Abstract / Summary
The decay of smooth muscle contractility is a major trigger of aging-related intestinal hypomotility, which imposes a substantial healthcare burden. Despite this, effective targeted therapy for this condition remains unavailable. Here, we identified the probiotic Bifidobacterium animalis subsp. lactis BL-99 as a microbiota modulator that restores gut motility through the bile acid (BA)-mediated rescue of smooth muscle contractile function. In a randomized, double-blind clinical trial (ChiCTR2300077583, with the primary endpoint of whole-gut transit time [WGTT], and secondary endpoints including bowel movement frequency, symptom severity, and quality-of-life measures) and naturally aged mouse models, BL-99 intervention significantly reduced the WGTT and concurrently remodeled the gut microbiota. This suppressed bile salt hydrolase-expressing bacteria, which preserved conjugated BA pools, including taurochenodeoxycholic acid (TCDCA). Mechanistic investigations revealed that BL-99 was associated with enhanced expression of the serum response factor (SRF)–myocardin (Myocd) transcriptional axis in colonic smooth muscle cells (SMCs), restoring contractile apparatus components (e.g., α-SMA, SM-MHC). Crucially, TCDCA administration recapitulated BL-99 regulation of intestinal SMC contractile protein expression by inhibiting the PI3K/AKT pathway. Our findings established a microbiota-BA-SMC signaling axis that ameliorates age-related intestinal hypomotility, positioning both BL-99 and TCDCA as precision therapeutic candidates targeting SMC-related dysmotility. Here, in a randomized, double-blind clinical trial in older adults, the authors show that probiotic Bifidobacterium animalis subsp. lactis BL-99 intervention reduces whole-gut transit time and remodels the gut microbiota suppressing bile salt hydrolase-expressing bacteria, further revealing a mechanistic role of taurochenodeoxycholic acid in the phenotype.