A specifically designed multi-biotic reduces uremic toxin generation and improves kidney function

Chronic kidney disease (CKD) is characterized by accumulation of uremic toxins (UTs), such as p-cresyl sulfate and indoxyl sulfate, generated through the transformation of tyrosine and tryptophan by the gut microbiota. Using an <i>ex vivo</i> Simulator of the Human Intestinal Microbial Ecosystem (SHIME) colonized with fecal samples from eight CKD patients or nine healthy volunteers, a higher bacterial generation of p-cresol and indoles post-amino acid enrichment, as well lower basal butyrate levels, in the feces of CKD patients were found. Through <i>in silico</i> data mining, we selected a probiotic strain lacking the capacity to produce UT, i.e. without genes for tryptophanase, tyrosinase and urease. <i>In vitro</i>, we confirmed the potential of cellobiose as a prebiotic supporting the growth of this strain. We further designed a novel specific multi-biotic for CKD (SynCKD) [containing a probiotic <i>Lactobacillus johnsonii NCC533</i>, a prebiotic (1% cellobiose), and a postbiotic (1% short and medium chain triglycerides C4-C8, a source of butyrate)]. SynCKD effectively curtailed UT precursor generation <i>ex vivo</i>. The <i>in vivo</i> efficacy of SynCKD (and the synergic effect) was established in two uremic rodent models, demonstrating lower plasma levels of UTs and enhancing kidney function after 6-8 weeks of treatment. These effects were linked to better gut microbial ecology. Metagenomic analysis revealed reduced microbial genes for tryptophan/tyrosine degradation. This study lays the foundation for SynCKD as a potential therapy to mitigate CKD progression.