Intestinal microbiota regulates the gut-thyroid axis: the new dawn of improving Hashimoto thyroiditis

Abstract

Intestinal microbiota plays an indispensable role in the host's innate immune system, which may be related to the occurrence of many autoimmune diseases. Hashimoto thyroiditis (HT) is one of the most common autoimmune diseases, and there is plenty of evidence indicating that HT may be related to genetics and environmental triggers, but the specific mechanism has not been proven clearly. Significantly, the composition and abundance of intestinal microbiota in patients with HT have an obvious difference. This phenomenon led us to think about whether intestinal microbiota can affect the progress of HT through some mechanisms. By summarizing the potential mechanism of intestinal microflora in regulating Hashimoto thyroiditis, this article explores the possibility of improving HT by regulating intestinal microbiota and summarizes relevant biomarkers as therapeutic targets, which provide new ideas for the clinical diagnosis and treatment of Hashimoto thyroiditis.

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“…In addition to functions related to the control of gastrointestinal homeostasis, metabolism, detoxification, and vitamin synthesis, the gut microbiota has a key role in the development of the lymphoid system, 70% of which constitutes the gut-associated lymphoid tissue (GALT), including macrophages, dendritic cells (DCs), T and B cells, and natural killer cells [ 70 , 74 ]. In healthy conditions, the microbiota has a symbiotic relationship with the host and preserves immune homeostasis through the activation of pattern recognition receptor/pathogen-associated molecular patterns (PRR–PAMP) [ 75 ]. As part of PRR–PAMP recognition, the endotoxins lipopolysaccharides (LPS) retrieved on the cell membrane of Gram-negative bacteria and other PAMPs activate PRRs (e.g., Toll-like receptors (TLRs), nucleotide-binding oligomerization domain leucine-rich repeat-containing receptors (NOD), retinoic acid-inducible gene 1-like receptors, and the C-type lectin receptors) expressed by immune cells and triggering both the innate and adaptive immune responses, thus limiting the colonization of pathobionts (opportunistic microbes whose proliferation derive from the imbalance in the homeostasis of symbiotic communities) [ 16 , 75 , 76 ].…”

“…In healthy conditions, the microbiota has a symbiotic relationship with the host and preserves immune homeostasis through the activation of pattern recognition receptor/pathogen-associated molecular patterns (PRR–PAMP) [ 75 ]. As part of PRR–PAMP recognition, the endotoxins lipopolysaccharides (LPS) retrieved on the cell membrane of Gram-negative bacteria and other PAMPs activate PRRs (e.g., Toll-like receptors (TLRs), nucleotide-binding oligomerization domain leucine-rich repeat-containing receptors (NOD), retinoic acid-inducible gene 1-like receptors, and the C-type lectin receptors) expressed by immune cells and triggering both the innate and adaptive immune responses, thus limiting the colonization of pathobionts (opportunistic microbes whose proliferation derive from the imbalance in the homeostasis of symbiotic communities) [ 16 , 75 , 76 ]. Furthermore, gut microbes are capable of producing short-chain fatty acids (SCFAs, e.g., acetate, butyrate, and propionate) from non-digestible dietary fibers, which, serving as an energy source for colon epithelial cells, contribute to the microbial proliferation and the integrity of the intestinal barrier [ 16 ].…”

“…Although AITD pathogenesis probably occurs due to an interplay between endogenous and exogenous factors, including genetic susceptibility, environmental factors, and autoimmunity, the recognized existence of a gut–thyroid axis and the gut as a relevant endocrine organ led to the hypothesis of a correlation between intestinal microorganisms and AITD [ 75 , 79 ]. Variations in circulating levels of thyroid hormones can be responsible for gastrointestinal disturbance; in particular, the history of overt hypothyroidism has been associated with bacterial overgrowth development in the small intestine, which in turn promotes clinical gastrointestinal symptoms [ 75 , 80 ].…”

“…Although AITD pathogenesis probably occurs due to an interplay between endogenous and exogenous factors, including genetic susceptibility, environmental factors, and autoimmunity, the recognized existence of a gut–thyroid axis and the gut as a relevant endocrine organ led to the hypothesis of a correlation between intestinal microorganisms and AITD [ 75 , 79 ]. Variations in circulating levels of thyroid hormones can be responsible for gastrointestinal disturbance; in particular, the history of overt hypothyroidism has been associated with bacterial overgrowth development in the small intestine, which in turn promotes clinical gastrointestinal symptoms [ 75 , 80 ]. On the other hand, in genetically susceptible subjects, perturbations of the gut microbiota composition or functionality by environmental factors (e.g., long-term diet changes, lifestyle, physical activity, drug therapies, diseases) contribute to the failure of immune tolerance and to the development of a number of immune-mediated disorders, including AITD [ 12 , 81 , 82 ].…”

“…2. Decreased abundance of SCFA-producing bacteria may cause a number of effects: (a) it suppresses the regulation of the sodium/iodine symporter (NIS) expression, the essential plasma membrane protein that mediates active iodide transport into the thyroid gland for thyroid hormone biosynthesis; (b) it reduces the balance ratio between the two main effectors in CD4 + T cells, namely T regulatory (Treg) cells, producing anti-inflammatory cytokines IL-10, transforming growth factor beta 1 (TGF-β1), and promoting tolerance to self and pathogen antigens, and T helper (Th) 17 cells, releasing pro-inflammatory cytokines IL-17 and playing a substantial role in autoimmune diseases; (c) it induces the shift of Th1 to Th2 cells, thus stimulating humoral immune responses against extracellular pathogens; and (d) it activates TLRs, in turn also expressed in thyroid follicular cells in response to various PAMPs, resulting in disruption of immune homeostasis and prolonged production of pro-inflammatory cytokines and chemokines [ 12 , 75 , 88 , 89 , 90 , 91 ]. In particular, the bond of LPS to TLR-4 triggers innate immune responses through the two major inflammation-related signaling pathways in cells, NF-κB and mitogen-activated protein kinase (MAPK), which activate the synthesis of the pro-inflammatory IL-6, associated with autoimmune disease development [ 92 ].…”