Fibroblast-to-myofibroblast differentiation in gut wall and abdominal soft tissue corrupts normal bowel function in “irritable bowel syndrome”: A hypothesis

• The hypothesis suggests a central role for intestinal myofibroblasts in the pathophysiology of IBS. • Myofibroblasts affect visceral organ function and integrity. • Myofibroblasts, via altered ECM, and through their communication with other cells, may be key drivers of enteric pathology. • Factors such as diet, herbicides, and other environmental and biochemical substances can stimulate intestinal myofibroblasts. • Identifying myofibroblast pathways provides a rationale for developing mechanism-based diagnostics & therapeutics for IBS. Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal discomfort, pain, and altered bowel habits, as well as extraintestinal manifestations such as fatigue, musculoskeletal pain, gastroesophageal reflux, depression, and anxiety. Despite prevalences of approximately 10% in the general population, its fundamental etiopathogenesis remains unclear. Current theories mainly point toward a multifactorial aetiology crediting psychological stress with a prominent role. The paradigms currently embraced for IBS are mainly based on, and emphasize, the gut-brain axis, visceral hypersensitivity, central sensitization, neuroendocrinology, dysbiosis, motility abnormalities, and post-infectious persistent low-grade mucosal inflammation. Yet, they don’t fully explain its diverse clinical presentations nor IBS’s symptomatic overlap with conditions such as fibrositis/fibromyalgia syndrome. Available treatments are mostly symptomatic and provide limited relief, indicating a still major gap in our mechanistic understanding. This paper proposes a hypothesis for IBS etiopathogenesis as an organic disease of the extracellular matrix driven by myofibroblast overactivity in the gut wall and abdominal soft tissue, along with downstream consequences stemming from tissue stiffness. This process is theorized to mechanically compress visceral structures and nerves, impair synchronized organ motility, and induce substrate stiffness-mediated visceral hypersensitivity. In this theoretical framework the extraintestinal manifestations reflect mechanistic overlap with fibromyalgia, which helps unify functional-psychosomatic syndromes as a medical entity with a shared organic mechanism. This mechanism, along with known mechanisms of gut dysbiosis and the gut-brain axis, helps explain “medically unexplained symptoms” of fibromyalgia-type syndromes and offers testable predictions for future research and suggests new avenues for IBS diagnosis and treatment.