The first study demonstrated a low-grade lymphocytic myenteric ganglionitis in 9 out of 10 patients with severe IBS. More recently, the same group published a followup study showing a lymphocytic infiltrate in 48/65 patients with enteric dysmotility, a newly described FGID entity characterized by severe abdominal symptoms and dysmotility on small bowel manometry. It is unknown what proportion of patients with functional dyspepsia and IBS actually show enteric dysmotility and myenteric plexus abnormalities. Possible mechanisms of symptom generation in FGID include direct activation of sensory neurons by immune mediators, but also disturbed motility linked to alterations in the enteric nervous system. Research in animal models of postinflammatory dysmotility indicated a selective loss of inhibitory innervation. In keeping with this mechanism, we previously reported impaired gastric accommodation in postinfectious functional dyspepsia patients which was linked to an impaired nitrergic relaxation of the fundus. In the current study we confirmed an important reduction of nitrergic neurons in the jejunal myenteric plexus of older BB-rats with myenteric ganglionitis. This finding was confirmed functionally by a decreased nitrergic contribution to the EFS-induced relaxation of the longitudinal smooth muscle under NANC conditions. Recently, we have reported impaired gastric accommodation related to impaired nitrergic inhibition in the BB-DP rat. Additional studies investigating intestinal transit and visceral hypersensitivity are necessary to definitely confirm the BB-DP rat as a model for FGID. Also, it will be worthwhile to investigate whether sex-related differences and psychopathology traits such as anxiety, psychological stress and depression, similar to human FGID, can also be found in this rat model. A potential weakness of our study is the fact that only jejunum was studied, while most symptoms of IBS are thought to originate from the lower gastrointestinal tract. However, also in IBS patients, abnormalities in permeability and inflammation are present in the proximal small intestine. Moreover, we reported altered permeability and immune activation in the duodenum of patients with functional dyspepsia. Nevertheless, involvement of other segments of the gastrointestinal tract like the colon or the stomach needs to be studied in detail in follow-up studies in the BB-rat. In conclusion, we propose the BB-rat as a spontaneous animal model to study the pathogenesis of FGID. In the current study we describe the sequence of early impaired mucosal integrity leading to a GDC-0879 progressive, transmural inflammatory reaction, ultimately resulting in a myenteric ganglionitis with concomitant loss of nitrergic neurons and disturbed motility in the jejunum. These findings suggest an early pathogenic role for the impaired barrier function in the BB-rat model.