Polysaccharide from Ribes nigrum L. Ameliorates Diabetic Kidney Injury in Mice by Modulating the GUDCA/GPBAR1 Axis through the Remodeling of the Gut Microbiota.

BCP treatment improved glucose homeostasis and alleviated renal inflammation and fibrosis in high-fat diet/streptozotocin-induced diabetic mice.

• The diabetic nephropathy model was induced using a high-fat diet combined with streptozotocin (HFD/STZ) in mice.
• BCP exerted therapeutic effects including improving glucose homeostasis.
• BCP treatment alleviated both renal inflammation and renal fibrosis in the DN mouse model.
• The study identified BCP as a potential novel dietary strategy for diabetic nephropathy.

BCP altered gut microbiota composition and notably enriched Akkermansia muciniphila in diabetic mice.

• Gut microbiota composition was assessed using 16S rRNA sequencing.
• BCP treatment notably enriched Akkermansia muciniphila among the altered gut microbiota communities.
• The role of A. muciniphila was validated through fecal microbiota transplantation (FMT) experiments.
• The enrichment of A. muciniphila was further validated via exogenous A. muciniphila administration.

A positive correlation was identified between Akkermansia muciniphila abundance and glycoursodeoxycholic acid (GUDCA) levels.

• The correlation was identified through combined 16S rRNA sequencing and metabolomic analysis.
• Exogenous A. muciniphila supplementation significantly increased the level of serum GUDCA in DN mice.
• GUDCA is a bile acid metabolite whose levels were modulated through gut microbiota remodeling by BCP.

Elevated GUDCA activated the bile acid receptor GPBAR1 in the kidney, suppressing NF-κB/NLRP3 inflammasome activation and TGF-β-mediated fibrosis.

• GUDCA acted through the bile acid receptor GPBAR1 (also known as TGR5) expressed in the kidney.
• GPBAR1 activation by GUDCA suppressed the NF-κB/NLRP3 inflammasome pathway.
• GPBAR1 activation also suppressed TGF-β-mediated fibrosis signaling.
• This mechanism defines the GUDCA/GPBAR1 axis as the key pathway mediating BCP's renoprotective effects.

BCP improves renal outcomes through a gut microbiota–bile acid metabolism axis, supporting its potential as a novel dietary strategy for diabetic nephropathy.

• The mechanism involves sequential steps: BCP remodels gut microbiota → enriches A. muciniphila → increases serum GUDCA → activates renal GPBAR1 → suppresses inflammation and fibrosis.
• The findings support BCP's potential as a novel dietary strategy for DN.
• The study used fecal microbiota transplantation to validate the causal role of gut microbiota changes in mediating BCP's effects.