Impact of Gut Microbiota on the Peripheral Nervous System in Physiological, Regenerative and Pathological Conditions

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TL;DR

This review summarizes current evidence that gut microbiota composition influences the peripheral nervous system (PNS) in health, regeneration, and disease. Key findings include that antibiotic-induced dysbiosis impairs somatic nerve regeneration, while probiotics, intermittent fasting, and short-chain fatty acids (e.g., propionate, butyrate) promote nerve repair and muscle health. Clinically, these insights suggest that modulating gut microbiota could be a novel therapeutic strategy for peripheral neuropathies, neuropathic pain, and neuromuscular disorders.

Full summary

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**Background:** The gut microbiota (GM) comprises trillions of microorganisms that influence host physiology through metabolic, immune, and neural signaling. While the GM's role in central nervous system (CNS) function is well-studied, its impact on the peripheral nervous system (PNS) is less understood. This narrative review synthesizes current knowledge on how GM composition affects the somatic and autonomic divisions of the PNS under physiological, regenerative, and pathological conditions.

**Methods:** The authors conducted a narrative review of the literature, focusing on studies published in recent years that investigated GM–PNS interactions. They searched for original research articles, reviews, and preclinical studies using animal models (e.g., germ-free mice, antibiotic-treated mice, fecal microbiota transplantation) and human observational studies. Key areas covered include somatic nerve injury and regeneration, the gut–muscle axis, autonomic nervous system (ANS) function, enteric nervous system (ENS) development, and pathological states such as neuropathic pain, autism spectrum disorder, hypertension, myasthenia gravis, and myopathies.

**Key Results:** - **Somatic nerve regeneration:** Oral antibiotic treatment in mice delayed corneal nerve regeneration after epithelial abrasion, an effect rescued by fecal microbiota transplantation (FMT) and probiotics (VSL#3). Similarly, antibiotics impaired motor recovery after sciatic nerve injury, which probiotics prevented. Intermittent fasting enhanced sciatic nerve regeneration via GM-dependent increases in indole-3-propionate (IPA) and neutrophil recruitment. Propionate, a short-chain fatty acid (SCFA), protected Schwann cells and dorsal root ganglia (DRG) from oxidative stress and promoted axon outgrowth in vitro. - **Gut–muscle axis:** Germ-free and antibiotic-treated mice showed reduced muscle mass, grip strength, and altered neuromuscular junction (NMJ) gene expression. FMT or SCFA supplementation (acetate, propionate, butyrate) restored muscle health. Dysbiosis prevented exercise-induced muscle adaptation, while probiotics (e.g., *Bifidobacterium*, *Lactobacillus*) improved muscle mass and function in aged mice. - **Autonomic nervous system:** Bilateral superior cervical ganglionectomy altered GM composition in rats. Vagotomy reduced risk of Parkinson's disease in human cohort studies and blocked depression-like behaviors in mice. Renal denervation improved cardiac function and gut barrier integrity in heart failure models. - **Enteric nervous system:** Germ-free mice exhibited hypertrophic myenteric neurons, reduced neuronal excitability, and altered gut motility. Butyrate increased cholinergic myenteric neurons and colonic motility via histone acetylation. SCFAs rescued neuronal loss in antibiotic-treated mice. - **Pathological conditions:** - *Neuropathic pain:* GM depletion (antibiotics or germ-free) prevented oxaliplatin-induced mechanical hyperalgesia in mice, mediated by LPS–TLR4 signaling in DRG macrophages. FMT from lean to obese diabetic mice reduced pain and nerve fiber loss. Probiotics attenuated paclitaxel-induced neurotoxicity in vitro. - *Autism spectrum disorder:* Dysbiosis (e.g., increased *Clostridium*, altered Firmicutes/Bacteroidetes ratio) and ANS dysfunction (parasympathetic hypoactivity, sympathetic hyperactivity) are common in autistic patients, suggesting a bidirectional gut–brain axis disruption. - *Hypertension:* Spontaneously hypertensive rats and hypertensive patients show reduced microbial diversity and increased Firmicutes/Bacteroidetes ratio. FMT from normotensive to hypertensive rats lowered blood pressure and plasma noradrenaline. Acetate reduced heart rate via β-1 adrenergic receptor blockade. - *Myasthenia gravis (MG):* MG patients exhibit dysbiosis (decreased Firmicutes/Actinobacteria, increased Bacteroidetes/Proteobacteria) and reduced fecal SCFAs (propionate, butyrate). GM signatures correlated with disease severity and distinguished MG from controls with 100% accuracy. In mice, FMT from MG patients impaired motor activity and upregulated inflammatory cytokines. - *Myopathies:* Duchenne muscular dystrophy (DMD) mice (mdx) show altered GM (increased *Prevotellaceae*) and metabolic profiles. Microbiota depletion reduced muscle inflammation and fibrosis but worsened metabolic dysregulation. Sodium butyrate restored muscle function and reduced endocannabinoid system overactivity in mdx mice.

**Clinical Implications:** The review highlights that GM modulation—via probiotics, prebiotics, FMT, or dietary interventions (e.g., intermittent fasting, SCFA supplementation)—holds therapeutic potential for PNS disorders, including peripheral nerve injuries, neuropathic pain, diabetic neuropathy, hypertension, MG, and DMD. However, most evidence comes from preclinical models, and human studies are limited. Key challenges include establishing causality, identifying specific bacterial strains and metabolites responsible for effects, and translating findings from rodent models to humans. Future research should use standardized gnotobiotic models and well-designed clinical trials to validate these approaches.