Lacticaseibacillus rhamnosus LRJ-1 alleviates constipation through promoting gut Bacteroides-derived γ-aminobutyric acid production

Abstract

Multiple gastrointestinal disorders are associated with impaired gut microbiota. Probiotic <i>Lacticaseibacillus rhamnosus</i> can improve bowel disorder, however, the action mechanism is poorly understood. We integrated multi-omics data from the gut metagenome, metabolome, and colon transcriptome of constipated mice underlying <i>L. rhamnosus</i> LRJ-1 treatment to provide insights into host-microbial metabolic pathway. We found that oral administration of <i>L. rhamnosus</i> LRJ-1 alleviated constipation in mice accompanied by the increased abundances of fecal γ-aminobutyric acid (GABA) and intestinal commensal <i>Bacteroides</i>, and the activation of host GABAergic synapses. <i>B. uniformis</i> was the most enriched <i>Bacteroides</i> species in constipated mice treated with <i>L. rhamnosus</i> LRJ-1, and contributed to the increased abundance of GABA in the gut. Administration of either <i>B. uniformis</i> ATCC 8492 or GABA alleviated constipation and increased gastrointestinal motility in constipated mice. Knockout of the GABA biosynthetic <i>gad</i> gene in <i>B. uniformis</i> ATCC 8492 decreased GABA production and blocked its beneficial effects on constipation. These results confirm the therapeutic potential of <i>L. rhamnosus</i> LRJ-1 in alleviating constipation through promoting gut commensal <i>Bacteroides</i>-derived GABA production. Targeting the gut microbiome to regulate GABA production may open new insights for efficient constipation treatment.