The irritable bowel syndrome (IBS) may well reflect a neurological problem emerging from disordered neurophysiology in the enteric nervous system (ENS), the central nervous system (CNS), or in both simultaneously. A normally functioning ENS is essential for a symptom-free gut: the gut does not work at all when the ENS is absent (e.g., Hirschsprung’s disease). This chapter deals mainly with enteric neuroimmune pathophysiology to the exclusion of multiple other explanations, hypotheses and theories, such as small intestinal bacterial overgrowth, gas generating foods, fructose malabsorption, maladjustment to life circumstances, among others that speak to IBS.

Concepts for the neuropathophysiology of the hallmark symptoms of IBS, which include abdominal pain, defecation urgency, bloating, and alterations in stool consistency, emerge in this chapter. Emphasis is focused on gaining acquaintance with the neurophysiology of visceral pain, ENS control of intestinal motility, and ENS control of mucosal secretion as a requirement for productive basic and translational interpretation of the hallmark symptoms.

Mastocytotic enteritis is explored as a biomarker in the context of the diarrhea-predominant form of IBS. This involves release by enteric mast cells of multiple inflammatory mediators that act in paracrine signaling manner at receptors expressed by ENS neurons and intramural sensory afferent terminals. Afferent sensitization amplifies nociceptive input to the CNS and becomes a factor in IBS-related pain.

Enteric mast cells use immunological memory to detect specific foreign antigens as they appear and reappear inside the gut lumen throughout the lifetime of an individual. Paracrine signaling relays the information on foreign antigen identity to the ENS. Paracrine signals, coming from mast cells, are interpreted in turn by the ENS as a labeled code for the presence of an antigenic threat in the intestinal lumen. The ENS interprets the signal as a potential threat to homeostatic integrity and “calls up,” from its program library, secretory and propulsive motor behavior organized for rapid and effectively expulsion of the menace. Commonalty of symptoms between postinfectious IBS and acute psychogenic stress in IBS are likely reflections of neuroimmune communication that includes degranulation of enteric mast cells.

Autoimmune-related enteric neuropathy underlies symptoms in disorders that include lower esophageal sphincter achalasia, intestinal pseudoobstruction, small-cell carcinoma in the lungs, and IBS. Functional symptoms in a subset of IBS patients reflect enteric neuronal damage or ablation related to circulating antienteric autoimmune antibodies.