Relation of Gut Microbes and L-Thyroxine Through Altered Thyroxine Metabolism in Subclinical Hypothyroidism Subjects

Zhenyu Yao, Meng Zhao, Ying Gong, Wenbin Chen, Qian Wang, Yilin Fu, Tian Guo, Jiajun Zhao, Ling Gao, Tao Bo, Zhenyu Yao, Meng Zhao, Ying Gong, Wenbin Chen, Qian Wang, Yilin Fu, Tian Guo, Jiajun Zhao, Ling Gao, Tao Bo

Abstract

Thyroxine metabolism is an important topic of pathogenesis research and treatment schedule of subclinical hypothyroidism (SCH). L-Thyroxine replacement therapy (LRT) is usually recommended for severe SCH patients only. Our previous studies reported that disordered serum lipid of mild SCH people could also benefit from LRT. However, the benefits were different among individuals, as shown by the variations in drug dosage that required to maintain thyroid-stimulating hormone (TSH) stability. Alternative pathways, such as sulfation and glucuronidation of iodothyronine, may play a role in thyroid hormones metabolism in peripheral tissues aside from thyroid. Conjugated thyroxine can be hydrolyzed and reused in tissues including gastrointestinal tract, in which gut microbiota are one of the most attractive physiological components. On this site, the roles of gut microbiota in thyroidal metabolism should be valued. In this study, a cross-sectional study was performed by analyzing 16S rDNA of gut microbiota in mild SCH patients treated with L-thyroxine or not. Subjects were divided by serum lipid level, L-thyroxine treatment, or L-thyroxine dosage, respectively. Relationship between gut microbiome and serum profile, L-thyroxine treatment, and dose were discussed. Other metabolic disorders such as type 2 diabetes and hypertension were also taken into consideration. It turned out that microbiome varied among individuals divided by dose and the increment of L-thyroxine but not by serum lipid profile. Relative abundance of certain species that were associated with thyroxine metabolism were found varied among different L-thyroxine doses although in relatively low abundance. Moreover, serum cholesterol may perform relevance effects with L-thyroxine in shaping microbiome. Our findings suggested that the differences in L-thyroxine dosage required to maintain TSH level stability, as well as the SCH development, which was displayed by the increased L-thyroxine doses in subsequent follow-up, had relationship with gut microbial composition. The reason may due to the differences in thyroxine metabolic capacity in gut. In addition, the metabolic similarity of iodothyronines and bile acid in gut also provides possibilities for the correlation between host's thyroxine and cholesterol levels. This study was registered with ClinicalTrials.gov as number NCT01848171.

Keywords: Clinical Trails; L-Thyroxine treatment; gut microbiome; subclinical hypothyroidism; thyroid hormone metabolism.

Copyright © 2020 Yao, Zhao, Gong, Chen, Wang, Fu, Guo, Zhao, Gao and Bo.

Figures

Figure 1
Figure 1
Trial profile. (A) All subjects were divided into the STG [subclinical hypothyroidism (SCH) with high serum triglyceride level] group, STC (SCH with high serum cholesterol level) group, SM (SCH with both high serum triglyceride and cholesterol level) group, and S (SCH with normal serum lipid profile) group according to the guidelines of Chinese adult dyslipidemia prevention and treatment (2016 edition). (B) All subjects were divided into L-thyroxine replacement therapy (LRT) group and NC group. In addition, subjects in LRT group were manually subdivided into low dose (L) group, middle dose (M) group, and high dose (H) group based on the doses of L-thyroxine.
Figure 2
Figure 2
Principle component analysis among different groups divided by (A) lipid profile, (B) with or without L-thyroxine treatment, (C) L-thyroxine dosage within the LRT group, and (D) the development of L-thyroxine dosage within the LRT group in genus levels. X- and Y-axes represent the first principal component (PCA1) and the second principal component (PCA2), respectively. The percentage in the brackets represents the relative contribution of the component to the total difference. Each sample corresponded to one dot in the graph. Different group is represented by different color.
Figure 3
Figure 3
Principle coordination analysis among different groups divided by (A) lipid profile, (B) with or without L-thyroxine treatment, (C) L-thyroxine dosage within the LRT group, and (D) the development of L-thyroxine dosage within the LRT group in genus levels. X- and Y-axes represent the first principal component (PCoA1) and the second principal component (PCoA2), respectively. The percentage in the brackets represents the relative contribution of the component to the total difference. Each sample corresponded to one dot in the graph. The circle summarized the area of gathering of the dots. Different groups, together with the circle, are represented by different colors.
Figure 4
Figure 4
Trial profile. Subjects in the L-thyroxine replacement therapy (LRT) group were manually subdivided into L-D (L-thyroxine dose increased) and L-ND groups (L-thyroxine did not increase) based on whether the dose had increased during the last 9 months or not.
Figure 5
Figure 5
Relative abundance analysis of some metabolic representative species. (A,B) Relative abundance of the genera Odoribacter and Enterococcus among groups divided by L-thyroxine dosage. (C–E) Relative abundance of the genera Alistipes, Anaerotruncus, and Ruminococcus divided by L-thyroxine dosage development within the LRT group. Error bars are calculated as a standard error (SEM). The differences among groups were compared using nonparametric tests. *p < 0.05, **p < 0.01, defined statistically significance.
Figure 6
Figure 6
Canonical correspondence analysis (CCA) was used to evaluate the possible association of gut microbes with environmental factors, in all samples (upper row), LRT groups (middle row), and NC group (lower row), respectively. The red arrows in the figure represent different environmental factors, gray arrows were set pointing to species, and the length of the gray arrows quantitatively indicated the correlation significance between certain species and environmental factors. The angle between any two arrows is representative of the correlation between certain species or species and environmental factors. The acute angle indicates positive correlation, and the obtuse angle is a negative correlation.

References

    1. Alberti K. G., Zimmet P. Z. (1998). Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. 15, 539–553. 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>;2-S
    1. Beaud D., Tailliez P., Anba-Mondoloni J. (2005). Genetic characterization of the beta-glucuronidase enzyme from a human intestinal bacterium, Ruminococcus gnavus. Microbiology 151, 2323–2330. 10.1099/mic.0.27712-0
    1. Bo T., Shao S., Wu D., Niu S., Zhao J., Gao L. (2017). Relative variations of gut microbiota in disordered cholesterol metabolism caused by high-cholesterol diet and host genetics. Microbiologyopen 6:491. 10.1002/mbo3.491
    1. Caporaso J. G., Kuczynski J., Stombaugh J., Bittinger K., Bushman F. D., Costello E. K., et al. . (2010). QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335–336. 10.1038/nmeth.f.303
    1. Chan A. A., Bashir M., Rivas M. N., Duvall K., Sieling P. A., Pieber T. R., et al. . (2016). Characterization of the microbiome of nipple aspirate fluid of breast cancer survivors. Sci. Rep. 6:28061. 10.1038/srep28061
    1. Collet T. H., Bauer D. C., Cappola A. R., Asvold B. O., Weiler S., Vittinghoff E., et al. . (2014). Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis. J. Clin. Endocrinol. Metab. 99, 3353–3362. 10.1210/jc.2014-1250
    1. Cooper D. S., Biondi B. (2012). Subclinical thyroid disease. Lancet 379, 1142–1154. 10.1016/S0140-6736(11)60276-6
    1. Desai M. S., Seekatz A. M., Koropatkin N. M., Kamada N., Hickey C. A., Wolter M., et al. . (2016). A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353 e1321. 10.1016/j.cell.2016.10.043
    1. Donohoe D. R., Garge N., Zhang X., Sun W., O'Connell T. M., Bunger M. K., et al. . (2011). The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526. 10.1016/j.cmet.2011.02.018
    1. Du X., Fang L., Xu J., Chen X., Zhang J., Bai Y., et al. . (2019). Prevalence, awareness, treatment and control of hypertension and sodium intake in Zhejiang Province, China: a cross-sectional survey in 2017. PLoS ONE 14:e0226756. 10.1371/journal.pone.0226756
    1. Feng J., Zhao F., Sun J., Lin B., Zhao L., Liu Y., et al. . (2019). Alterations in the gut microbiota and metabolite profiles of thyroid carcinoma patients. Int. J. Cancer 144, 2728–2745. 10.1002/ijc.32007
    1. Fisher K., Phillips C. (2009). The ecology, epidemiology and virulence of Enterococcus. Microbiology 155, 1749–1757. 10.1099/mic.0.026385-0
    1. Flores R., Shi J., Gail M. H., Gajer P., Ravel J., Goedert J. J. (2012). Association of fecal microbial diversity and taxonomy with selected enzymatic functions. PLoS ONE 7:e39745. 10.1371/journal.pone.0039745
    1. Gao N., Zhang W., Zhang Y. Z., Yang Q., Chen S. H. (2013). Carotid intima-media thickness in patients with subclinical hypothyroidism: a meta-analysis. Atherosclerosis 227, 18–25. 10.1016/j.atherosclerosis.2012.10.070
    1. Garber J. R., Cobin R. H., Gharib H., Hennessey J. V., Klein I., Mechanick J. I., et al. . (2012). Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 22, 1200–1235. 10.1089/thy.2012.0205
    1. Ge X., Pan J., Liu Y., Wang H., Zhou W., Wang X. (2018). Intestinal crosstalk between microbiota and serotonin and its impact on gut motility. Curr. Pharm. Biotechnol. 19, 190–195. 10.2174/1389201019666180528094202
    1. Gerard P. (2013). Metabolism of cholesterol and bile acids by the gut microbiota. Pathogens 3, 14–24. 10.3390/pathogens3010014
    1. Granado-Serrano A. B., Martin-Gari M., Sanchez V., Riart Solans M., Berdun R., Ludwig I. A., et al. . (2019). Faecal bacterial and short-chain fatty acids signature in hypercholesterolemia. Sci. Rep. 9:1772. 10.1038/s41598-019-38874-3
    1. Grimaldi R., Gibson G. R., Vulevic J., Giallourou N., Castro-Mejia J. L., Hansen L. H., et al. . (2018). A prebiotic intervention study in children with autism spectrum disorders (ASDs). Microbiome 6:133. 10.1186/s40168-018-0523-3
    1. Hays M. T. (1988). Thyroid hormone and the gut. Endocr. Res. 14, 203–224. 10.3109/07435808809032986
    1. Hazenberg M. P., de Herder W. W., Visser T. J. (1988). Hydrolysis of iodothyronine conjugates by intestinal bacteria. FEMS Microbiol. Rev. 4, 9–16.
    1. Huang S., Pang D., Li X., You L., Zhao Z., Cheung P. C., et al. . (2019). A sulfated polysaccharide from Gracilaria Lemaneiformis regulates cholesterol and bile acid metabolism in high-fat diet mice. Food Funct. 10, 3224–3236. 10.1039/C9FO00263D
    1. Kemp P. F., Aller J. Y. (2004). Bacterial diversity in aquatic and other environments: what 16S rDNA libraries can tell us. FEMS Microbiol. Ecol. 47, 161–177. 10.1016/S0168-6496(03)00257-5
    1. Kester M. H., Kaptein E., Van Dijk C. H., Roest T. J., Tibboel D., Coughtrie M. W., et al. . (2002). Characterization of iodothyronine sulfatase activities in human and rat liver and placenta. Endocrinology 143, 814–819. 10.1210/endo.143.3.8686
    1. Kolodziejczyk A. A., Zheng D., Shibolet O., Elinav E. (2019). The role of the microbiome in NAFLD and NASH. EMBO Mol. Med. 11:9302. 10.15252/emmm.201809302
    1. Konrad P., Chojnacki J., Kaczka A., Pawlowicz M., Rudnicki C., Chojnacki C. (2018). Thyroid dysfunction in patients with small intestinal bacterial overgrowth. Pol. Merkur. Lekarski 44, 15–18.
    1. Lawson P. A., Song Y., Liu C., Molitoris D. R., Vaisanen M. L., Collins M. D., et al. . (2004). Anaerotruncus colihominis gen. nov., sp. nov., from human faeces. Int. J. Syst. Evol. Microbiol. 54, 413–417. 10.1099/ijs.0.02653-0
    1. Liu L. S., Writing Group of Chinese Guidelines for the Management of Hypertension . (2011). 2010 Chinese guidelines for the management of hypertension. Zhonghua Xin Xue Guan Bing Za Zhi 39, 579–615.
    1. Liu X. L., He S., Zhang S. F., Wang J., Sun X. F., Gong C. M., et al. . (2014). Alteration of lipid profile in subclinical hypothyroidism: a meta-analysis. Med. Sci. Monit. 20, 1432–1441. 10.12659/MSM.891163
    1. McQuade C., Skugor M., Brennan D. M., Hoar B., Stevenson C., Hoogwerf B. J. (2011). Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors: a PreCIS database study. Thyroid 21, 837–843. 10.1089/thy.2010.0298
    1. Minarikova Z., Gaspar L., Kruzliak P., Celecova Z., Oravec S. (2014). The effects of treatment on lipoprotein subfractions evaluated by polyacrylamide gel electrophoresis in patients with autoimmune hypothyroidism and hyperthyroidism. Lipids Health Dis 13:158. 10.1186/1476-511X-13-158
    1. Natividad J. M., Verdu E. F. (2013). Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. Pharmacol. Res. 69, 42–51. 10.1016/j.phrs.2012.10.007
    1. Nicolucci A. C., Hume M. P., Martinez I., Mayengbam S., Walter J., Reimer R. A. (2017). Prebiotics reduce body fat and alter intestinal microbiota in children who are overweight or with obesity. Gastroenterology 153, 711–722. 10.1053/j.gastro.2017.05.055
    1. Ochs N., Auer R., Bauer D. C., Nanchen D., Gussekloo J., Cornuz J., et al. . (2008). Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann. Intern. Med. 148, 832–845. 10.7326/0003-4819-148-11-200806030-00225
    1. Palermo F. A., Mosconi G., Avella M. A., Carnevali O., Verdenelli M. C., Cecchini C., et al. . (2011). Modulation of cortisol levels, endocannabinoid receptor 1A, proopiomelanocortin and thyroid hormone receptor alpha mRNA expressions by probiotics during sole (Solea solea) larval development. Gen. Comp. Endocrinol. 171, 293–300. 10.1016/j.ygcen.2011.02.009
    1. Pearce S. H., Brabant G., Duntas L. H., Monzani F., Peeters R. P., Razvi S., et al. . (2013). 2013 ETA guideline: management of subclinical hypothyroidism. Eur. Thyroid J. 2, 215–228. 10.1159/000356507
    1. Pedersen H. K., Gudmundsdottir V., Nielsen H. B., Hyotylainen T., Nielsen T., Jensen B. A., et al. . (2016). Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376–381. 10.1038/nature18646
    1. Polansky H., Javaherian A. (2015). The latent cytomegalovirus decreases telomere length by microcompetition. Open Med. 10, 294–296. 10.1515/med-2015-0042
    1. Rodondi N., den Elzen W. P., Bauer D. C., Cappola A. R., Razvi S., Walsh J. P., et al. . (2010). Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 304, 1365–1374. 10.1001/jama.2010.1361
    1. Rotondi M., Magri F., Chiovato L. (2010). Risk of coronary heart disease and mortality for adults with subclinical hypothyroidism. JAMA 304:2481. 10.1001/jama.2010.1786
    1. Sanna S., van Zuydam N. R., Mahajan A., Kurilshikov A., Vich Vila A., Vosa U., et al. . (2019). Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat. Genet. 51, 600–605. 10.1038/s41588-019-0350-x
    1. Sayin S. I., Wahlstrom A., Felin J., Jantti S., Marschall H. U., Bamberg K., et al. . (2013). Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235. 10.1016/j.cmet.2013.01.003
    1. Sun Z., Pei W., Guo Y., Wang Z., Shi R., Chen X., et al. . (2019). Gut microbiota-mediated NLRP12 expression drives the attenuation of dextran sulphate sodium-induced ulcerative colitis by Qingchang Wenzhong Decoction. Evid. Based Complement Alternat. Med. 2019:9839474. 10.1155/2019/9839474
    1. Thomas C., Pellicciari R., Pruzanski M., Auwerx J., Schoonjans K. (2008). Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov. 7, 678–693. 10.1038/nrd2619
    1. Togo A. H., Valero R., Delerce J., Raoult D., Million M. (2016). “Anaerotruncus massiliensis,” a new species identified from human stool from an obese patient after bariatric surgery. New Microb. New Infect. 14, 56–57. 10.1016/j.nmni.2016.07.015
    1. Turnbaugh P. J., Hamady M., Yatsunenko T., Cantarel B. L., Duncan A., Ley R. E., et al. . (2009). A core gut microbiome in obese and lean twins. Nature 457, 480–484. 10.1038/nature07540
    1. Virili C., Centanni M. (2015). Does microbiota composition affect thyroid homeostasis? Endocrine 49, 583–587. 10.1007/s12020-014-0509-2
    1. Visser T. J. (1996). Pathways of thyroid hormone metabolism. Acta Med. Austriaca 23, 10–16.
    1. Wu S. Y., Green W. L., Huang W. S., Hays M. T., Chopra I. J. (2005). Alternate pathways of thyroid hormone metabolism. Thyroid 15, 943–958. 10.1089/thy.2005.15.943
    1. Wu S. Y., Huang W. S., Chopra I. J., Jordan M., Alvarez D., Santini F. (1995). Sulfation pathway of thyroid hormone metabolism in selenium-deficient male rats. Am. J. Physiol 268, E572–E579. 10.1152/ajpendo.1995.268.4.E572
    1. Yang T., Santisteban M. M., Rodriguez V., Li E., Ahmari N., Carvajal J. M., et al. . (2015). Gut dysbiosis is linked to hypertension. Hypertension 65, 1331–1340. 10.1161/HYPERTENSIONAHA.115.05315
    1. Zhang X., Shao S., Zhao L., Yang R., Zhao M., Fang L., et al. . (2019). ER stress contributes to high-fat diet-induced decrease of thyroglobulin and hypothyroidism. Am. J. Physiol. Endocrinol. Metab. 316, E510–E518. 10.1152/ajpendo.00194.2018
    1. Zhao M., Liu L., Wang F., Yuan Z., Zhang X., Xu C., et al. . (2016). A worthy finding: decrease in total cholesterol and low-density lipoprotein cholesterol in treated mild subclinical hypothyroidism. Thyroid 26, 1019–1029. 10.1089/thy.2016.0010
    1. Zhao M., Zhang X., Gao L., Song Y., Xu C., Yu C., et al. . (2018). Palmitic acid downregulates Thyroglobulin (Tg), Sodium Iodide Symporter (NIS), and Thyroperoxidase (TPO) in human primary thyrocytes: a potential mechanism by which lipotoxicity affects thyroid? Int. J. Endocrinol. 2018:4215848. 10.1155/2018/4215848
    1. Zhou L., Li X., Ahmed A., Wu D., Liu L., Qiu J., et al. . (2014). Gut microbe analysis between hyperthyroid and healthy individuals. Curr. Microbiol. 69, 675–680. 10.1007/s00284-014-0640-6
    1. Zollner G., Marschall H. U., Wagner M., Trauner M. (2006). Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol. Pharm. 3, 231–251. 10.1021/mp060010s

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