Buyang Huanwu Decoction promotes neurorepair after spinal cord injury through a Lactobacillus johnsonii–indole-3-lactic acid–AhR–PI3K/Akt axis

BACKGROUND: Spinal cord injury (SCI) induces gut microbiota dysbiosis, which significantly affects recovery. Buyang Huanwu Decoction (BHD), a traditional Chinese medicine formula, has shown therapeutic effects on SCI. Although BHD is known to modulate gut microbiota, whether its benefits are mediated through the gut-spinal cord axis remains unclear. METHODS: A rat SCI model was established. BHD was administered orally, and fecal microbiota transplantation (FMT) from BHD-treated rats (BHD-FMT) was performed to assess neuroprotective and gut-protective effects. Behavioral testing, histology, and immunofluorescence evaluated motor recovery, inflammation, and neuroregeneration. Gut microbiota profiling was performed using 16S rDNA sequencing and metagenomics, while targeted metabolomics quantified tryptophan metabolites. Transcriptomics validated key pathways, and a microbiota-metabolite-signaling network was constructed. RESULTS: BHD significantly improved motor function, reduced spinal inflammation, and promoted neuronal survival and axonal regeneration. It restored gut function, reduced colonic inflammation, and enhanced ZO-1 and Occludin expression, which were further confirmed by FMT. BHD-FMT reshaped the gut microbiota and enriched Lactobacillus johnsonii, which correlated positively with recovery. Metabolomics showed increased tryptophan metabolites, including indole-3-lactic acid (ILA) and indole-3-propionic acid (IPA), with ILA strongly associated with functional improvement. Transcriptomic analysis and Western blot validation demonstrated that BHD-FMT activated the AhR-PI3K/Akt pathway, which was suppressed by an AhR antagonist. CONCLUSION: BHD promotes neuroregeneration after SCI by reshaping gut microbiota and enhancing tryptophan metabolism, potentially exerting its effects through the L. johnsonii-ILA-AhR-PI3K/Akt network. These findings reveal a gut-spinal cord axis-mediated mechanism of BHD and highlight microecological targets for SCI therapy.