The Microbiome in Systemic Sclerosis: Pathophysiology and Therapeutic Potential

Abstract

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disease with unknown etiology characterized by multi-organ fibrosis. Despite substantial investigation on SSc-related cellular and molecular mechanisms, effective therapies are still lacking. The skin, lungs, and gut are the most affected organs in SSc, which act as physical barriers and constantly communicate with colonized microbiota. Recent reports have documented a unique microbiome signature, which may be the pathogenic trigger or driver of SSc. Since gut microbiota influences the efficacy and toxicity of oral drugs, evaluating drug-microbiota interactions has become an area of interest in disease treatment. The existing evidence highlights the potential of the microbial challenge as a novel therapeutic option in SSc. In this review, we have summarized the current knowledge about molecular mechanisms of SSc and highlighted the underlying role of the microbiome in SSc pathogenesis. We have also discussed the latest therapeutic interventions using microbiomes in SSc, including drug-microbiota interactions and animal disease models. This review aims to elucidate the pathophysiological connection and therapeutic potential of the microbiome in SSc. Insights into the microbiome will significantly improve our understanding of etiopathogenesis and developing therapeutics for SSc.

Keywords: animal model; bioavailability; microbiota; oral drugs; systemic sclerosis.

Figure 1

Pathological processes involved in SSc. The main pathophysiological hallmarks of SSc are immune disorders, vasculopathy, and fibrosis in tissues and organs. Diverse innate and adaptive immune cells are involved in EC activation and fibrosis. Vascular alterations and trans-differentiation toward myofibroblasts contribute to inflammation and fibrosis in the perivascular space and surrounding tissues.

Figure 2

Proposed mechanism of SSc-associated gastrointestinal involvement. GIT involvement of SSc is likely associated with neuropathy and myopathy caused by the activation of the immune system. Th2 CD4 T cells induce myofibroblast formation and subsequent perivascular and interstitial fibrosis, affecting GIT dysmotility. Anti-muscarinic receptor (M₃-R) autoantibodies can reduce GIT contractility by interfering with the acetylcholine binding on intestinal smooth muscle. Additionally, dysbiosis of commensal gut microbiota, which may regulate NO production, may influence blood flow, mucosal integrity, and GIT motility. Diminished peristalsis and luminal content stasis may be involved in the development of GI manifestations in SSc.

Figure 3

Microbiota alterations in the gut, skin, and lungs of patients with SSc.