Helicobacter pylori, a Gram-negative bacterium that infects the human stomach and accounts for about half of infections worldwide, is difficult to eliminate by the human immune system. Previous studies have shown that H. pylori infection rates are on a decline but still high in developing countries (Maluf et al., 2020). H. pylori infection has been linked to the pathogenesis of numerous diseases of the upper digestive tract, including gastric cancer, gastric ulcer, and gastritis. Moreover, this infection has also been associated with many extragastric diseases, including hematological, allergic, neurological, ophthalmic, metabolic, and dermatologic diseases (Pero et al., 2019; Gravina et al., 2020). Based on these pieces of evidence, it is necessary to explore the relationship between H. pylori infection with other extragastric diseases. Thyroid nodule (TN), which has a prevalence rate of 20%–70% especially in women and the elderly, is a common clinical disorder (Schiaffino et al., 2020). Notably, recent advancements in ultrasonic resolution have also improved the detection rate of TN types (Yu et al., 2020). Previous studies have shown that although TN types are mostly benign, approximately 5%–15% of them may develop into malignancies (Chambara and Ying, 2019). Despite the reliability of the current diagnostics and treatment therapies for TN types, the pathogenesis remains unclear, and several risk factors, including diet, environment, genetics, and abnormal inflammation, have been documented.

Previous studies on the association between H. pylori infection and thyroid diseases have mostly focused on thyroid autoimmunity, and the correlation between H. pylori infection and thyroid autoimmune diseases, such as Graves disease and Hashimoto thyroiditis, has been reported (Benvenga and Guarneri, 2016; Kohling et al., 2017; Figura et al., 2019). Shen et al. (2013) found that H. pylori infection was positively associated with the risk of TN types. Currently, the biological mechanisms that may explain the association mainly include molecular mimicry and dysbiosis (Zhang et al., 2018; Cuan-Baltazar and Soto-Vega, 2020; Docimo et al., 2020). Molecular mimicry theory suggests that there are at least 14 proteins of H. pylori antigen epitope similar to the local amino acid sequence of thyroid endogenous proteins (Benvenga and Guarneri, 2016). This structural similarity can trigger an immune cross-reaction and chronic thyroid inflammation, which may explain the reactive hyperplasia induced by H. pylori infection (Shi et al., 2013). T helper (Th) cells also play an indirect role in this mechanism, which may co-induce the formation of TN types (Shi et al., 2013; Cuan-Baltazar and Soto-Vega, 2020). In addition, intestinal flora affects endocrine signals through the brain–gut axis, and the intestinal microbial diversity of TN patients is significantly higher than that of healthy population (Zhang et al., 2019). It has been found that Lactobacillus, as an important intestinal flora, participates in protecting the thyroid gland from oxidative damage, while H. pylori infection has an inhibitory effect on the survival of this bacterium, which may be related to the pathogenesis of TN types (Iino et al., 2018; Zhang et al., 2019). Although these findings have indicated relationships and potential physiological mechanisms, there is still need for validation using large population epidemiological investigations.

Here, we designed a case-control study to verify the relationship between H. pylori infection and the risk of TN types. Our results provide valuable insights into the etiology of TN types and are expected to guide future designing of management strategies for this common disorder.

Although previous reports have shown that H. pylori infection is involved in various thyroid diseases, very few of these studies analyzed large sample sizes. Results of the present study, comprising a population-based case-control study of community residents and workers from different organizations or companies, indicated that H. pylori infection was not significantly associated with the risk of TN types, which were in contrast with previous reports (Shen et al., 2013). We validated this lack of significant association through ordinal logistic regression analyses.

The findings of our study, as well as those from published literature, indicated that the theoretical mechanisms underlying the possible association between H. pylori infection and the risk of TN types are not rigorous. Molecular mimicry is considered a possible mechanism underlying the relationship between H. pylori infection and pathophysiology mechanisms of thyroid diseases. In fact, previous evidence has suggested that infection-induced chronic inflammation could be a crucial cause of TN types, which may also be related to the structural similarity between H. pylori epitope antigen and thyroid autoantigen (Yu et al., 2019; Liu et al., 2020). It has been reported that 14 proteins of H. pylori antigen epitope are similar to thyroid endogenous proteins, including the segments of human thyrotropin receptor, thyroid autoantigen, and sodium iodide symporter (Benvenga and Guarneri, 2016). Moreover, previous studies have revealed the structural similarities between H. pylori epitope and H-K-ATPase in the thyroid gland as well. Furthermore, immune responses, induced by H. pylori infection, have been shown to indirectly cause Th1 activation and apoptosis and promote secretion of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interferon-gamma (INF-γ), thereby causing thyroid tissue injury and inflammation (Cuan-Baltazar and Soto-Vega, 2020). However, molecular mimicry has only been used to explain the autoimmune thyroid pathophysiology caused by H. pylori infection; thus, it may not explain the comprehensive induction of TN type development. Another possible theoretical mechanism is dysbiosis. Although the composition of gut microbiome of TN patients differs from that of healthy controls (Zhang et al., 2019; Docimo et al., 2020), there is no definite evidence to affirm that H. pylori infection can directly induce such differences in the gut microbiome and the dysbiosis clearly causes TN types.

Results of the present study further indicated that control variables, including gender, age, and BMI, were significantly correlated with the risk of TN types, which was consistent with findings from previous studies (Kwong et al., 2015; Zheng, 2015; Jasim et al., 2020). Collectively, it may imply that the results of this study are reliable and better reflect the association between H. pylori infection and the risk of TN types. Based on our results, we can consider that female, increase in age, and BMI were all risk factors for TN types, while the potential interactions in effects across different confounding factors may also have an impact on the risk of TN types. Therefore, it is possible that the influence of these confounders or selection bias in study population might contribute to false positive results of H. pylori infection associated with TN types that has been previously reported. Our results also suggested that higher diastolic pressure might be a risk factor for TN types. This is similar to the findings of Li et al. (2020) who reported that higher systolic pressure was positively correlated with increased risk of TN types in a female cross‐sectional study. The mechanism may be that H. pylori infection often induces an increase in serum fibrinogen, which interferes with the release of nitric oxide from vascular endothelium. This mechanism tends to inhibit normal relaxation of blood vessels, while vasoconstriction is the main factor leading to increased diastolic BP (Migneco et al., 2003). However, the potential biological mechanisms underlying the observed association between diastolic pressure and the risk of TN types necessitate further exploration using animal experiments or cohort studies.

This study had some limitations. Firstly, we also compiled family history including past diseases suffered and lifestyle habits of the study population, which may be potential confounding factors. However, the information was incomplete due to low response rate of supplementary questionnaires; thus, it was not finally included in the regression models. In addition, considering the feasibility of the study implementation, there may be other potential confounding factors such as radiation exposure to head and neck that have not been collected as well, and these factors may also have an impact on the results. Secondly, there may still be potential selection bias in study population. Patients with a high risk for malignant TN types, diagnosed with TI-RADS5 or TI-RADS6, are few in this research. This might be attributed to the fact that residents and workers with higher TI-RADS grades may be more inclined to directly choosing hospital treatment, as opposed to receiving physical examination at a health management center, though residents and workers in the surveyed areas had a high prevalence of regular health screenings. Moreover, Anhui is one of the most densely populated provinces in eastern China. Actually, the included participants in this research were mainly from urban areas of Anhui, and the majority was from the capital city, Hefei. These factors may also affect the representation of the study population. Finally, this study employed a case-control survey design; thus, it was difficult to analyze the causality between potential risk factors and TN types. Therefore, further better designed studies are needed to validate these results.

In summary, we found no significant correlation between H. pylori infection and neither TN type risk nor the degree of its malignant differentiation, indicating that H. pylori infection neither promotes nor induces TN types. Therapies for eliminating H. pylori are not recommended for TN patients as an independent measure to reduce the risk of malignant differentiation. Further explorations, using large prospective studies, are needed to fully elucidate the association between H. pylori infection and more thyroid disorders.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by The Ethics Committee of the First Affiliated Hospital of Anhui Medical University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

HW: Research design. X-SW: Article drafting and data analysis. GJ: Data collation and analysis. Y-HL, T-TY, and Y-WZ: Data collation. X-HX, KL, and Y-TL: Data collection. M-WC and H-QH: Revisions of article. All authors contributed to the article and approved the submitted version.

This study was supported by the National Key R&D Program of China (2020YFC2006500, 2020YFC2006502).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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