Intestinal permeability linked to inflammation and myofibroblast accumulation in Graves' orbitopathy.
Graves' orbitopathy (GO) results from continuous  stimulation of the TSH (thyroid-stimulating hormone) receptor by autoantibodies. Orbital pre-adipocytes and fibroblasts express the TSH receptor, resulting in expanded retro-orbital tissue and eventually limited eye movement. Recent studies have shown that patients with Graves' disease have a disturbed gut microbiome composition, which has been associated with increased intestinal permeability. This study hypothesizes that enhanced intestinal permeability may aggravate orbital inflammation and, thus, increase myofibroblast differentiation and the degree of fibrosis.   Using a unique Graves's cohort with available serum, fecal, and retro-orbital tissue samples, we link gut intestinal permeability to inflammation and fibrosis in GO.  GO patients displayed significantly higher levels of serum markers of intestinal permeability than healthy controls. The increased intestinal permeability was accompanied by augmented expression of genes marking immune cell infiltration and encoding key proteins for immune cell adhesion, antigen presentation, and cytokine signalling in the orbital tissue. Macrophage influx was positively linked to the extent of T cell influx and fibroblast activation within GO-affected orbital tissues. Moreover, serum lipopolysaccharide-binding protein levels significantly correlated with the abundance of specific Gram-negative gut bacteria, linking the gut to local orbital inflammation.   These data indicate that translocation of bacterial compounds to the systemic circulation in GO may aggravate inflammatory processes within the orbital tissue and, subsequently, augments myofibroblast activation.