Targeting γ-aminobutyric acid pathways in irritable bowel syndrome: bridging central nervous system, enteric dysfunction, and the microbiota-gut-brain axis

Irritable bowel syndrome (IBS) is a complex and multifaceted disorder of the gut-brain interaction. Recent evidence suggests that γ-aminobutyric acid (GABA) may be involved in the development of IBS symptoms. Indeed, the GABAergic system exerts many gastrointestinal functions, such as modulation of visceral pain, intestinal motility, intestinal barrier integrity and immune response. GABA receptors and transporters are present and may influence intestinal functions at multiple levels: in the central nervous system, in the enteric nervous system and at the gut epithelial level. Furthermore, the gut microbiota is capable of producing GABA. This may also suggest a direct link between. intestinal microbiota composition and GABAergic tone within the microbiota gut-brain axis. Confirming the involvement of GABAergic dysregulation in IBS, altered GABA signaling and reduced GABA levels have been observed in this disease, especially in diarrhea-predominant subtypes. This review explores the possible roles of GABAergic dysregulation in IBS pathogenesis across multiple levels: in the central nervous system circuits, at the intestinal level, and in the microbiota-gut-brain axis interactions. Moreover, preclinical and limited clinical data regarding possible therapeutic approaches targeting the GABAergic system in IBS are discussed in the review. These include GABA receptor modulators, dietary supplements, probiotics producers of GABA and novel combinations such as GABA-Melissa officinalis. However, despite promising results, current evidence on these approaches is limited and mainly based on animal models. Therefore, randomized clinical trials are needed to establish the efficacy of GABA-based products in IBS management.