disorders and gastrointestinal dysmotility: an old association. Front Physiol. 2024 May 2;15:1389113. DOI: 10.3389/fphys.2024.1389113. PMID: 38803365; PMCID: PMC11129086. DOI: https://doi.org/10.3389/fphys.2024.1389113
Borrego-Ruiz A, Borrego JJ. An updated overview on the relationship between human gut microbiome dysbiosis and psychiatric and psychological disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2024;128:110861. DOI: 10.1016/j.pnpbp.2023.110861. DOI: https://doi.org/10.1016/j.pnpbp.2023.110861
Roager HM, Hansen LBS, Bahl MI, Frandsen HL, Carvalho V, Gøbel RJ, Dalgaard MD, Plichta DR, Sparholt MH, Vestergaard H, Hansen T, Sicheritz-Pontén T, Nielsen HB, Pedersen O, Lauritzen L, Kristensen MB, Gupta R, Licht TR. Colonic transit time is related to bacterial metabolism and mucosal turnover in the gut. Nat Microbiol. 2016;1(9):16093. DOI: 10.1038/nmicrobiol.2016.93. DOI: https://doi.org/10.1038/nmicrobiol.2016.93
Ghosh SS, Wang J, Yannie PJ, Ghosh S. Intestinal barrier dysfunction, LPS translocation, and disease development. J Endocr Soc. 2020 Feb 20;4(2):bvz039. DOI: 10.1210/jendso/bvz039. PMID: 32099951; PMCID: PMC7033038. DOI: https://doi.org/10.1210/jendso/bvz039
Iwamoto Y, Kimura T, Itoh T, Mori S, Sasaki T, Sugisaki T, et al. Structural and functional differences in auto-antibody positive compared to auto-antibody negative hypothyroid patients with chronic thyroiditis. Sci Rep. 2023 Sep 20;13:15542. DOI: 10.1038/s41598-023-42765-z. DOI: https://doi.org/10.1038/s41598-023-42765-z
El-Zawawy HT, Ahmed SM, El-Attar EA, Ahmed AA, Roshdy YS, Header DA. Study of gut microbiome in Egyptian patients with autoimmune thyroid diseases. Int J Clin Pract. 2021 May;75(5):e14038. DOI: 10.1111/ijcp.14038. PMID: 33482041. DOI: https://doi.org/10.1111/ijcp.14038
Zhao H, Yuan L, Zhu D, Sun B, Du J, Wang J. Alterations and mechanism of gut microbiota in Graves’ disease and Hashimoto’s thyroiditis. Pol J Microbiol. 2022;71(2):173-89. DOI: 10.33073/pjm-2022-016. DOI: https://doi.org/10.33073/pjm-2022-016
Bargiel P, Szczuko M, Stachowska L, Prowans P, Czapla N, Markowska M, Petriczko J, Kledzik J, Jędrzejczyk-Kledzik A, Palma J, Zabielska P, Maciejewska-Markiewicz D. Microbiome metabolites and thyroid dysfunction. J Clin Med. 2021;10(16):3609. DOI: 10.3390/jcm10163609. DOI: https://doi.org/10.3390/jcm10163609
Sessa L, Malavolta E, Sodero G, Cipolla C, Rigante D. The conspiring role of gut microbiota as primer of autoimmune thyroid diseases: a scoping focus. Autoimmun Rev. 2025 Apr 30;24(5):103780. DOI: 10.1016/j.autrev.2025. 103780. Epub 2025 Feb 17. PMID:39971108. DOI: https://doi.org/10.1016/j.autrev.2025.103780
Spaggiari G, Brigante G, De Vincentis S, Cattini U, Roli L, De Santis MC, et al. Probiotics ingestion does not directly affect thyroid hormonal parameters in hypothyroid patients on levothyroxine treatment. Front Endocrinol (Lausanne). 2017 Nov 14;8:316. DOI: 10.3389/fendo.2017. 00316. PMID:29184537. DOI: https://doi.org/10.3389/fendo.2017.00316
Fenneman AC, van der Meulen N, van Hunsel F, van Wijk F, Boekholdt SM, Kootte RS, Nieuwdorp M, Fliers E, Netea MG, van Trotsenburg ASP, la Fleur SE, van Vliet-Ostaptchouk JV, Keestra S, van Schaik RHN, de Ruiter K, Swaab DF, Biermasz NR, Koot BG, Kors JA, van der Spek AH, van Rossum EFC, van der Spoel E. Protocol for a double-blinded randomised controlled trial to assess the effect of faecal microbiota transplantations on thyroid reserve in patients with subclinical autoimmune hypothyroidism in the Netherlands: the IMITHOT trial. BMJ Open. 2023 Sep;13(9):e074556. DOI: 10.1136/bmjopen-2023-074556. PMID:37721713; PMCID:PMC10509240. DOI: https://doi.org/10.1136/bmjopen-2023-073971
Farzi A, Fröhlich EE, Holzer P. Gut microbiota and the neuroendocrine system. Neurotherapeutics. 2018 Jan; 15(1):5-22. DOI:10.1007/s13311-017-0600-5. DOI: https://doi.org/10.1007/s13311-017-0600-5
Khadka M, Kafle B, Sharma S. Prevalence of thyroid dysfunction in irritable bowel syndrome. J Univ Coll Med Sci. 2018;4(2):1. DOI: 10.3126/jucms.v4i2.19082. DOI: https://doi.org/10.3126/jucms.v4i2.19082
Yeşilova A, Bilge M, Gökden Y, Adaş M. Irritable bowel syndrome in women with euthyroid Hashimoto’s thyroiditis: is there any relationship between thyroid autoimmunity and irritable bowel syndrome? Cerrahpasa Med J. 2023;47:123-8. DOI:10.5152/cjm.2022.22054. DOI: https://doi.org/10.5152/cjm.2022.22054
Labus JS, Bolus R, Chang L, Wiklund I, Naesdal J, Mayer EA, Naliboff BD. The Visceral Sensitivity Index: development and validation of a gastrointestinal symptom-specific anxiety scale. Aliment Pharmacol Ther. 2004 Jan 1;20(1):89-97. DOI: 10.1111/j.1365-2036.2004.02007.x. DOI: https://doi.org/10.1111/j.1365-2036.2004.02007.x
Saigo T, Tayama J, Hamaguchi T, Nakaya N, Tomiie T, Bernick PJ, Kanazawa M, Labus JS, Naliboff BD, Shirabe S, Fukudo S. Gastrointestinal specific anxiety in irritable bowel syndrome: validation of the Japanese version of the visceral sensitivity index for university students. Biopsychosoc Med. 2014 Mar 21;8(1):10. DOI: 10.1186/1751-0759-8-10. DOI: https://doi.org/10.1186/1751-0759-8-10
Neverovskyi A, Shypulin V, Mikhnova N. Translation and validation of the Ukrainian version of the visceral sensitivity index for patients with irritable bowel syndrome. Prz Gastroenterol. 2023;18(3):313-9. DOI: 10.5114/pg.2023. 131391. DOI: https://doi.org/10.5114/pg.2023.131391
Davin-Regli A, Pagès JM. Enterobacter aerogenes and Enterobacter cloacae: versatile bacterial pathogens confronting antibiotic treatment. Front Microbiol. 2015 May 18;6:392. DOI: 10.3389/fmicb.2015.00392. PMID: 26042091; PMCID: PMC4435039. DOI: https://doi.org/10.3389/fmicb.2015.00392
Parveen N, Chittawar S, Khandelwal D. Gut-thyroid axis and emerging role of probiotics in thyroid disorders. Thyroid Res Pract. 2025 Jan–Apr;21(1):4–12. DOI: 10.4103/trp.trp_12_24 DOI: https://doi.org/10.4103/trp.trp_12_24
Xiong Y, Zhu X, Luo Q. Causal relationship between gut microbiota and autoimmune thyroiditis: a Mendelian study. Heliyon. 2024 Feb 15;10(3):e25652. DOI: 10.1016/j.heliyon.2024.e25652. DOI: https://doi.org/10.1016/j.heliyon.2024.e25652
Fröhlich E, Wahl R. Thyroid autoimmunity: role of anti-thyroid antibodies in thyroid and extra-thyroidal diseases. Front Immunol. 2017 May 9;8:521. DOI: 10.3389/fimmu.2017.00521. PMID: 28536577; PMCID: PMC5422478. DOI: https://doi.org/10.3389/fimmu.2017.00521
Liu J, Qin X, Lin B, Cui J, Liao J, Zhang F, Lin Q. Analysis of gut microbiota diversity in Hashimoto’s thyroiditis patients. BMC Microbiol. 2022 Dec 24;22(1):318. DOI: 10.1186/s12866-022-02739-z. PMID: 36564707; PMCID: PMC9789560. DOI: https://doi.org/10.1186/s12866-022-02739-z
Docimo G, Cangiano A, Romano RM, Filograna Pignatelli M, Offi C, Amoresano Paglionico V, et al. The human microbiota in endocrinology: implications for pathophysiology, treatment, and prognosis in thyroid diseases. Front Endocrinol (Lausanne). 2020 Dec 4;11:586529. DOI: 10.3389/fendo.2020.586529. PMID: 33343507; PMCID: PMC7746874. DOI: https://doi.org/10.3389/fendo.2020.586529
Cadena-Ullauri S, Guevara-Ramírez P, Paz-Cruz E, Ruiz-Pozo VA, Tamayo-Trujillo R, Zambrano AK. Microbiota dysbiosis impact on the metabolism of T3 and T4 hormones and its association with thyroid cancer. Front Cell Dev Biol. 2025 Jun 2;13:1589726. DOI: 10.3389/fcell.2025.1589726. PMID: 40530335; PMCID: PMC12171323. DOI: https://doi.org/10.3389/fcell.2025.1589726
Legakis I, Chrousos GP, Chatzipanagiotou S. Thyroid diseases and intestinal microbiome. Horm Metab Res. 2023 Dec;55(12):813–818. DOI: 10.1055/a-2190-3847. PMID: 37820693. DOI: https://doi.org/10.1055/a-2190-3847
Rodiño-Janeiro BK, Vicario M, Alonso-Cotoner C, Pascua-García R, Santos J. A review of microbiota and irritable bowel syndrome: Future in therapies. Adv Ther. 2018 Mar;35(3):289–310. DOI: 10.1007/s12325-018-0673-5. PMID: 29498019. DOI: https://doi.org/10.1007/s12325-018-0673-5
Ouyang Q, Xu Y, Ban Y, Li J, Cai Y, Wu B, Hao Y, Sun Z, Zhang M, Wang M, Wang W, Zhao Y. Probiotics and prebiotics in subclinical hypothyroidism of pregnancy with small intestinal bacterial overgrowth. Probiotics Antimicrob Proteins. 2024 Apr;16(2):579–588. DOI: 10.1007/s12602-023-10068-4. DOI: https://doi.org/10.1007/s12602-023-10068-4
Fang L, Ning J. Recent advances in gut microbiota and thyroid disease: pathogenesis and therapeutics in autoimmune, neoplastic, and nodular conditions. Front Cell Infect Microbiol. 2024 Dec 24;14:1465928. DOI: 10.3389/fcimb.2024.1465928. DOI: https://doi.org/10.3389/fcimb.2024.1465928
Onofrijchuk JA, Svintsitskyi IA, Solovyova GA. Sklad kyshkovoho mikrobiomu y chastota syndromu nadmirnoho bakterial'noho rostu v patsiyentiv iz syndromom podraznenoyi kyshky iz zakrepamy ta tyreoyidytom Khashymoto z hipotyreozom: pilotne odnotsentrove kros sektsiyne doslidzhennya [Gut microbiome composition and incidence of bacterial overgrowth syndrome in patients with irritable bowel syndrome with constipation and Hashimoto's thyroiditis with hypothyroidism: a pilot single-center cross-sectional study]. Endokrynologia. 2024;29(4):324–330. Ukrainian. DOI: 10.31793/1680-1466.2024.29-4.324. DOI: https://doi.org/10.31793/1680-1466.2024.29-4.324
Wei M, Mehravar S, Leite G, Naji P, Barlow GM, Hosseini A, et al. Relationship between hypothyroidism, risk of small intestinal bacterial overgrowth, and duodenal microbiome alterations. J Clin Endocrinol Metab. 2025 Sep 5:dgaf495. DOI: 10.1210/clinem/dgaf495. PMID: 40908532. DOI: https://doi.org/10.1210/clinem/dgaf495
Sawicka-Gutaj N, Gruszczyński D, Zawalna N, Nijakowski K, Muller I, Karpiński T, Salvi M, Ruchała M. Microbiota alterations in patients with autoimmune thyroid diseases: a systematic review. Int J Mol Sci. 2022 Nov 3;23(21):13450. DOI: 10.3390/ijms232113450. PMID: 36362236; PMCID: PMC9654225. DOI: https://doi.org/10.3390/ijms232113450
Pujo J, De Palma G, Lu J, Galipeau HJ, Surette MG, Collins SM, Bercik P. Gut microbiota modulates visceral sensitivity through calcitonin gene-related peptide (CGRP) production. Gut Microbes. 2023;15(1):2188874. DOI: 10. 1080/19490976.2023.2188874. PMID: 36939195; PMCID: PMC10038053. DOI: https://doi.org/10.1080/19490976.2023.2188874
Singh M, Narayan J, Thakur R, Bhattacharya S, Sonkar SK, Ali W. Association of stress and primary hypothyroidism. J Family Med Prim Care. 2024 Mar;13(3): 1073–1078. DOI: 10.4103/jfmpc.jfmpc_845_23. PMID: 38736825; PMCID: PMC11086806. DOI: https://doi.org/10.4103/jfmpc.jfmpc_845_23
Lucarini E, Di Pilato V, Parisio C, Micheli L, Toti A, Pacini A, et al. Visceral sensitivity modulation by faecal microbiota transplantation: the active role of gut bacteria in pain persistence. Pain. 2022 May;163(5):861–877. DOI: 10.1097/j.pain.0000000000002438. PMID: 34393197; PMCID: PMC9009324. DOI: https://doi.org/10.1097/j.pain.0000000000002438
