Multi-omics reveal that two probiotic strains associated with the gut microbiome and host metabolome contribute to the efficacy of Lactobacillus intervention in alleviating feline chronic kidney disease

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Background Gut dysbiosis in patients with chronic kidney disease (CKD) contributes to deteriorating CKD progression. However, alterations in microbial function and their association with metabolic pathways in feline CKD pathophysiology remain unclear. Our previous findings revealed that Lactobacillus mix (Lm) intervention alleviates CKD progression by recovering dysbiotic gut microbiota and harmonizing the gut environment. Therefore, this study aimed to evaluate the efficacy of Lm intervention in feline CKD and elucidate the mechanisms underlying host-microbe interactions. Results We performed full-length 16S rRNA amplicon sequencing and untargeted metabolomics in a pilot study of cats with stage 2–3 CKD to characterize the intricate interactions between the gut microbiome and serum metabolome. During the eight weeks of Lm intervention, creatinine and blood urea nitrogen levels were reduced or maintained in most cats with CKD. Similarly, gut-derived uremic toxins (GDUT) were downregulated in the serum. Gut microbiome data revealed that Lm markedly improved intestinal diversity, altered the levels of specific bacterial taxa, and upregulated microbial functions, especially those involved in the GDUT and short-chain fatty acid (SCFA) biosynthesis pathways. Furthermore, the distribution of Lm strains was higher in cats who exhibited better outcomes after Lm intervention. The modulation of microbial functions involved GDUT (tyrosine, tryptophan, and phenylalanine metabolism) and SCFA (pyruvate, propanoate, and butanoate metabolism) biosynthesis pathways. Gut-derived metabolites were more explicit in high responders among cats with CKD, demonstrating the downregulation of indoxyl sulfate, p-cresyl sulfate, and phenyl sulfate. This result further demonstrated the upregulation of acetic acid, butyric acid, and propionic acid. Finally, the abundance of Lm strains was negatively or positively correlated with GDUT and SCFA levels. Conclusions This study demonstrates an Lm-mediated interconnection between the modulation of microbial composition, metabolic reactions, and metabolite profiles. Moreover, Lm intervention contributed to varied individualized outcomes in the levels of gut-derived metabolites and kidney function in cats with CKD. This indicates that the colonization of probiotic strains intrinsically impacts their efficacy in alleviating CKD, suggesting that identifying crucial factors influencing microbial colonization is essential for developing adaption strategies to improve outcomes.