Elevated Levels of Circulating Biomarkers Related to Leaky Gut Syndrome and Bacterial Translocation Are Associated With Graves’ Disease

Abstract

BackgroundA growing number of studies have found dysbiosis of the intestinal microbiota in patients with Graves’ disease (GD). The intestinal epithelial barrier serves as the first line of defense, protecting the immune system from excessive stimulation of microbiota and toxins. Most autoimmune diseases are associated with a gut barrier dysfunction (leaky gut) which allows bacterial translocation. However, to date, potential correlations between intestinal barrier dysfunction and GD have not been explored.MethodsSerum lipopolysaccharide (LPS), intestinal fatty acid-binding protein (I-FABP), zonulin, D-lactate, and diamine oxidase (DAO) were measured to assess barrier integrity in 91 patients with GD (61 initial GD and 30 euthyroid GD) and 44 healthy controls. The quality of life (QOL) of patients with GD was assessed using the thyroid-specific patient-reported outcome (ThyPRO-39) questionnaire.ResultsThe serum levels of LPS, I-FABP, zonulin, and D-lactate were significantly higher in patients with initial GD than in healthy controls. Logistic regression analysis revealed that zonulin and D-lactate were independently associated with risk for GD and circulating zonulin could effectively distinguish patients with initial GD from healthy controls. Correlation analyses showed that I-FABP, LPS, and D-lactate were positively associated with FT4 and negatively associated with TSH. In addition, circulating LPS, zonulin, and D-lactate levels were all independent predictors of TRAb levels. Moreover, higher circulating LPS levels in patients with GD were associated with more severe hyperthyroidism (higher concentrations of FT3, FT4, and TRAb and lower TSH concentrations) and worse scores of hyperthyroid and eye symptoms.ConclusionPatients with initial GD show a disrupted intestinal barrier, characterized by elevated levels of leaky gut biomarkers. Increased intestinal permeability and bacterial translocation were associated with TRAb levels and hyperthyroidism in GD. Further research is required to elucidate the underlying mechanisms.

Efficacy evaluation of probiotics combined with prebiotics in patients with clinical hypothyroidism complicated with small intestinal bacterial overgrowth during the second trimester of pregnancy

“…Intestinal leakage is an important mechanism leading to the inflammatory state of the body. Intestinal epithelial cells are connected by tight junctions and seal cell bypass to act as a selective osmotic barrier ( Zheng et al., 2021 ). When intestinal leakage occurs, disturbance of intestinal flora may lead to an increase in intestinal permeability, bacterial translocation, and the abundance of inflammation-related flora, such as Gammaproteobacteria and Pasteurellaceae .…”

The Endotoxin Hypothesis of Parkinson's Disease

“…LPS is present in food products 13 and blood levels of LPS rise transiently after a high‐fat meal (‘metabolic endotoxemia ’ ), 14 so diet affects circulating LPS levels. LPS levels are also elevated in patients with liver disease, obesity, and intestinal permeability 15‐17 …”

“…LPS levels are also elevated in patients with liver disease, obesity, and intestinal permeability. [15][16][17] Although the gut is the main source of LPS in the body, systemic bacterial infections can increase blood LPS levels and PD risk. For example, periodontitis (gum disease) increases blood LPS levels, 18 and is associated with a 1.4-fold increased risk of PD, and dental scaling to reduce infection also reduces PD risk.…”

Establishing the cut-offs of leaky gut syndrome diagnostic: where are we now?

“…LGS can be associated with bacterial translocation and entry of toxins into systemic circulation, resulting with numerous gastrointestinal disorders and extra-intestinal diseases (Table 1) (Takiishi et al, 2017;Binienda et al, 2020;DiTommaso et al, 2021). These include, but are not limited to: 1) inflammatory bowel disorders (IBD) (Michielan and D'Incà, 2015;Jaworska et al, 2019;Turpin et al, 2020), 2) necrotising enterocolitis (NEC) (Jaworska et al, 2019), 3) irritable bowel syndrome (Shulman et al, 2014;Michielan andD'Incà, 2015, Jaworska et al, 2019), 4) gluten-related disorders, such as celiac disease, wheat-associated allergy and non-celiac gluten/wheat sensitivity (Cardoso-Silva et al, 2019;Jaworska et al, 2019), 5) non-alcoholic fatty liver disease (Michielan and D'Incà, 2015;Kessoku et al, 2021;Portincasa et al, 2022), 6) metabolic syndrome (Chakaroun et al, 2020), 7) type 1 (Fasano, 2020) and type 2 diabetes (Chakaroun et al, 2020), 8) Parkinson disease, 9) Alzheimer's disease,10) dementia, 11) autism spectrum disorders, 12) schizophrenia, 13) major depressive disorders, chronic fatigue syndrome or myalgic encephalomyelitis, multiple sclerosis, ankylosing spondylitis, cancer (glinoma, hepatocellular carcinoma) (Obrenovich, 2018;Fasano, 2020), allergic asthma (Farshchi et al, 2017), autoimmune thyroid diseases (AITD) Hashimoto's thyroiditis (HT), Graves' disease (GD) (Knezevic et al, 2020;Zheng et al, 2021), and systemic lupus erythematosus (SLE) (Paray et al, 2020). Altered intestinal permeability has been described in some conditions, such as sepsis, systemic inflammatory response syndrome (SIRS), multiple organ failure (MOF), acute pancreatitis, major surgery and severe trauma (Michielan and D'Incà, 2015).…”