Interpreting ME/CFS Patient Clusters Through a Regional Gut-Barrier Model

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is marked by heterogeneous symptom clusters and only partial or short-lived responses to interventions. A unifying mechanistic model which can explain either patient clusters or treatment responses has been lacking. Methods: This hypothesis generating research examined symptom cluster data from Vaes et al. (2023)[@vaes2023] and interpreted the largest clusters through the lens of paracellular gut-barrier physiology. We considered both leak and pore pathways across four regions of the gastrointestinal tract (duodenum/jejunum, ileum, proximal colon, distal colon), with special attention to the gating role of the distal colon mucus barrier. Results: Mapping cluster symptoms to regional barrier dysfunction suggests that symptom heterogeneity can be explained by a single underlying mechanism—pathological paracellular permeability—manifesting at varying sites and intensities. In this framework, all clusters show proximal colon involvement, while roughly half display additional multi-site patterns extending from the duodenum to the distal colon.