Distal Colon Motor Dysfunction in Mice with Chronic Kidney Disease: Putative Role of Uremic Toxins

Abstract

Although gastrointestinal complications are a common feature of patients with chronic kidney disease (CKD), the impact of uremia on bowel motility remains poorly understood. The present study was, therefore, designed to investigate the impact of uremia on gut motility. Kidney failure was induced in mice by chemical nephrectomy using an adenine diet (0.25% w/w). Gastrointestinal transit time and colon motility were explored in vivo and ex vivo. Colons from control mice were incubated with uremic plasma or uremic toxins (urea, indoxyl-sulfate or p-cresyl-sulfate) at concentrations encountered in patients with end-stage renal disease. Mice fed an adenine diet for 3 weeks exhibited a 3-fold increase in plasma urea (p < 0.001) evidencing kidney failure. The median gastrointestinal transit time was doubled (1.8-fold, p < 0.001) while a reduction in colonic propulsive motility was observed in CKD mice (3-fold, p < 0.001). Colon from CKD mice exhibited an abnormal pattern of contraction associated with a blunted maximal force of contraction. Control colons incubated with plasma from hemodialysis patients exhibited a blunted level of maximal contraction (p < 0.01). Incubation with urea did not elicit any difference but incubation with indoxyl-sulfate or p-cresyl-sulfate decreased the maximal force of contraction (−66% and −55%, respectively. p < 0.01). Taken together, these data suggest that uremia impairs colon motility probably through the retention of uremic toxins. Colon dysmotility might contribute to the gastrointestinal symptoms often reported in patients with CKD.

Constipation in chronic kidney disease: it is time to reconsider

“…A recent experimental study by Hoibian et al suggested a mechanism that links CKD-related gut dysbiosis to constipation [16]. In this study, adenine-induced CKD mice showed a 1.8-fold longer gastrointestinal transit time than the control mice.…”

“…Wu et al reported that the colonic transit time of patients treated with hemodialysis (HD) or peritoneal dialysis (PD) was significantly longer than that of age and sex-matched healthy subjects [15]. Delayed intestinal transit was also observed in CKD animal models [16][17][18]. Thus, constipation in CKD may primarily be classified as the slow transit type.…”

Preliminary evaluation of fecal fatty acid concentrations in cats with chronic kidney disease and correlation with indoxyl sulfate and p‐cresol sulfate

“…In addition, decreased gastrointestinal motility has been linked directly to uremia by causing dysbiosis and colonic inflammation secondary to increased uremic toxin exposure in rodent models . In an ex vivo rodent model, incubation of colons with the gut‐derived uremic toxins IS and pCS, but not urea, was shown to decrease force of contraction by 66% and 55%, respectively . This finding supports the idea that uremia directly causes impaired colonic motility, although other factors such as dehydration and hypokalemia also may be factors.…”

“…For example, isovaleric acid has been shown to cause colonic smooth muscle relaxation in an ex vivo rodent model . In addition, decreased gastrointestinal motility has been linked directly to uremia by causing dysbiosis and colonic inflammation secondary to increased uremic toxin exposure in rodent models . In an ex vivo rodent model, incubation of colons with the gut‐derived uremic toxins IS and pCS, but not urea, was shown to decrease force of contraction by 66% and 55%, respectively .…”

Constipation in CKD

“…With a few notable exceptions, the strict dietary restrictions (e.g., low-fiber diets [to avoid hyperkalemia] and limited fluid intake [to avoid volume overload]), frequent use of constipation-inducing medications (e.g., phosphate binders, potassiumlowering agents, calcium channel blockers, opioids, iron supplements, and antidepressants), uremic toxins, and altered gut microbiota, all of which are typically present in patients with CKD, may further contribute to increase the prevalence of constipation in this particular population. 6, [77][78][79] The greater reported prevalence of constipation in patients on HD (vs. PD) may be attributable to their stricter dietary restriction, longer physical restraint during dialysis treatment (and potential resultant stool withholding), and/or more rapid and greater volume removal (ultrafiltration). 6 Constipation and Gut Microbiota in CKD Over the past few decades, the characteristics and functions of gut microbiota have been extensively studied, and emerging evidence has revealed the biological links of altered gut microbiota (i.e., gut dysbiosis) with both constipation and CKD.…”