The guanylate cyclase C agonist linaclotide ameliorates the gut–cardio–renal axis in an adenine-induced mouse model of chronic kidney disease

Abstract

Background Cardiorenal syndrome is a major cause of mortality in patients with chronic kidney disease (CKD). However, the involvement of detrimental humoral mediators in the pathogenesis of cardiorenal syndrome is still controversial. Trimethylamine-N-oxide (TMAO), a hepatic metabolic product of trimethylamine generated from dietary phosphatidylcholine or carnitine derived by the gut microbiota, has been linked directly with progression of cardiovascular disease and renal dysfunction. Thus, targeting TMAO may be a novel strategy for the prevention of cardiovascular disease and chronic kidney disease. Methods Linaclotide, a guanylate cyclase C agonist, was administered to adenine-induced renal failure (RF) mice and changes in renal function and levels of gut-derived uremic toxins, as well as the gut microbiota community, were analyzed using metabolomic and metagenomic methods to reveal its cardiorenal effect. Results Linaclotide decreased the plasma levels of TMAO at a clinically used low dose of 10 μg/kg in the adenine-induced RF mouse model. At a high concentration of 100 μg/kg, linaclotide clearly improved renal function and reduced the levels of various uremic toxins. A reduction in TMAO levels following linaclotide treatment was also observed in a choline-fed pro-atherosclerotic model. Linaclotide ameliorated renal inflammation and fibrosis and cardiac fibrosis, as well as decreased the expression of collagen I, transforming growth factor-β, galectin-3 (Gal-3) and ST2 genes. Plasma levels of Gal-3 and ST2 were also reduced. Because exposure of cardiomyocytes to TMAO increased fibronectin expression, these data suggest that linaclotide reduced the levels of TMAO and various uremic toxins and may result in not only renal, but also cardiac, fibrosis. F4/80-positive macrophages were abundant in small intestinal crypts in RF mice, and this increased expression was decreased by linaclotide. Reduced colonic claudin-1 levels were also restored by linaclotide, suggesting that linaclotide ameliorated the ‘leaky gut’ in RF mice. Metagenomic analysis revealed that the microbial order Clostridiales could be responsible for the change in TMAO levels. Conclusion Linaclotide reduced TMAO and uremic toxin levels and could be a powerful tool for the prevention and control of the cardiorenal syndrome by modification of the gut–cardio–renal axis.

Constipation in CKD

“…In a study using an adenineinduced renal failure mouse model, Mishima et al 19 demonstrated that lubiprostone ameliorated the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment, suggesting its therapeutic potential for CKD. Recently, similar renoprotective properties have also been demonstrated for both lactulose and linaclotide in animal studies, 20,21 with a notable reduction in plasma trimethylamine-N-oxide levels additionally observed in linaclotide-treated (vs. untreated) mice. 21 Furthermore, recent findings on the efficacy of fecal microbiota transplantation for the treatment of slow-transit constipation have underscored the importance of fecal microbial composition on the gut motility, implying the need for the development of novel gut microbiotatargeted strategies for the treatment of constipation.…”

“…Recently, similar renoprotective properties have also been demonstrated for both lactulose and linaclotide in animal studies, 20,21 with a notable reduction in plasma trimethylamine-N-oxide levels additionally observed in linaclotide-treated (vs. untreated) mice. 21 Furthermore, recent findings on the efficacy of fecal microbiota transplantation for the treatment of slow-transit constipation have underscored the importance of fecal microbial composition on the gut motility, implying the need for the development of novel gut microbiotatargeted strategies for the treatment of constipation. 130,131 From the standpoint of practical application, lactulose typically has fewer adverse effects than other commonly used laxatives (e.g., stimulants) and may be easily available at an affordable cost.…”

“…In addition, the potential safety concerns about the use of these agents (e.g., drug-induced nephrotoxicity and electrolyte disturbances) 5,128 may lead to possible undertreatment of constipation in patients with CKD, which could potentially contribute to their excess morbidity and mortality. In this context, the unique pharmacological properties of a few constipation agents, such as lactulose, a chloride channel activator (lubiprostone), and a guanylate cyclase C agonist (linaclotide), [19][20][21]129 may deserve special attention. In a study using an adenineinduced renal failure mouse model, Mishima et al 19 demonstrated that lubiprostone ameliorated the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment, suggesting its therapeutic potential for CKD.…”

“…12,13 Furthermore, recent evidence also has revealed that constipation is independently associated with adverse clinical outcomes such as CKD progression, CV events, and mortality, [14][15][16][17][18] which, in turn, suggests that constipation could potentially serve as a new therapeutic target for these outcomes. The advent of new drug classes for constipation, some of which shows unique renoprotective properties with improvement of gut microbiota, [19][20][21] has further expanded the potential of constipation management as a novel therapeutic strategy for diseases related to altered gut microbiota like CKD.…”

Untitled

“…All mice from this group exhibited body weight loss that we can explain by the low palatability of adenine diet for mice and consequently a reduced food intake as described in numerous recent studies. [19][20][21] A high adenine diet (ranging 0.2% to 0.3%) is known to induce CKD in mice via the development of tubulointerstitial nephropathy, [22][23][24] whereas 5/6Nx is regarded as a model of nephron reduction followed by glomerulosclerosis due to hyperfiltration injury. 25 In our study, kidney histology and PCR analysis are in accordance with the literature with an increase in renal inflammation and fibrosis in adenine-fed mice and increased glomerular collagen deposition in the remnant kidney of 5/6Nx mice.…”