Nephrology · Medical Literature
Lactiplantibacillus plantarum WJL ameliorates chronic kidney disease by inhibiting fibroblast growth factor 21 adaptive stress response via low protein diet.
Abstract
Low-protein diets (LPD) are recommended in chronic kidney disease (CKD) to reduce disease progression. However, their clinical efficacy and safety are debated due to the risk of protein-energy wasting. A deeper mechanistic understanding is therefore required. Herein, the metabolic effects of LPD in both murine models and a randomized controlled trial in nondiabetic CKD patients were investigated, focusing on glucose homeostasis, plasmatic uremic toxin (UTs) levels, gut microbiota remodeling, and endocrine adaptations. In both experimental and clinical settings, LPD improved glucose tolerance and significantly decreased circulating levels of gut-derived UTs while reducing body weight (-33% weight gain in mice and a decrease in body mass index of ~-0.5 kg/m2 in humans). These metabolic improvements were associated with alterations in gut microbiota composition and function, including the downregulation of microbial pathways involved in aromatic amino acid biosynthesis. In both mice and patients, LPD triggered a significant hepatic induction of fibroblast growth factor 21 (FGF21), an endocrine regulator of amino acid deficiency (+2.9-fold in human and 28-fold in mice) FGF21 levels correlated negatively with lean mass and positively with fat mass and glycemic control, supporting a dual role in metabolic adaptation and catabolic signaling. To mitigate the adverse nutritional effects of LPD, we administered Lactiplantibacillus plantarum WJL (LpWJL), a probiotic previously found to enhance growth of under nutritional stress in CKD mice. LpWJL restored circulating amino acid levels, suppressed FGF21 induction (-26%) and stress-related biosynthetic responses, and preserved body weight (+247% weight gain) and composition, without impairing the benefits of LPD on kidney and metabolic parameters. The present findings identify UTs and FGF21 as crucial factors of the metabolic response to LPD, and support microbiota-targeted strategies, such as LpWJL supplementation, to enhance LPD efficacy. Clinical trials are, however, required to confirm their relevance in CKD management.
Clinical relevance
In nondiabetic patients with chronic kidney disease (CKD), does a low-protein diet (LPD) improve key metabolic parameters via gut microbiota remodeling and FGF21-mediated endocrine signaling, and can adjunctive Lactiplantibacillus plantarum WJL (LpWJL) probiotic supplementation mitigate the nutritional risks of LPD while preserving its metabolic benefits? __SNAPSHOT__ {"studyDesign":"Hybrid translational study: parallel murine experimental models combined with a randomized controlled trial (RCT) component in human CKD patients","setting":"Not fully reported from abstract alone; includes both animal laboratory and clinical settings in nondiabetic CKD patients","sampleSize":"Not reported (human RCT arm sample size not specified in the abstract); murine cohort size not reported","population":"Nondiabetic patients with chronic kidney disease (CKD); murine CKD models used in parallel","intervention":"Low-protein diet (LPD); with a secondary arm administering Lactiplantibacillus plantarum WJL (LpWJL) probiotic in CKD mice on LPD","comparator":"Standard diet (murine models); comparator for the human RCT arm not fully specified in the abstract","primaryOutcome":"Metabolic effects of LPD including glucose homeostasis, circulating uremic toxin (UT) levels, gut microbiota remodeling, and endocrine adaptations (FGF21 induction); impact of LpWJL on nutritional parameters and FGF21 suppression","followUp":"Not reported","fundingSource":"Not reported"}
Key findings
In both murine and human settings, LPD improved glucose tolerance and significantly reduced circulating gut-derived uremic toxin levels. Body weight was reduced: mice on LPD showed −33% weight gain, and human patients experienced a decrease in BMI of approximately −0.5 kg/m². These metabolic improvements were associated with gut microbiota compositional and functional changes, including downregulation of microbial pathways involved in aromatic amino acid biosynthesis — a pathway directly linked to uremic toxin precursor production. LPD triggered significant hepatic induction of fibroblast growth factor 21 (FGF21), an endocrine sensor of amino acid deficiency, with a +2.9-fold increase in humans and a 28-fold increase in mice. FGF21 levels correlated negatively with lean mass and positively with fat mass and glycemic control, suggesting a dual role in metabolic adaptation and catabolic signaling. To address the nutritional risks of LPD, LpWJL probiotic was administered to CKD mice on LPD. LpWJL restored circulating amino acid levels, suppressed FGF21 induction by −26%, attenuated stress-related biosynthetic responses, and preserved body weight (+247% weight gain vs. LPD alone), without impairing the established metabolic benefits of LPD. Absolute effect sizes, confidence intervals, and p-values for the primary human RCT outcomes were not reported in the abstract. NNT/NNH cannot be calculated from available data.
Practice implications
This study establishes a mechanistic link between LPD, gut microbiota remodeling, uremic toxin reduction, and hepatic FGF21 induction in both a murine CKD model and a human nondiabetic CKD cohort, providing translational biological plausibility for LPD's benefits in CKD. The identification of FGF21 as a biomarker of catabolic stress under LPD — correlating inversely with lean mass — is clinically important given the well-documented risk of protein-energy wasting with prolonged LPD. The LpWJL probiotic data are currently murine only; no human clinical data on LpWJL supplementation are reported in this abstract. Whether LpWJL translates these protective effects into human CKD patients on LPD has not been established. The study population was restricted to nondiabetic CKD patients, limiting generalizability to the large and clinically dominant diabetic CKD population. The abstract does not report eGFR trajectories, proteinuria, or hard renal endpoints (e.g., dialysis initiation, doubling of serum creatinine), so it is not known whether the observed metabolic improvements translate to meaningful nephroprotection over time. Because only an abstract was available for this analysis, full methodology, statistical rigor, randomization details, and blinding cannot be assessed. Results should be interpreted as hypothesis-generating and mechanistically informative rather than practice-defining. __LIMITATIONS__ Only an abstract was available; complete methodology, statistical analyses, confidence intervals, and p-values for human outcomes are not assessable.,Human RCT sample size is not reported; underpowered trials in CKD are common and limit reliability of effect estimates.,The LpWJL probiotic intervention was conducted exclusively in murine models; no human data on probiotic supplementation are presented, precluding any clinical translation of the LpWJL findings.,The magnitude of FGF21 induction differs dramatically between species (+2.9-fold in humans vs. 28-fold in mice), raising questions about the cross-species validity of the murine mechanistic model.,No hard renal endpoints (eGFR decline rate, time to dialysis, doubling of serum creatinine, mortality) are reported; outcomes are surrogate metabolic markers.,Study restricted to nondiabetic CKD patients — the largest CKD subgroup (diabetic nephropathy) is excluded, severely limiting generalizability.,Follow-up duration is not reported, so durability of metabolic benefits and long-term nutritional safety cannot be assessed.,Potential confounding from dietary adherence, baseline CKD staging heterogeneity, and concurrent nephroprotective therapy is not addressed in the abstract.,Funding source not reported; independence from commercial probiotic interests cannot be verified.,The clinical significance of a −0.5 kg/m² BMI reduction and +2.9-fold FGF21 induction in humans is uncertain without patient-level body composition data and lean mass measurements. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This translational study provides novel mechanistic evidence that LPD reduces uremic toxins and improves glucose metabolism in nondiabetic CKD partly through gut microbiota remodeling and hepatic FGF21 induction, with FGF21 serving as a potential biomarker of catabolic stress. In murine CKD models, the probiotic Lactiplantibacillus plantarum WJL suppressed LPD-induced FGF21 and preserved lean body mass without negating LPD's metabolic benefits, but this has not yet been demonstrated in humans. Clinicians should not alter LPD prescribing practices or adopt LpWJL supplementation based on this abstract alone; confirmatory human trials with hard renal endpoints and nutritional safety data are required.