Chronic kidney disease after 5/6 nephrectomy disturbs the intestinal microbiota and alters intestinal motility

Abstract

Organ-organ crosstalk is involved in homeostasis. Gastrointestinal symptoms are common in patients with renal failure. The aim of this study was to elucidate the relationship between gastrointestinal motility and gastrointestinal symptoms in chronic kidney disease. We performed studies in C57BL/6 mice with chronic kidney disease after 5/6 nephrectomy. Gastrointestinal motility was evaluated by assessing the ex vivo responses of ileum and distal colon strips to electrical field stimulation.Feces were collected from mice, and the composition of the gut microbiota was analyzed using 16S ribosomal RNA sequencing. Mice with chronic kidney disease after 5/6 nephrectomy showed a decreased amount of stool, and this constipation was correlated with a suppressed contraction response in ileum motility and decreased relaxation response in distal colon motility. Spermine, one of the uremic toxins, inhibited the contraction response in ileum motility, but four types of uremic toxins showed no effect on the relaxation response in distal colon motility. The 5/6 nephrectomy procedure disturbed the balance of the gut microbiota in the mice. The motility dysregulation and constipation were resolved by antibiotic treatments. The expression levels of interleukin 6, tumor necrosis factor-α, and iNOS in 5/6 nephrectomy mice were increased in the distal colon but not in the ileum. In addition, macrophage infiltration in 5/6 nephrectomy mice was increased in the distal colon but not in the ileum. We found that 5/6 nephrectomy altered gastrointestinal motility and caused constipation by changing the gut microbiota and causing colonic inflammation. These findings indicate that renal failure was remarkably associated with gastrointestinal dysregulation.

Constipation in chronic kidney disease: it is time to reconsider

“…Of note, antibiotic therapy improved intestinal dysmotility, fecal amounts, and the expression of cytokines. In addition, they reported that in an ex vivo procedure similar to Hoibian's study, an incubation with spermine had a negative impact on intestinal motility, whereas that with IS did not [18]. This discordance may be attributable to the difference in IS concentration and in the incubation time.…”

“…The expression levels of interleukin-6, tumor necrosis factor-α, and inducible nitric oxide synthesis were increased in the gut of uremic rats. Using the same animal models, Nishiyama et al showed that uremia induced gut dysbiosis, intestinal dysmotility, a decreased amount of feces, as well as intestinal inflammation [18]. Of note, antibiotic therapy improved intestinal dysmotility, fecal amounts, and the expression of cytokines.…”

“…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.…”

Biological characteristics of IL-6 and related intestinal diseases

“…The negative correlation between IL-6 level and muscle contractility was also verified in an experiment using repeated LPS injection to induce muscularis cross-tolerance to POI. And this relation, mainly via the NF-kB, was not shown in mucosa, indicating the exclusive effects IL-6 exert on the muscularis [77], this phenomenonis also elucidated in UC [78] as well as diseases in other organs [79] and various kinds of colonic damages [80,81].…”

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

“…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 .…”