Gut Microbiota Modulation and Its Implications on Neuropathic Pain: A Comprehensive Literature Review

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TL;DR

This review synthesizes preclinical and limited clinical evidence linking gut microbiota (GM) dysbiosis to neuropathic pain (NP) conditions including chemotherapy-induced peripheral neuropathy, diabetic neuropathy, trauma-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, and low back pain. Key mediators of the gut–brain axis—such as short-chain fatty acids, lipopolysaccharide, tryptophan metabolites, and serotonin—are implicated in NP pathophysiology. The review highlights probiotics, faecal microbiota transplantation, and dietary supplements as potential therapeutic strategies, but emphasizes that most data are preclinical and translation to clinical practice requires further research.

Full summary

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**Background:** Neuropathic pain (NP) is defined by the International Association for the Study of Pain as pain caused by a lesion or disease of the somatosensory nervous system. Its pathophysiology involves neural dysfunction, maladaptive plasticity, and immune responses. Current treatments have limited efficacy and significant side effects, prompting exploration of novel strategies. The gut microbiota (GM), comprising over 10^14 microorganisms—predominantly bacteria from phyla Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria—plays a crucial role in host physiology via metabolic, antimicrobial, and immunomodulatory activities. Dysbiosis has been linked to metabolic, cardiovascular, neurological, gastrointestinal, and renal diseases. The gut–brain axis, a bidirectional communication network involving the vagus nerve, immune mediators, and metabolites, offers a potential target for NP management. This narrative review aims to synthesize current knowledge on GM modulation as a therapeutic strategy for NP.

**Methods:** This is a comprehensive literature review based on previously conducted studies; no new human or animal studies were performed by the authors. The review covers preclinical and clinical evidence on GM modulation in NP, focusing on probiotics, faecal microbiota transplantation (FMT), diet, and supplements. It discusses mechanisms of gut–brain communication, including short-chain fatty acids (SCFAs), lipopolysaccharide (LPS), tryptophan metabolites, serotonin, gamma-aminobutyric acid (GABA), bile acids, and inflammasome activation. The review examines NP conditions: chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy (DN), trauma-induced neuropathic pain (TINP), trigeminal neuralgia (TN), postherpetic neuralgia (PHN), and low back pain (LBP).

**Key Results:** - **CIPN:** In mice, oxaliplatin-induced mechanical hyperalgesia was diminished in germ-free (GF) mice and antibiotic-treated mice; restoration of GM nullified protection. The LPS-TLR4 pathway in dorsal root ganglia (DRG) was implicated. Paclitaxel-induced pain was reduced in antibiotic-treated mice and in a mouse strain (B129) resistant to NP; reciprocal FMT transferred pain susceptibility. Probiotic formulations (DSF, SLAB51) mitigated paclitaxel-induced neurotoxicity in vitro and in vivo. FMT alleviated paclitaxel-induced neuropathy in rats via TLR4 pathway interference. - **DN:** Clinical studies show GM composition differs between DN patients and controls: Firmicutes and Actinobacteria increased, Bacteroidetes decreased; at genus level, Bacteroides and Faecalibacterium decreased, while Escherichia-Shigella, Lachnoclostridium, Blautia, Megasphaera, and Ruminococcus increased. FMT from lean donors improved insulin sensitivity in metabolic syndrome patients. In mice, antibiotic-induced GM modulation improved diabetes and neuropathic pain; FMT from lean to obese neuropathic mice prevented mechanical allodynia and thermal hyperalgesia and reduced nerve fiber loss via decreased DRG neuronal hyperexcitability (ryanodine receptor 2-dependent Ca2+ release). A single case report described remission of painful DN after FMT in an obese type II diabetic woman. - **TINP:** In chronic constriction injury (CCI) mice, GM composition differed from sham: increased Helicobacter, Phascolarctobacterium, Christensenella, Blautia, Streptococcus, Rothia, Lactobacillus; decreased Ignatzschineria, Butyricimonas, Escherichia, AF12, Corynebacterium. Antibiotic pretreatment reduced thermal hyperalgesia and inhibited spinal glial cell activation. FMT from control to antibiotic-treated mice restored NP. However, a large case–control study found that oral fluoroquinolone or amoxicillin-clavulanate therapy correlated with increased peripheral neuropathy incidence. - **TN:** Palmatine, an alkaloid, improved mechanical allodynia in a rat TN model (infraorbital nerve ligation) and modulated the BDNF/TRKB pathway. In colitis models, palmatine increased Bacteroidetes and Firmicutes and decreased Proteobacteria, preventing GM dysbiosis. - **PHN:** A cross-sectional study (27 PHN patients vs. 27 controls) found 37 genera differed: PHN patients had higher Escherichia-Shigella, Streptococcus, Ligilactobacillus, Clostridia; lower Eubacterium, Butyricicoccus, Tyzzerella, Dorea, Parasutterella, Romboutsia, Megamonas, Agathobacter. Strong links between GM and clinical manifestations were reported. - **LBP:** Intervertebral lumbar discs (ILDs) are not sterile; 355 bacterial species identified, with protective Firmicutes and Actinobacteria abundant in normal discs. In a mouse model of lumbar disc herniation (LDH), Lactobacillus paracasei S16 improved behavioral outcomes, increased cell proliferation, reduced apoptosis, and mitigated abnormal inflammatory response (decreased proinflammatory cytokines, increased anti-inflammatory cytokines, altered Th1/Th2/Th17/Treg ratios). In patients with chronic LBP and Modic changes, 1-year supplementation with Lactobacillus Rhamnosus GG showed slight improvement. A cohort study of 36 overweight/obese individuals found those with LBP had higher levels of Adlercreutzia, Roseburia, and Uncl. Christensenellaceae, linked to BMI, serum adipsin, and leptin. A case report showed FMT eased pain in refractory ankylosing spondylitis.

**Clinical Implications:** The review suggests that GM modulation—via probiotics, FMT, diet, and supplements—holds promise as an adjunctive strategy for NP management, particularly for CIPN, DN, TINP, TN, PHN, and LBP. However, most evidence is preclinical, with high heterogeneity and limited translation to humans. The precise mechanisms (e.g., LPS-TLR4 pathway, SCFA signaling, inflammasome activation, neurotransmitter modulation) are complex and not fully elucidated. Future research should focus on standardized animal models, long-term stable GF animals, and well-designed clinical trials to establish causality and optimize therapeutic protocols. Collaboration among pain specialists, neuroscientists, gastroenterologists, and other disciplines is essential to advance this field.