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SignificanceAlcohol-dependent subjects frequently develop emotional symptoms that contribute to the persistence of alcohol drinking. These subjects are also characterized by gastrointestinal disturbances. In this study, we showed that alcohol-dependent subjects with altered intestinal permeability had also altered gut-microbiota composition and activity and remained with high scores of depression, anxiety, and alcohol craving after a short-term detoxification program. These results are consistent with the existence of a gut–brain axis in alcohol dependence, in which the gut microbiota could alter the gut-barrier function and influence behavior in alcohol dependence. Therefore, this study opens a previously unidentified field of research for the treatment and the management of alcohol dependence, targeting the gut microbiota. Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut–brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.

Although there has been increasing interest in the use of high protein diets, little is known about dietary protein related changes in the mammalian metabolome. We investigated the influence of protein intake on selected tryptophan and phenolic compounds, derived from both endogenous and colonic microbial metabolism. Furthermore, potential inter-species metabolic differences were studied. For this purpose, 29 healthy subjects were allocated to a high (n = 14) or low protein diet (n = 15) for 2 weeks. In addition, 20 wild-type FVB mice were randomized to a high protein or control diet for 21 days. Plasma and urine samples were analyzed with liquid chromatography-mass spectrometry for measurement of tryptophan and phenolic metabolites. In human subjects, we observed significant changes in plasma level and urinary excretion of indoxyl sulfate (P 0.004 and P 0.001), and in urinary excretion of indoxyl glucuronide (P 0.01), kynurenic acid (P 0.006) and quinolinic acid (P 0.02). In mice, significant differences were noted in plasma tryptophan (P 0.03), indole-3-acetic acid (P 0.02), p-cresyl glucuronide (P 0.03), phenyl sulfate (P 0.004) and phenylacetic acid (P 0.01). Thus, dietary protein intake affects plasma levels and generation of various mammalian metabolites, suggesting an influence on both endogenous and colonic microbial metabolism. Metabolite changes are dissimilar between human subjects and mice, pointing to inter-species metabolic differences with respect to protein intake.

BackgroundIn ulcerative colitis (UC) butyrate metabolism is impaired due to a defect in the butyrate oxidation pathway and/or transport. In the present study we correlated butyrate uptake and oxidation to the gene expression of the butyrate transporter SLC16A1 and the enzymes involved in butyrate oxidation (ACSM3, ACADS, ECHS1, HSD17B10, and ACAT2) in UC and controls.MethodsColonic mucosal biopsies were collected during endoscopy of 88 UC patients and 20 controls with normal colonoscopy. Butyrate uptake and oxidation was measured by incubating biopsies with 14C-labeled Na-butyrate. To assess gene expression, total RNA from biopsies was used for quantitative reverse-transcription polymerase chain reaction (qRT-PCR). In 20 UC patients, gene expression was reassessed after treatment with infliximab.ResultsButyrate uptake and oxidation were significantly decreased in UC versus controls (P < 0.001 for both). Butyrate oxidation remained significantly reduced in UC after correction for butyrate uptake (P < 0.001), suggesting that the butyrate oxidation pathway itself is also affected. Also, the mucosal gene expression of SLC16A1, ACSM3, ACADS, ECHS1, HSD17B10, and ACAT2 was significantly decreased in UC as compared with controls (P < 0.001 for all). In a subgroup of patients (n = 20), the gene expression was reassessed after infliximab therapy. In responders to therapy, a significant increase in gene expression was observed. Nevertheless, only ACSM3 mRNA levels returned to control values after therapy in the responders groups.ConclusionsThe deficiency in the colonic butyrate metabolism in UC is initiated at the gene expression level and is the result of a decreased expression of SLC16A1 and enzymes in the β-oxidation pathway of butyrate.

Protein fermentation results in production of metabolites such as ammonia, amines and indolic, phenolic and sulfur-containing compounds. In vitro studies suggest that these metabolites might be toxic. However, human and animal studies do not consistently support these findings. We modified protein fermentation in healthy subjects to assess the effects on colonic metabolism and parameters of gut health, and to identify metabolites associated with toxicity. After a 2-week run-in period with normal protein intake (NP), 20 healthy subjects followed an isocaloric high protein (HP) and low protein (LP) diet for 2 weeks in a cross-over design. Protein fermentation was estimated from urinary p-cresol excretion. Fecal metabolite profiles were analyzed using GC-MS and compared using cluster analysis. DGGE was used to analyze microbiota composition. Fecal water genotoxicity and cytotoxicity were determined using the Comet assay and the WST-1-assay, respectively, and were related to the metabolite profiles. Dietary protein intake was significantly higher during the HP diet compared to the NP and LP diet. Urinary p-cresol excretion correlated positively with protein intake. Fecal water cytotoxicity correlated negatively with protein fermentation, while fecal water genotoxicity was not correlated with protein fermentation. Heptanal, 3-methyl-2-butanone, dimethyl disulfide and 2-propenyl ester of acetic acid are associated with genotoxicity and indole, 1-octanol, heptanal, 2,4-dithiapentane, allyl-isothiocyanate, 1-methyl-4-(1-methylethenyl)-benzene, propionic acid, octanoic acid, nonanoic acid and decanoic acid with cytotoxicity. This study does not support a role of protein fermentation in gut toxicity. The identified metabolites can provide new insight into colonic health. ClinicalTrial.gov NCT01280513.

Wheat bran extract (WBE) is a food-grade soluble fibre preparation that is highly enriched in arabinoxylan oligosaccharides. In this placebo-controlled cross-over human intervention trial, tolerance and effects on colonic protein and carbohydrate fermentation were studied. After a 1-week run-in period, sixty-three healthy adult volunteers consumed 3, 10 and 0 g WBE/d for 3 weeks in a random order, with 2 weeks' washout between each treatment period. Fasting blood samples were collected at the end of the run-in period and at the end of each treatment period for analysis of haematological and clinical chemistry parameters. Additionally, subjects collected a stool sample for analysis of microbiota, SCFA and pH. A urine sample, collected over 48 h, was used for analysis of p-cresol and phenol content. Finally, the subjects completed questionnaires scoring occurrence frequency and distress severity of eighteen gastrointestinal symptoms. Urinary p-cresol excretion was significantly decreased after WBE consumption at 10 g/d. Faecal bifidobacteria levels were significantly increased after daily intake of 10 g WBE. Additionally, WBE intake at 10 g/d increased faecal SCFA concentrations and lowered faecal pH, indicating increased colonic fermentation of WBE into desired metabolites. At 10 g/d, WBE caused a mild increase in flatulence occurrence frequency and distress severity and a tendency for a mild decrease in constipation occurrence frequency. In conclusion, WBE is well tolerated at doses up to 10 g/d in healthy adults volunteers. Intake of 10 g WBE/d exerts beneficial effects on gut health parameters.

Whether or not abdominal symptoms occur in subjects with small intestinal lactose malabsorption might depend on differences in colonic fermentation. To evaluate this hypothesis, we collected fecal samples from subjects with lactose malabsorption with abdominal complaints (LM-IT, n = 11) and without abdominal complaints (LM-T, n = 8) and subjects with normal lactose digestion (NLD, n = 15). Lactose malabsorption was diagnosed using a 13C-lactose breath test. Colonic fermentation was characterized in fecal samples at baseline and after incubation with lactose for 3 h, 6 h and 24 h through a metabolomics approach using gas chromatography-mass spectrometry (GC-MS). Fecal water cytotoxicity was analyzed using a colorimetric assay. Fecal water cytotoxicity was not different between the three groups (Kruskall-Wallis p = 0.164). Cluster analysis of the metabolite patterns revealed separate clusters for NLD, LM-T and LM-IT samples at baseline and after 24 h incubation with lactose. Levels of 5-methyl-2-furancarboxaldehyde were significantly higher in LM-IT and LM-T compared to NLD whereas those of an unidentified aldehyde were significantly higher in LM-IT compared to LM-T and NLD. Incubation with lactose increased short chain fatty acid (SCFA) concentrations more in LM-IT and LM-T compared to NLD. In conclusion, fermentation patterns were clearly different in NLD, LM-IT and LM-T, but not related to differences in fecal water cytotoxicity.

Wheat bran extract (WBE), containing arabinoxylan-oligosaccharides that are potential prebiotic substrates, has been shown to modify bacterial colonic fermentation in human subjects and to beneficially affect the development of colorectal cancer (CRC) in rats. However, it is unclear whether these changes in fermentation are able to reduce the risk of developing CRC in humans. The aim of the present study was to evaluate the effects of WBE on the markers of CRC risk in healthy volunteers, and to correlate these effects with colonic fermentation. A total of twenty healthy subjects were enrolled in a double-blind, cross-over, randomised, controlled trial in which the subjects ingested WBE (10 g/d) or placebo (maltodextrin, 10 g/d) for 3 weeks, separated by a 3-week washout period. At the end of each study period, colonic handling of NH3 was evaluated using the biomarker lactose[15N, 15N′]ureide, colonic fermentation was characterised through a metabolomics approach, and the predominant microbial composition was analysed using denaturing gradient gel electrophoresis. As markers of CRC risk, faecal water genotoxicity was determined using the comet assay and faecal water cytotoxicity using a colorimetric cell viability assay. Intake of WBE induced a shift from urinary to faecal 15N excretion, indicating a stimulation of colonic bacterial activity and/or growth. Microbial analysis revealed a selective stimulation of Bifidobacterium adolescentis. In addition, WBE altered the colonic fermentation pattern and significantly reduced colonic protein fermentation compared with the run-in period. However, faecal water cytotoxicity and genotoxicity were not affected. Although intake of WBE clearly affected colonic fermentation and changed the composition of the microbiota, these changes were not associated with the changes in the markers of CRC risk.

Defective detoxification of sulfides leads to damage to the mucosa and may play a role in the etiology of ulcerative colitis (UC). The colonic mucosal thiosulfate sulfurtransferase (TST) enzyme removes H2S by conversion to the less toxic thiocyanate. In this study we measured colonic mucosal TST enzyme activity and gene expression in UC and controls. In addition, the influence of sulfides on butyrate oxidation was evaluated.MethodsColonic mucosal biopsies were collected from 92 UC patients and 24 controls. TST activity was measured spectrophotometrically. To assess gene expression, total RNA from biopsies was used for quantitative reverse-transcription polymerase chain reaction (RT-PCR). In 20 UC patients, gene expression was reassessed after their first treatment with infliximab. To evaluate the effect of sulfides on butyrate oxidation, biopsies were incubated with 1.5 mM NaHS.ResultsTST enzyme activity and gene expression were significantly decreased in UC patients vs. controls (P < 0.001). UC patients, classified into disease activity subgroups, showed a significantly decreased TST activity and gene expression in the subgroups as compared to healthy subjects (P < 0.05 for all). In 20 patients, gene expression was reassessed after their first infliximab therapy. In responders to infliximab, a significant increase in TST gene expression was observed. However, TST mRNA levels did not return to control values after therapy in the responders. In controls, but not in UC, sulfide significantly decreased butyrate oxidation.ConclusionsWe found an impaired detoxification mechanism of sulfide at TST protein and RNA level in UC. Inflammation was clearly associated with the observed TST deficiency.

Background/Objectives: Lactose-[ 15 N, 15 N]-ureide is used to study the fate of the colonic urea-nitrogen metabolism. During the passage through the gastrointestinal tract, lactose ureide is hydrolysed to glucose ureide, which is absorbed to a limited extent from the small intestine and is excreted urinarily. In the present study, a procedure has been developed to quantify the urinary excretion of glucose-[ 15 N, 15 N]-ureide. In addition, urine and faecal samples obtained during a dietary intervention study with the prebiotic lactulose were retrospectively analysed. Subjects/Methods: The glucose ureide and lactose ureide content was measured by GC–MS in 19 healthy volunteers. After consumption of a standard test meal containing 75 mg lactose-[ 15 N, 15 N]-ureide, six healthy volunteers performed a fractionated 24 h urine collection to investigate the urinary excretion of glucose-[ 15 N, 15 N]-ureide. In 13 volunteers, the effect of lactulose administration on the urinary excretion of glucose-[ 15 N, 15 N]-ureide was analysed. Results: The urinary excretion of glucose-[ 15 N, 15 N]-ureide reached its maximum level in the 3–6 h urine collection and decreased in the 6–9 h urine. The label was still detectable in the 9–24 h urine collection. The cumulative excretion of 15 N-labelled glucose ureide after 24 h amounted 12.91%. No significant differences in glucose-[ 15 N, 15 N]-ureide excretion were found in either of the urine fractions after administration of lactulose, compared with baseline. In none of the urine samples lactose-[ 15 N, 15 N]-ureide was detected. Conclusions: In conclusion, the results obtained in the present study indicated that the percentage dose glucose-[ 15 N, 15 N]-ureide recovered in urine is rather constant and not influenced by the presence of lactulose.