Indoxyl sulfate (IS) and p-cresyl sulfate (pCS), 2 important protein-bound uremic toxins, are independent risk factors for cardiovascular disease in patients with end-stage renal disease. Indole and p-cresol are gut microbiome-generated precursors of IS and pCS. The aim of the present study was to determine whether inulin-type fructans (ITFs) reduce the production of indole and p-cresol by altering their producing bacteria in patients with peritoneal dialysis. Patients receiving peritoneal dialysis for >3 mo without diabetes and not using antibiotics were recruited to a randomized, double-blind, placebo-controlled, crossover trial of ITF intervention over 36 wk (12-wk washout). The primary outcomes were gut microbiome, fecal indole and p-cresol, indole-producing bacteria, p-cresol-producing bacteria, and serum IS and pCS. The secondary outcomes were fecal pH, 24-h urine, and dialysis removal of IS and pCS. Of 21 individuals randomly assigned, 15 completed the study. The daily nutrient intakes, including protein, tryptophan, and tyrosine, were isostatic during the prebiotic, washout, and placebo intervention. There were no baseline differences in the outcomes of interest between treatments. For fecal indole, its concentrations did not change significantly in either treatment. However, there was a trend toward the treatment-by-time effect (P = 0.052), with a quantitative reduction in the ITF treatment and an increase in the control. The difference in the changes between the 2 treatments was significant (-10.07 ± 7.48 μg/g vs +13.35 ± 7.66 μg/g; P = 0.040). Similar to Bacteroides thetaiotaomicron, there was a difference over time between the 2 treatments, with a significant treatment and time interaction effect (P = 0.047). There were no treatment, time, or interaction effects for fecal p-cresol, serum IS and pCS, 24-h urine, and dialysis removal of IS and pCS. Our results suggested that ITFs restricted the increase in gut microbiome-generated indole in patients with peritoneal dialysis. This trial was registered at http://www.chictr.org.cn/showproj.aspx?proj=21228 as ChiCTR-INR-17013739.

Epidemiological findings on the association between bisphenol A (BPA, 2,2-bis-(4-hydroxyphenyl)propane) exposure and type 2 diabetes mellitus (T2DM) are paradoxical. In animal studies, BPA has been shown to disrupt pancreatic function and blood glucose homeostasis even at a reference ‘safe’ level during perinatal period. In this study, we explored the effects of long-term paternal exposure to a ‘safe’ level of BPA on parents themselves and their offspring. Adult male genitor rats fed with either standard chow diet (STD) or high-fat diet (HFD) were treated respectively with either vehicle or BPA (50 μg/kg per day) for 35 weeks. The male rats treated with vehicle or BPA for 21 weeks were then used as sires, and the adult female rats were fed with STD during the gestation and lactation. Offspring rats were weaned on postnatal day 21 and fed with STD in later life. Metabolic parameters were recorded on the adult male rats and their adult offspring. BPA exposure disrupted glucose homeostasis and pancreatic function, and HFD aggravated these adverse effects. However, BPA exposure did not alter body weight, body fat percentage, or serum lipid. In addition, the paternal BPA exposure did not cause adverse reproductive consequence or metabolic disorder in the adult offspring. Our findings indicate that chronic exposure to a predicted ‘safe’ dose of BPA contributes to glucose metabolic disorders, and that HFD aggravates these adverse effects in paternal rats.

Bisphenol A (BPA), a typical environmental endocrine-disrupting chemical, induces epigenetic inheritance. Whether histone acetylation plays a role in these effects of BPA is largely unknown. Here, we investigated histone acetylation in male rats after long-term exposure to a ‘safe’ dose of BPA. Twenty adult male rats received either BPA (50 μg/kg·bw/day) or a vehicle diet for 35 weeks. Decreased protein lysine-acetylation levels at approximately ~17 kDa and ~25 kDa, as well as decreased histone acetylation of H3K9, H3K27 and H4K12, were detected by Western blot analysis of testes from the treated rats compared with controls. Additionally, increased protein expression of deacetylase Sirt1 and reduced binding of Sirt1, together with increased binding of estrogen receptor β (ERβ) to caveolin-1 (Cav-1), a structural protein component of caveolar membranes, were detected in treated rats compared with controls. Moreover, decreased acetylation of Cav-1 was observed in the treated rats for the first time. Our study showed that long-term exposure to a ‘safe’ dose of BPA reduces histone acetylation in the male reproductive system, which may be related to the phenotypic paternal-to-offspring transmission observed in our previous study. The evidence also suggested that these epigenetic effects may be meditated by Sirt1 via competition with ERβ for binding to Cav-1.