Tamoxifen Promotes Sustained Bifidobacterium Enrichment in the Gut Microbiota of Male and Female Rats After Spinal Cord Injury

Spinal cord injury (SCI) triggers complex secondary injury cascades that limit neurological recovery. Tamoxifen (TAM), a selective estrogen receptor modulator, exerts neuroprotective effects in experimental SCI, although its underlying mechanisms remain unknown. Given the emerging role of gut microbiota dysregulation in SCI, we investigated whether TAM-associated recovery is accompanied by alterations in gut microbial composition and predicted function. We conducted a longitudinal, sex-inclusive analysis of 61 Sprague–Dawley rats of both sexes assigned to naïve (NAÏVE), sham-placebo (SHAM PLB), sham-TAM (SHAM TAM), injured-placebo (INJ PLB), or injured-TAM (INJ TAM) groups. Injured animals received a moderate T10 contusion followed by a 21-day TAM (0.71 mg/day) or placebo pellet, and fecal samples were collected at 0, 7, 14, 21, and 28 days post-injury. Fecal samples were analyzed by 16S rRNA gene sequencing. Results showed that TAM induced sustained shifts in microbial community composition, with treatment-associated divergence emerging at 14 days post-injury (DPI) in females and 21 DPI in males. Bifidobacterium exhibited the most consistent TAM-associated enrichment across sexes. Bifidobacterium abundance was negatively associated with recovery in INJ PLB animals and positively associated with INJ TAM animals; because behavioral and microbiome measurements were not made in the same animals, these associations are hypothesis-generating only. PICRUSt2 analysis revealed TAM-associated changes in predicted microbial function, including increased glycogen degradation pathways from 14 DPI onward in both sexes. Together, these findings identify sustained TAM-associated taxonomic and predicted functional remodeling of the gut microbiota following SCI.