Lactulose, a Disaccharide Prebiotic, Improves the Gut-Kidney Axis via Enhancement of Akkermansia Muciniphila Production.

KEY POINTS: Lactulose, a synthetic disaccharide, promotes Akkermansia muciniphila proliferation. The oral administration of both live and pasteurized forms of Akkermansia muciniphila significantly improved renal function in CKD-induced mice. Lactulose as a prebiotic therapeutic agent exerts the therapeutic effects on the gut-kidney axis via enhancing Akkermansia muciniphila production.

BACKGROUND

Recently, we reported that lactulose, a synthetic disaccharide used to treat chronic constipation, improved the gut-renal axis in mice with adenine-induced CKD. However, the underlying mechanism remains unclear. Akkermansia muciniphila (AKK), a next-generation probiotic, mitigates multiorgan dysfunction, including kidney impairment, by modulating intestinal health. This study aimed to investigate whether lactulose induces AKK proliferation and contributes to its renoprotective effects.

METHODS

CKD was induced in 7-week-old male C57BL/6N mice by administering 0.2% adenine for 4 weeks. After adenine discontinuation, the CKD mice received oral administration of lactulose (7.5% or 10%) or AKK (2×10 CFU/mouse) for 3 weeks. Intestinal permeability was assessed by measuring plasma levels of fluorescent probe for fluorescein isothiocyanate-dextran (4 kDa) and lipopolysaccharides. The composition of the gut microbiota was analyzed using 16S rRNA sequencing.

RESULTS

Lactulose administration significantly ameliorated renal impairment in CKD mice and improved intestinal barrier integrity by increasing intestinal mucosal thickness. In addition, lactulose modulated CKD-induced gut dysbiosis, thereby altering microbiota diversity and composition with a notable increase in AKK abundance. This was further supported by in vitro findings that demonstrated a significant increase in AKK proliferation upon lactulose treatment. Similar to lactulose, oral administration of AKK (both live and pasteurized forms) for 3 weeks attenuated renal damage in CKD mice. Moreover, both forms of AKK significantly improved intestinal barrier function by enhancing mucosal integrity.

CONCLUSIONS

Our findings suggest that lactulose functions as an in vivo AKK inducer, exerting renoprotective effects by improving intestinal barrier function in CKD. These results highlight the potential of lactulose as a prebiotic therapeutic agent for CKD management.