GUT-DERIVED UREMIC TOXICITY IN LIONS (PANTHERA LEO) WITH CHRONIC KIDNEY DISEASE: A POTENTIAL THERAPEUTIC TARGET?

Abstract

Lions (Panthera leo) share an intrinsic susceptibility to chronic kidney disease (CKD) with other species of the Felidae. Interestingly, specific gut-derived uremic toxins-indoxyl sulfate, p-cresyl sulfate, and trimethylamine N-oxide (TMAO)-find their origin in amino acids highly abundant in the strict carnivorous feline diet. These toxins are well-recognized mediators of renal tubular inflammation and are associated with disease progression in cats. Therefore, a potential causal involvement of gut-derived uremic toxicity in the pathophysiology of CKD can be hypothesized in Felidae. However, it remains undetermined whether increased accumulation of these toxins is interconnected with renal dysfunction in other Felidae. Therefore, the present study aimed at uncovering shifts in gut-derived uremic toxins and related pathways associated with renal dysfunction in lions by using a targeted metabolomic approach, comparing serum and urine profiles of lions diagnosed with CKD (n = 6) and healthy controls (n = 9). Our results show that selected gut-derived uremic toxins (indoxyl sulfate, P = 0.017; TMAO, P = 0.021; and p-cresyl sulfate, P = 0.020) were increased in lions with renal dysfunction. Our study further underscores the role of a decreasing glomerular filtration rate and tubular dysfunction in toxin accumulation. Especially, indoxyl sulfate showed increased serum-to-urine ratios indicative of renal retention. However, TMAO demonstrated a different pattern, suggesting alternative mechanisms for its elevation in CKD, such as augmented intestinal microbial formation or adsorption of its precursor trimethylamine. Moreover, clear associations between circulating uremic toxin concentrations and renal proteinuria, a marker of tubular dysfunction or damage, were observed, further substantiating the potential underlying role of gut-derived uremic toxicity in the pathophysiology of CKD in lions. Collectively, our findings form a first rationale to implement dietary modifications aimed at mitigating toxin burden in the management of Felidae diagnosed with CKD.