GLP-1 Receptor Agonists, Gut Microbiota, and Chronic Pain: Nutritional Signaling at the Gut–Brain Axis

Background/Objectives: Chronic pain affects more than one in five adults worldwide and is increasingly conceptualized as a disorder of the gut–brain axis. Gut microbial dysbiosis, characterized by reduced alpha-diversity and depletion of short-chain fatty acid (SCFA)-producing taxa such as Faecalibacterium prausnitzii, Lachnospiraceae, and Roseburia, has been mechanistically linked to pain sensitization. Glucagon-like peptide-1 (GLP-1), a nutrient-sensing enteroendocrine hormone, and its pharmacological receptor agonists (GLP-1RAs) both reshape the gut microbiota and modulate pain across multiple phenotypes. This review synthesizes preclinical and clinical evidence positioning the gut microbiota as a proposed nutritional intermediary that links GLP-1RA pharmacology to chronic pain modulation. Methods: We conducted a narrative synthesis of studies retrieved from PubMed, Embase, and Web of Science from inception through 30 June 2026, spanning GLP-1 nutrient sensing, gut microbial alterations in pain, GLP-1RA effects on the microbiome, microbiota-dependent mechanisms, and clinical pain outcomes. Results: GLP-1 is secreted by L-cells in response to nutrients and microbial SCFAs, signaling to the brain through vagal and humoral routes. GLP-1RAs enrich the same anti-inflammatory, SCFA-producing taxa that are depleted in chronic pain, and their anti-inflammatory actions require an intact microbiota. Mechanistically, GLP-1RAs suppress pain through spinal microglial GLP-1 receptor (GLP-1R)/interleukin-10/beta-endorphin signaling, Nucleotide-binding oligomerization domain (NOD)-, Leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibition, and receptor-independent transient receptor potential vanilloid 1 (TRPV1) blockade, largely independent of glycemic control or weight loss. Clinically, evidence is strongest for knee osteoarthritis and idiopathic intracranial hypertension headache, with emerging signals in fibromyalgia, visceral pain, and reduced opioid use. Conclusions: The gut microbiota is proposed to act as both a therapeutic target and a mechanistic intermediary in GLP-1RA-mediated analgesia, a model that awaits direct confirmation in humans. Pain-specific trials incorporating dietary and microbiome endpoints are needed.