Connecting Psychological Processes to Epigenetic Regulation in the Progression of Non-Alcoholic Fatty Liver Disease and Irritable Bowel Syndrome

Irritable Bowel Syndrome (IBS) and Non-Alcoholic Fatty Liver Disease (NAFLD) are traditionally viewed as disorders of distinct organ systems. IBS is a gut–brain axis disorder characterized by abdominal pain, altered bowel habits, and psychological comorbidities, while NAFLD is the hepatic manifestation of metabolic syndrome and is associated with obesity and diabetes. Increasing evidence reveals shared pathophysiological mechanisms leading to dysfunction of the gut–liver–brain axis (GLBA) in both disorders, including psychological distress, gut dysbiosis, impaired intestinal permeability, systemic inflammation, and altered neuroendocrine signaling. Neuroimaging studies have shown that changes in the activity of brain regions involved in interoception, stress regulation, and emotional control may contribute to the development of both disorders. Chronic psychological distress activates the hypothalamic–pituitary–adrenal (HPA) axis, leading to increased cortisol release, alterations in gut microbial composition, and reduced vagal tone. This cascade increases intestinal permeability and microbial translocation, promoting hepatic inflammation and exacerbating gastrointestinal symptoms. Epigenetic control has emerged as a crucial intermediary, linking psychological experiences to long-lasting molecular changes. Chronic distress can impair the GLBA through epigenetic modifications of stress-related genes such as FKBP5 and NR3C1. Notably, psychological interventions may partially reverse these molecular changes, improving outcomes in both disorders. In this review, we explore how psychological distress shapes the clinical trajectories of IBS and NAFLD through GLBA dysfunction and neuroepigenetic reprogramming. Understanding these shared pathways opens the door to innovative, multidisciplinary strategies aimed at modulating the GLBA to improve outcomes in both disorders.