Microbiota and Thyroid Interaction in Health and Disease
Authors: Eleonore Fröhlich, Richard Wahl
Journal: Trends in Endocrinology and Metabolism (2019)

The microbiota influences the uptake of iodine, selenium, and iron, and the microbiota may alter the availability of L-thyroxine and toxicity of PTU.Several findings, including the altered microbiota composition in patients with thyroid disorders, the prominent metabolism of thyroid hormones by the microbiota, and that germ-free rats have smaller thyroids than normal rats, support the hypothesis that the gut microbiota also plays a prominent role in thyroid function of the host.A variety of recent studies suggest that the gut microbiota has an enormous impact on human health and disease, and alimentary modulation of the gut microbiota by ingestion of pre, pro-, post-, and synbiotics has been advocated for a variety of diseases.Autoimmune thyroid disorders and metaplastic atrophic gastritis are particularly linked. The microbiota has been identified as an important factor in health and in a variety of diseases. An altered microbiota composition increases the prevalence of Hashimoto's thyroiditis (HT) and Graves' disease (GD). Microbes influence thyroid hormone levels by regulating iodine uptake, degradation, and enterohepatic cycling. In addition, there is a pronounced influence of minerals on interactions between host and microbiota, particularly selenium, iron, and zinc. In manifest thyroid disorders, the microbiota may affect L-thyroxine uptake and influence the action of propylthiouracil (PTU). Although it is relatively well documented that thyroid disorders are linked to the composition of the microbiota, the role of specific genera and the potential use of therapies targeting the microbiota are less clear. The microbiota has been identified as an important factor in health and in a variety of diseases. An altered microbiota composition increases the prevalence of Hashimoto's thyroiditis (HT) and Graves' disease (GD). Microbes influence thyroid hormone levels by regulating iodine uptake, degradation, and enterohepatic cycling. In addition, there is a pronounced influence of minerals on interactions between host and microbiota, particularly selenium, iron, and zinc. In manifest thyroid disorders, the microbiota may affect L-thyroxine uptake and influence the action of propylthiouracil (PTU). Although it is relatively well documented that thyroid disorders are linked to the composition of the microbiota, the role of specific genera and the potential use of therapies targeting the microbiota are less clear. The intestinal microbiota (see Glossary; Box 1) plays a prominent role in gastrointestinal homeostasis and may represent an additional contributing factor to thyroid disorders [1.Young V.B. The intestinal microbiota in health and disease.Curr. Opin. Gastroenterol. 2012; 28: 63-69Crossref PubMed Scopus (131) Google Scholar]. The influence of the microbiota on depression, neurodegenerative diseases, heart disease, obesity, diabetes, immunological disorders, inflammatory bowel diseases, and cancer appears to be established [2.Garcia-Castillo V. et al.Microbiota dysbiosis: a new piece in the understanding of the carcinogenesis puzzle.J. Med. Microbiol. 2016; 65: 1347-1362Crossref PubMed Scopus (73) Google Scholar]. The microbiota may explain why the prevalence of goiter, which has been associated with insufficient iodine (I−) intake, is not correlated to low iodine excretion in South India, and why in Japan hypothyroidism is more prevalent in iodine-rich than in iodine-poor areas [3.Kerakada N. et al.Prevalence of iodine deficiency among multinodular goiter patients: a South Indian study.Int. Surg. J. 2017; 4: 680-684Crossref Google Scholar, 4.Leung A.M. Braverman L.E. Consequences of excess iodine.Nat. Rev. Endocrinol. 2014; 10: 136-142Crossref PubMed Scopus (321) Google Scholar].Box 1The Gut MicrobiotaIt has been reported that the microbiota comprises 2 kg, representing 39 trillion bacteria, in a 70 kg person consisting of 30 trillion human cells. Its action is not limited to local effects in the gut because 20% of host blood metabolites are derived from commensal bacteria. Positive effects for the host include prevention of growth of pathogens, education of the immune system, caloric salvage, the production of short-chain fatty acids (SCFAs), vitamin E and folate, drug metabolism, and deconjugation of bile salts [56.Wilson I.D. Nicholson J.K. Gut microbiome interactions with drug metabolism, efficacy, and toxicity.Transl. Res. 2017; 179: 204-222Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar]. Schmidt et al. listed four main components that determine the composition of the microbiota, (i) microbiome-intrinsic factors including composition, age-dependence, disease, and stochastic effects; (ii) environmental factors comprising the local environment and vertical transmission, for example from the mother, household, and family; (iii) lifestyle including diet, medication, culture, and physical activity; and (iv) host genetics (body mass index, adaptive and innate immunity, and sex [57.Schmidt T.S.B. et al.The human hut microbiome: from association to modulation.Cell. 2018; 172: 1198-1215Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]).Colonization of the gut appears to start already during intrauterine life and is determined by the type of delivery. The first composition of the infant gut resembles the microbiota of the maternal vagina (normal delivery) or skin (Cesarean section). Breast-feeding later plays an important role in the further development of the gut microbiota. The microbiota in children shows high interindividual variation and consists of a relatively low number of bacterial species. After 3 years of life the gut microbiota of the adult is fully developed, the basal composition of which is unique for the individual and remains stable throughout adulthood, with limited variations caused by diet, antibiotic treatment, and challenge with exogenous microbes. Culture-related and geographic differences in the diet appear to be linked to differences in microbiota composition. Phyla enriched in the gastrointestinal (GI) tract are Firmicutes in USA and Russia, whereas Bacteroidetes genus Bacteroides spp. are dominant in France, Jamaica, Spain, China, Korea, and Denmark, and Bacteroidetes genus Prevotella spp. in Germany, Malawi, India, Peru, and Venezuela. Actinobacteria genus Bifidobacterium spp. dominated in Singapore, Indonesia, Scotland, and Sweden. The list demonstrates that classification based only on geographic differences is not possible. More detailed analysis shows that age also markedly influences geographic differences. Bacteroides are active in the hydrolysis and fermentation of exogenous dietary fiber and endogenous mucins. The prevalence of Bacteroides was higher in Italy than in Germany, but differences between adults and elderly individuals within one country were also pronounced [58.Mueller S. et al.Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study.Appl. Environ. Microbiol. 2006; 72: 1027-1033Crossref PubMed Scopus (701) Google Scholar]. It has been reported that the microbiota comprises 2 kg, representing 39 trillion bacteria, in a 70 kg person consisting of 30 trillion human cells. Its action is not limited to local effects in the gut because 20% of host blood metabolites are derived from commensal bacteria. Positive effects for the host include prevention of growth of pathogens, education of the immune system, caloric salvage, the production of short-chain fatty acids (SCFAs), vitamin E and folate, drug metabolism, and deconjugation of bile salts [56.Wilson I.D. Nicholson J.K. Gut microbiome interactions with drug metabolism, efficacy, and toxicity.Transl. Res. 2017; 179: 204-222Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar]. Schmidt et al. listed four main components that determine the composition of the microbiota, (i) microbiome-intrinsic factors including composition, age-dependence, disease, and stochastic effects; (ii) environmental factors comprising the local environment and vertical transmission, for example from the mother, household, and family; (iii) lifestyle including diet, medication, culture, and physical activity; and (iv) host genetics (body mass index, adaptive and innate immunity, and sex [57.Schmidt T.S.B. et al.The human hut microbiome: from association to modulation.Cell. 2018; 172: 1198-1215Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]). Colonization of the gut appears to start already during intrauterine life and is determined by the type of delivery. The first composition of the infant gut resembles the microbiota of the maternal vagina (normal delivery) or skin (Cesarean section). Breast-feeding later plays an important role in the further development of the gut microbiota. The microbiota in children shows high interindividual variation and consists of a relatively low number of bacterial species. After 3 years of life the gut microbiota of the adult is fully developed, the basal composition of which is unique for the individual and remains stable throughout adulthood, with limited variations caused by diet, antibiotic treatment, and challenge with exogenous microbes. Culture-related and geographic differences in the diet appear to be linked to differences in microbiota composition. Phyla enriched in the gastrointestinal (GI) tract are Firmicutes in USA and Russia, whereas Bacteroidetes genus Bacteroides spp. are dominant in France, Jamaica, Spain, China, Korea, and Denmark, and Bacteroidetes genus Prevotella spp. in Germany, Malawi, India, Peru, and Venezuela. Actinobacteria genus Bifidobacterium spp. dominated in Singapore, Indonesia, Scotland, and Sweden. The list demonstrates that classification based only on geographic differences is not possible. More detailed analysis shows that age also markedly influences geographic differences. Bacteroides are active in the hydrolysis and fermentation of exogenous dietary fiber and endogenous mucins. The prevalence of Bacteroides was higher in Italy than in Germany, but differences between adults and elderly individuals within one country were also pronounced [58.Mueller S. et al.Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study.Appl. Environ. Microbiol. 2006; 72: 1027-1033Crossref PubMed Scopus (701) Google Scholar]. Diabetes mellitus is the most common endocrine pathology encountered in clinical practice, followed by thyroid disorders. Thyroid disorders are usually linked to localized (nodules) or general (goiter) enlargement of the thyroid. The prevalence of thyroid nodules depends on the identification method, and ranges from 4% to 7% by palpation and from 20% to 76% by ultrasound in the adult population of the USA [5.Popoveniuc G. Jonklaas J. Thyroid nodules.Med. Clin. North Am. 2012; 96: 329-349Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar]. Frequencies encountered at surgery and autopsy are reported to be between 50% and 65%. In addition to genetic disposition, common risk factors for thyroid disorders are I− insufficiency, age, and sex [6.Strieder T.G. et al.Risk factors for and prevalence of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease.Clin. Endocrinol. 2003; 59: 396-401Crossref PubMed Scopus (187) Google Scholar]. Severe iodine deficiency is linked to hypothyroidism, mild to moderate deficiencies cause multifocal autonomous growth of the thyroid, and excess of iodine is associated with thyroid autoimmunity [7.Chung H. Iodine and thyroid function.Ann. Pediatr. Endocrinol. Metab. 2014; 19: 8-12Crossref PubMed Google Scholar]. Deficiency of iron and selenium are further causes for thyroid disorders, mainly hypothyroidism. Thyroid-stimulating hormone (TSH) levels increase with age, but thyroid dysfunction appears to be most prevalent in the middle-aged population [8.Canaris G.J. et al.The Colorado thyroid disease prevalence study.Arch. Intern. Med. 2000; 160: 526-534Crossref PubMed Scopus (1945) Google Scholar]. Sex differences observed in the middle-aged population decrease with age. Autoimmune diseases (AIDs) in general, and particularly those affecting the thyroid gland, are diagnosed more frequently in women than in men. A similar imbalance in the prevalence of non-communicable diseases that cause 70% of all deaths worldwide (e.g., cardiovascular disease, cancer, chronic respiratory disease, and diabetes) has not been observed [9.Nugent R. Jamison D. What can a UN health summit do?.Sci. Transl. Med. 2011; 3100cm125Crossref Scopus (6) Google Scholar]. There are different levels where the microbiota could act on thyroid function (Figure 1, Key Figure). Region, diet (iodine supply), obesity, age, sex hormones, and AID influence the composition of the intestinal microbiota. Reciprocally, the microbiota has been linked to the prevalence of AID, influencing estrogen and iodine levels, and affecting obesity. Further, it influences the enterohepatic cycling of thyroid hormones, the bioavailability of levothyroxine (L-thyroxine), and the metabolism of the anti-hyperthyroid drug propylthiouracil (PTU). The influence of the microbiota on thyroid function, dysfunction, and the treatment of thyroid diseases will be discussed in this review. Autoimmune thyroid diseases are the most prevalent organ-specific autoimmune diseases and affect 2–5% of the population. Microbial products, particularly short-chain fatty acids (SCFAs), can serve as an energy source for enterocytes and, together with thyroid hormones, enhance enterocyte differentiation and strengthen intercellular tight junctions [10.Kunc M. et al.Microbiome impact on metabolism and function of sex, thyroid, growth and parathyroid hormones.Acta Biochim. Pol. 2016; 63: 189-201PubMed Google Scholar]. An altered microbiota composition in the gut, on the other hand, promotes the development of AID by several hypothesized mechanisms including the generation of self-antigens by post-translational modification of proteins, lipopolysaccharide (LPS)-induced Toll-like receptor 4 activation, induction of a type 1 (Th1) to type 2 (Th2) T helper cell shift, reducing the integrity of intercellular junctions (leaky gut), and inducing transcriptomic, proteomic, and metabolic changes. HT and GD are the major causes of hypothyroidism and hyperthyroidism, respectively. Although both are AIDs, the involved immunological processes are different. The main immunologic features of GD are circulating antibodies against the TSH receptor. HT is characterized by the presence of autoreactive T cells and antibodies against thyroperoxidase and thyroglobulin that lead to destruction of the thyroid gland. It is therefore possible that the role of microbiota is also different. In both autoimmune thyroid diseases (AITDs) the severity of the disease is not correlated to antibody levels. Furthermore, anxiety and depression in GD are not linked to thyroid function or thyroid autoimmunity [11.Bové K. et al.Anxiety and depression are more prevalent in patients with Graves' disease than in patients with nodular goitre.Eur. Thyroid J. 2014; 3: 173-178Crossref PubMed Scopus (26) Google Scholar]. Direct effects on mood by thyroid hormones are unlikely because subclinical hyperthyroidism is associated with better mood compared to euthyroid subjects. An abundance of Actinobacter and Enterobacteriacae was noted in all mood disorders, whereas Faecalibacterium spp. were decreased [12.Huang T. et al.Current understanding of gut microbiota in mood disorders: an update of human studies.Front. Genet. 2019; 10: 98Crossref PubMed Scopus (113) Google Scholar] relative to the distribution of phyla (see classification of bacteria) in the normal gut (Box 2). In addition, the GABA-producing Lactobacillaceae and Bifidobacteria were decreased, and Clostridium and Prevotella were increased, in major depression. Because it is known that microbial metabolites act on the central nervous system, microbial products may lead to the different manifestations. A contribution of the microbiota to AITD has been proposed because transfer of microbiota from conventional to specific pathogen-free (SPF) rats increased their susceptibility to HT. Owing to molecular mimicry, Lactobacillus spp. and Bifidobacterium spp. may induce antibodies crossreacting with thyroperoxidase and thyroglobulin [13.Kiseleva E.P. et al.The role of components of Bifidobacterium and Lactobacillus in pathogenesis and serologic diagnosis of autoimmune thyroid diseases.Benef. Microbes. 2011; 2: 139-154Crossref PubMed Scopus (33) Google Scholar]. The composition of microbiota appears to play an important role in the susceptibility of mouse strains to GD. Several genera of Paludibacter and Allobaculum, Limibacter, Anaerophaga, and Ureaplasma were enriched in susceptible C57BL/6J mice compared to the less-susceptible BALB/c strain [14.Moshkelgosha S. et al.Gut microbiome in BALB/c and C57BL/6J mice undergoing experimental thyroid autoimmunity associate with differences in immunological responses and thyroid function.Horm. Metab. Res. 2018; 50: 932-941Crossref PubMed Scopus (33) Google Scholar]. Patients with GD or HT produce anti-gliadin, anti-transglutaminase, and anti-yeast (Saccharomyces cerevisiae) antibodies. Studies in humans reported a higher abundance of Prevotellaceae and Pasteurellaceae in patients, whereas Enterobacteriaceae, Veillonellaceae, and Rikenellaceae were significantly lower in the disease group compared to controls [15.Ishaq H.M. et al.Molecular alteration analysis of human gut microbial composition in Graves' disease patients.Int. J. Biol. Sci. 2018; 14: 1558-1570Crossref PubMed Scopus (50) Google Scholar]. Compared to healthy controls, a decrease in Bifidobacteria and Lactobacillaceae, and an increase in Enterococcus spp., were reported in hyperthyroid patients [16.Zhou L. et al.Gut microbe analysis between hyperthyroid and healthy individuals.Curr. Microbiol. 2014; 69: 675-680Crossref PubMed Scopus (64) Google Scholar].Box 2Predominant Phyla of the GutIn the human gut, Firmicutes and Bacteroidetes are the predominant phyla. In people on high-carbohydrate diets, Firmicutes dominate together with Bacteroidetes of the genus Prevotella. Bacteroidetes, with Bacteroides as the main genus, predominate when diets rich in protein and fat are ingested [59.De Filippo C. et al.Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 14691-14696Crossref PubMed Scopus (3717) Google Scholar]. Use of antibiotics, chlorinated water, and non-fermented food decreases microbial diversity. Other important factors include host genetics, geographical region, physical exercise, drugs, age, and disease. The high-fat, high-sugar (Western) diet together with mainly sedentary activity result in a predominance of Firmicutes over other phyla, as well as a lower degree of diversity, compared to a low-fat, high-polysaccharide diet. Changes in microbiota composition can be induced to a substantial extent only via long-term changes in dietary habits. The Firmicutes:Bacteroidetes ratio is influenced by body mass index (BMI). Below a BMI of 33, women have lower ratios than men, whereas above BMI 33 men have higher ratios [60.Haro C. et al.Intestinal microbiota is influenced by gender and body mass index.PLoS One. 2016; 11e0154090Crossref PubMed Scopus (366) Google Scholar]. Obesity-induced changes in the microbiota may thus be suggested as an additional factor to explain the reported correlation between thyroid diseases and (central) obesity. Studies have reported a lower abundance of Bacteroidetes and a higher proportion of Firmicutes in women than in men. Males exhibit an increased abundance of Bacteroides and Prevotella compared to females. The lack of sex-related differences in microbiota composition between men and women in postmenopausal women supports a link to estrogen and progesterone levels [61.Santos-Marcos J.A. et al.Influence of gender and menopausal status on gut microbiota.Maturitas. 2018; 116: 43-53Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar].The microbiota has a higher metabolic capacity than the human host, and assists in digesting resistant starch to produce a variety of compounds, mainly SCFAs. Butyrate is not only an energy source for enteric microbiota but also displays anti-inflammatory and antitumor effects in the host. The composition of the microbiota determines resistance against colonization by pathogens; thus, it is not surprising that patients suffering from IBDs possess bacterial community structures that are different from those of healthy controls. The most frequently used term to describe the changed composition of microbiota in diseased versus healthy individuals is dysbiosis. This use is under debate because the link between changes in microbiota composition and disease has only been shown in few models (obesity and IBD), and both the causes and effects of disease are called dysbiosis [62.Olesen S.W. Alm E.J. Dysbiosis is not an answer.Nat. Microbiol. 2016; 1: 16228Crossref PubMed Scopus (68) Google Scholar]. The link between altered microbiota composition and IBD is hypothesized to be reciprocal. Although the microbiota promotes IBD development, chronic inflammation favors an imbalance in the composition of the microbiota by altering the oxidative and metabolic environment of the intestine. In the human gut, Firmicutes and Bacteroidetes are the predominant phyla. In people on high-carbohydrate diets, Firmicutes dominate together with Bacteroidetes of the genus Prevotella. Bacteroidetes, with Bacteroides as the main genus, predominate when diets rich in protein and fat are ingested [59.De Filippo C. et al.Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 14691-14696Crossref PubMed Scopus (3717) Google Scholar]. Use of antibiotics, chlorinated water, and non-fermented food decreases microbial diversity. Other important factors include host genetics, geographical region, physical exercise, drugs, age, and disease. The high-fat, high-sugar (Western) diet together with mainly sedentary activity result in a predominance of Firmicutes over other phyla, as well as a lower degree of diversity, compared to a low-fat, high-polysaccharide diet. Changes in microbiota composition can be induced to a substantial extent only via long-term changes in dietary habits. The Firmicutes:Bacteroidetes ratio is influenced by body mass index (BMI). Below a BMI of 33, women have lower ratios than men, whereas above BMI 33 men have higher ratios [60.Haro C. et al.Intestinal microbiota is influenced by gender and body mass index.PLoS One. 2016; 11e0154090Crossref PubMed Scopus (366) Google Scholar]. Obesity-induced changes in the microbiota may thus be suggested as an additional factor to explain the reported correlation between thyroid diseases and (central) obesity. Studies have reported a lower abundance of Bacteroidetes and a higher proportion of Firmicutes in women than in men. Males exhibit an increased abundance of Bacteroides and Prevotella compared to females. The lack of sex-related differences in microbiota composition between men and women in postmenopausal women supports a link to estrogen and progesterone levels [61.Santos-Marcos J.A. et al.Influence of gender and menopausal status on gut microbiota.Maturitas. 2018; 116: 43-53Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. The microbiota has a higher metabolic capacity than the human host, and assists in digesting resistant starch to produce a variety of compounds, mainly SCFAs. Butyrate is not only an energy source for enteric microbiota but also displays anti-inflammatory and antitumor effects in the host. The composition of the microbiota determines resistance against colonization by pathogens; thus, it is not surprising that patients suffering from IBDs possess bacterial community structures that are different from those of healthy controls. The most frequently used term to describe the changed composition of microbiota in diseased versus healthy individuals is dysbiosis. This use is under debate because the link between changes in microbiota composition and disease has only been shown in few models (obesity and IBD), and both the causes and effects of disease are called dysbiosis [62.Olesen S.W. Alm E.J. Dysbiosis is not an answer.Nat. Microbiol. 2016; 1: 16228Crossref PubMed Scopus (68) Google Scholar]. The link between altered microbiota composition and IBD is hypothesized to be reciprocal. Although the microbiota promotes IBD development, chronic inflammation favors an imbalance in the composition of the microbiota by altering the oxidative and metabolic environment of the intestine. Intestines of GD patients contain higher levels of antibodies against Yersinia enterocolica and Helicobacter pylori, greater colonization by yeast, and less colonization by Bacteroides compared to healthy guts. Microbiota species diversity in hypothyroid patients is higher than in healthy controls. This may be explained by effects related to the longer gastrointestinal (GI) transit time commonly seen in hypothyroid patients. Low cell turnover, low redox potential, and long transit times were proposed as main reasons for the higher diversity of microbiota in the colon [17.Roager H.M. et al.Colonic transit time is related to bacterial metabolism and mucosal turnover in the gut.Nat. Microbiol. 2016; 1: 16093Crossref PubMed Scopus (225) Google Scholar]. Although high diversity has been interpreted as positive for human health, negative effects may also result, namely increased protein catabolism, decreased polyphenol conversion and mucus secretion, and decreased epithelial turnover. Increased tryptophan metabolism, on the other hand, promotes the formation of anti-inflammatory indole derivatives. Levels of Bacteroides richness and diversity similar to those of healthy subjects have also been reported for HT patients, and differences in 27 genera correlated with clinical symptoms [18.Zhao F. et al.Alterations of the gut microbiota in Hashimoto's thyroiditis patients.Thyroid. 2018; 28: 175-186Crossref PubMed Scopus (91) Google Scholar]. The microbiota also influences the progression and course of the disease. Mice with Graves' ophthalmopathy (GO) had decreased levels of Bacteroidetes and increased amounts of Firmicutes in their intestines [19.Masetti G. et al.Gut microbiota in experimental murine model of Graves' orbitopathy established in different environments may modulate clinical presentation of disease.Microbiome. 2018; 6: 97Crossref PubMed Scopus (42) Google Scholar]. This finding mirrors the observations in GD patients. Lactobacillus reuteri supplementation improved thyroid function in mice by increasing free thyroxine (T4), thyroid mass, and physiological parameters such as slimness and skin structure [10.Kunc M. et al.Microbiome impact on metabolism and function of sex, thyroid, growth and parathyroid hormones.Acta Biochim. Pol. 2016; 63: 189-201PubMed Google Scholar]. In broiler chickens, lactic acid bacteria supplementation also increased thyroid hormone levels [higher triiodothyronine (T3):T4 ratio in blood]. These findings appear to indicate that, despite considerable interspecies differences in taxonomic profiles, specific microbial species have similar functions across species. Both HT and GD usually start before menopause, and a role for estrogen in modulating the composition of the microbiota may be considered [20.Baker J.M. et al.Estrogen–gut microbiome axis: physiological and clinical implications.Maturitas. 2017; 103: 45-53Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar]. During perimenopause, progesterone levels decline more than estrogen levels, and the estrogen:progesterone ratio increases. Microbiota may affect estrogen levels by recycling secreted estrogens through β-glucuronidase activity and by the production of estrogenic metabolites. In addition to affecting mineral processing (iodide, selenium, iron, zinc), discussed below, the microbiota may also influence the metabolism of drugs used to treat thyroid disease (summarized in Box 3).Box 3Role of the Microbiota in Therapy of Thyroid DiseasesThe efficacy of oral L-thyroxine supplementation via its absorption in stomach, duodenum, and jejunum by different transporters may depend on the extent to which the microbiota degrades thyroid hormones by oxidation. Higher microbiota numbers in cases of bacterial overgrowth might require higher doses of L-thyroxine. SIBO is defined as the presence of microorganisms exceeding 106 colony-forming units/ml in intestinal aspirates. In hypothyroidism, where the pH of the stomach often increases and gastric motility decreases, reduced protein cleavage in the stomach and bacterial overgrowth may take place [63.Yaylali O. et al.Does hypothyroidism affect gastrointestinal motility?.Gastroenterol. Res. Pract. 2009; 2009529802Crossref PubMed Scopus (34) Google Scholar]. One study suggested that altered colonization of the GI with microbiota, such as due to infections with Helicobacter pylori, leads to the requirement for higher doses of L-thyroxine [64.Centanni M. Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches.Endocrine. 2013; 43: 8-9Crossref PubMed Scopus (43) Google Scholar]. Because of the need for L-thyroxine dissolution at acid pH, it is likely that the increased pH in patients harboring Helicobacter pylori is the main reason for decreased absorption. On the other hand, doses of L-thyroxine therapy to normalize T4 levels in hypothyroid patients with SIBO did not significantly