The Thyroid – SIBO Connection by Polina Mak, ND
Abstract
The purpose of this review is to explore the evidence for a causal link between hypothyroidism and Small Intestinal Bacterial Overgrowth (SIBO). Upon reading the paper, the clinician will have a good understanding of when to assess a hypothyroid patient for Small Intestinal Bacterial Overgrowth (SIBO) and the hypothesized pathophysiology behind this link.
Introduction
Hypothyroidism, prevalent in women, the elderly, and certain ethnic groups, is the result of inadequate production of thyroid hormone or the inadequate action of thyroid hormone in target tissues. Primary hypothyroidism is the principal manifestation of hypothyroidism, but other causes include central deficiency of thyrotropin-releasing hormone (TRH) or thyroid-stimulating hormone (TSH), or consumptive hypothyroidism from excessive inactivation of thyroid hormone. Hypothyroidism is defined as either clinical (elevation in the TSH and low levels of FT4) or subclinical (primary hypothyroidism with levels of FT4 are normal with an elevated serum TSH) in nature (Almandoz and Gharib 2012). The wide array of symptoms of hypothyroidism indicates an effect on metabolism and dysfunction in multiple organ systems. Treatment in most cases involves oral administration of exogenous synthetic thyroid hormone.
When a patient presents with hypothyroid symptoms, clinicians may not consider the significant risk for Small Intestinal Bacterial Overgrowth (SIBO) as a consequence of reduced intestinal motility and constipation. However, this is an important underlying pathology to investigate especially if other abdominal symptoms are present such as bloating and abdominal pain, even if mild. The clinical manifestations of SIBO depend upon the severity of disease. While one would assume that the greater the quantity of bacteria, the greater the symptom, this has not been well studied (Sachdev and Pimentel 2013). SIBO can be asymptomatic yet present itself in other conditions outside the gut such as hypothyroidism and autoimmunity (Gasbarrini et al 2007, Patil 2014, Pimentel et al 2002). Today, SIBO is perceived as a condition underlying a wide range of intestinal and even extraintestinal diseases (Quigley et al 2020). Indeed, the pathogenesis of SIBO is still not completely understood.
The most up to date definition of SIBO is an increase in the number of bacteria in the upper gastrointestinal tract, specifically a jejunal aspirate culture exceeding 103 CFU/mL (Takakura and Pimentel 2020). Normally, fewer than 103 organisms/mL are found in the upper small intestine and they consist of Gram-positive bacteria (Dukowicz et al 2007). In a clinical setting, an alternative method for SIBO diagnosis is used; namely a breath test after the ingestion of either 75g of glucose or 10g of lactulose substrate. Hydrogen (H2) and Methane (CH4) gases are measured thereafter, which are produced as a result of microbial metabolism. The North American consensus defines a rise in H2 gas ≥ 20ppm from baseline within 90 minutes of substrate ingestion or a CH4 gas level ≥ 10ppm at any time to be diagnostic for SIBO (Takakura and Pimentel 2020). A third type of gas, hydrogen sulfide (H2S), has recently been explored as another marker of bacterial overgrowth in novel breath testing (the trio-Smart breath test) but needs further investigation. This type of SIBO is sometimes deduced clinically.
SIBO is associated with a variety of symptoms including bloating, abdominal pain, flatulence, abdominal cramping, nausea, constipation, and diarrhea. The type of microbial flora present will play an important role in the manifestation of signs and symptoms of SIBO. Many pathogenic microorganisms can contribute to intestinal overgrowth, including E. coli, Enterococcus, Klebsiella, and Methanobrevibacter smithii (Chojnacki et al 2021). Gram-negative coliforms release toxins called Lipopolysaccharides (LPS), such as Klebsiella species, that damage the intestinal villi and mucosa, creating an inflammation cascade and interfering with the absorptive function of the gut, in turn increasing one’s risk for gut dysbiosis and autoimmunity. This presentation may sometimes be confused for and mimic tropical sprue.
It has been recently proposed that, as M. smithii can overgrow in areas of the gut outside of the small intestine and is not technically characterised as a bacterium, the term intestinal methanogen overgrowth (IMO) is a more appropriate term in cases of methane-positive breath testing (Takakura and Pimentel 2020). Although measurement of CH4 is not always included, the North American consensus and the recent SIBO guidelines both recommend that CH4 be measured concurrently with H2 during breath testing.
The signs and symptoms of SIBO can also arise from the malabsorption of nutrients, alteration in intestinal permeability, inflammation, and/or immune activation that arises from the pathologic bacterial fermentation within the small bowel. A positive H2 breath test has been associated with diarrhea-dominant IBS (IBS-D) and IBS with mixed bowel habits (IBS-M). A predominance of bacteria that metabolize bile salts to unconjugated or insoluble compounds may lead to fat malabsorption or bile acid diarrhea. A positive CH4 breath test is indicative of methanogen overgrowth, which has been associated with constipation-dominant IBS (IBS-C). Microorganisms that preferentially metabolize carbohydrates to short-chain fatty acids and gas may produce bloating without diarrhea because the metabolic products can be absorbed. SIBO could be one of the possible causes of irritable bowel syndrome (IBS) and is more common in females (Chojnacki et al 2021), just like hypothyroidism (Dunn and Turner 2016). The prevalence of SIBO in IBS varies from 30 to 85% depending on the source used (Pimentel et al 2000). High recurrence rates after successful antibiotic treatment emphasise the need to identify aetiological factors (Lauritano et al 2014). It is still unclear if SIBO is a cause, a consequence, or just a phenomenon in relation to the other GI tract disorders (Quigley et al 2020).
The SIBO – Hypothyroid Connection
It has been shown that intestinal dysmotility is one of the risk factors for the development of SIBO (Bohm et al 2013). Gastrointestinal system disorders are often ignored in hypothyroidism because of other systemic symptoms of cardiovascular, neuromuscular, and ocular disorders with thyroid dysfunctions. However, there are reports of disorders of motility and transport functions in the digestive system resulting from hypothyroidism (Yaylali et al 2009). A reduction in the motor activity of the stomach, small intestine, and colon has been reported as well as delayed intestinal transit time in hypothyroid patients. The most probable pathological reason is the intestinal edema due to mucopolysaccharide accumulation in gastrointestinal tissue (Yaylali et al 2009). As a result, changes in the motor activity of the digestive system may result in gastric distension and constipation in hypothyroidism.
Yaylali et al (2009) indeed showed that hypothyroidism significantly decreased gastroesophageal motility in their study of 30 female patients with primary hypothyroidism. Patients with primary hypothyroidism, without any systemic disorder, were followed for two to four months and were all suffering from minor dyspeptic problems; however, none of them suffered from severe gastrointestinal system complaints such as nausea, vomiting, abdominal pain, or constipation. They were examined via gastroesophageal endoscopy. The goal of the research was to determine if there was atrophic gastritis and/or other probable gastric pathologies affecting esophagogastric motor parameters.
Motility disturbances in the form of significantly higher mean esophageal transit time and gastric emptying time were seen in patients with hypothyroidism compared with the control group, showing that motility disturbances in hypothyroidism can lead to gastrointestinal dysfunction overall (Yaylali et al 2009).
Comparing the esophagogastric scintigraphic parameters in the patients with those of healthy cases, Yaylali et al (2009) found a significant reduction in both gastric and esophageal motor functions. These results were similar to previous published studies showing that hypothyroidism affects gastrointestinal system motility (Brechmann et al 2017, Patil 2014, Wang et al 2021). Esophageal transit time and gastric emptying half-time values were found to be significantly higher, while the esophageal emptying value was significantly lower in hypothyroid patients. Therefore, hypothyroid patients show significant reduction in gastric emptying, potentially predisposing them to SIBO as bacteria would have more time to ferment carbohydrates from the diet in one’s stomach/small intestine.
Furthermore, it was proposed that thyroid autoantibodies arising from autoimmune thyroid diseases may lead to atrophic gastritis and mucosal atrophy of the fundus can occur without symptoms. Frequently, there is autoimmune pathogenesis, and it may even develop into pernicious anemia and gastric malignancy in the following years. In the case of hypothyroidism, mucinous material (mucopolysaccharide/hyaluronic acid) may accumulate in gastrointestinal system mucosa, which may lead to dysmotility – more likely in chronic cases (Yaylali et al 2009).
A subset of patients with SIBO show reduced motility with fewer phase III contractions of the migrating motor complexes (Pimentel et al 2002). Brechmann et al (2017) studied 1809 patients who underwent H2 breath testing. It was found that impairment of the gastric acid barrier, impairment of intestinal clearance, immunological factors (drug-induced immunosuppression), altered thyroid gland metabolism (hypothyroidism/levothyroxine therapy) and diabetes mellitus were associated with SIBO. Further analysis revealed that gastric surgery, stenoses, medical immunosuppression, and levothyroxine were the strongest predictors of SIBO, with levothyroxine therapy being the strongest contributor. Therefore, it appears that patients with hypothyroidism and substitution of levothyroxine show a higher risk of SIBO.
A case control study by Lauritano et al (2008) has already revealed a high prevalence of SIBO in patients with autoimmune thyroiditis and hypothyroidism. Multivariate analysis confirmed that levothyroxine therapy is a stronger predictor of SIBO than hypothyroidism. The underlying mechanism is unclear. One might speculate that hypothyroidism leads to hypomotility, but, surprisingly, levothyroxine therapy is even more powerfully correlated with SIBO than hypothyroidism, and does not reverse the hypomotility effects of hypothyroidism.
It has been reported that SIBO may be present in more than half of patients with hypothyroidism (Almandoz and Gharib 2012). One study (Lauritano et al 2007) looked at 50 patients with a history of overt hypothyroidism due to autoimmune thyroiditis. Diagnosis of bacterial overgrowth was based on a positive hydrogen glucose breath test. Bacterial overgrowth positive patients were treated with 1,200mg rifaximin/day for one week. A glucose breath test, gastrointestinal symptoms, and thyroid hormone plasma levels were reassessed one month after treatment. A total of 27 patients with a history of hypothyroidism demonstrated a positive result to the breath test (54%), compared with only two individuals in the control group (5%). The difference was statistically significant. Moreover, abdominal discomfort, flatulence, and bloating were significantly more prevalent in the bacterial overgrowth positive group, so this needs to be paid careful attention to as well when assessing a patient’s risk.
Conclusion
In summary, hypothyroid patients with abdominal discomfort, flatulence or bloating should be assessed for SIBO. Based on the research reviewed in this paper, a history of hypothyroidism is indeed associated with the development of bacterial overgrowth in the small intestine. Breath testing is useful to diagnose SIBO before antibiotic treatment. The cause of SIBO is varied, and this may need to be determined in order to prevent the common recurrence of this condition. A focus on prevention in SIBO is also important in order to avoid repeated courses of antibiotics. Treatment of the underlying cause such as hypothyroidism is the primary mode of prevention.
Studies evaluated above found that impaired immune response, impaired intestinal clearance, and hypothyroidism are the key pathways for the development of small intestinal bacterial overgrowth. The strongest effects derive from levothyroxine treatment and/or the presence of hypothyroidism, although the relevant mechanism of action remains unclear. Intestinal motor dysfunction associated with hypothyroidism could be a strong predisposing factor to bacterial overgrowth in the small intestine.
Impairment of intestinal clearance and levothyroxine use are among the most important contributors for the development of SIBO (Brechmann et al 2017). The pathogenesis of SIBO and underlying predisposing conditions are insufficiently understood, yet three main pathogenetic pathways have been hypothesised: hypo or achlorhydria, impaired intestinal clearance, and immunosuppression.
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