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ObjectiveThe colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.DesignTo investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.ResultsPropionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.ConclusionsThese data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.Trial registration numberNCT00750438.

Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation--a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.

INTRODUCTION AND OBJECTIVES: An obese-type human microbiota with an increased Firmicutes:Bacteroidetes ratio has been described that may link the gut microbiome with obesity and metabolic syndrome (MetS) development. Dietary fat and carbohydrate are modifiable risk factors that may impact on MetS by altering the human microbiome composition. We determined the effect of the amount and type of dietary fat and carbohydrate on faecal bacteria and short chain fatty acid (SCFA) concentrations in people ‘at risk’ of MetS. DESIGN: A total of 88 subjects at increased MetS risk were fed a high saturated fat diet (HS) for 4 weeks (baseline), then randomised onto one of the five experimental diets for 24 weeks: HS; high monounsaturated fat (MUFA)/high glycemic index (GI) (HM/HGI); high MUFA/low GI (HM/LGI); high carbohydrate (CHO)/high GI (HC/HGI); and high CHO/low GI (HC/LGI). Dietary intakes, MetS biomarkers, faecal bacteriology and SCFA concentrations were monitored. RESULTS: High MUFA diets did not affect individual bacterial population numbers but reduced total bacteria and plasma total and LDL-cholesterol. The low fat, HC diets increased faecal Bifidobacterium ( P =0.005, for HC/HGI; P =0.052, for HC/LGI) and reduced fasting glucose and cholesterol compared to baseline. HC/HGI also increased faecal Bacteroides ( P =0.038), whereas HC/LGI and HS increased Faecalibacterium prausnitzii ( P =0.022 for HC/HGI and P =0.018, for HS). Importantly, changes in faecal Bacteroides numbers correlated inversely with body weight ( r =−0.64). A total bacteria reduction was observed for high fat diets HM/HGI and HM/LGI ( P =0.023 and P =0.005, respectively) and HS increased faecal SCFA concentrations ( P <0.01). CONCLUSION: This study provides new evidence from a large-scale dietary intervention study that HC diets, irrespective of GI, can modulate human faecal saccharolytic bacteria, including bacteroides and bifidobacteria. Conversely, high fat diets reduced bacterial numbers, and in the HS diet, increased excretion of SCFA, which may suggest a compensatory mechanism to eliminate excess dietary energy.

Directed modulation of the colonic bacteria to metabolize lactose effectively is a potentially useful approach to improve lactose digestion and tolerance. A randomized, double-blind, multisite placebo-controlled trial conducted in human subjects demonstrated that administration of a highly purified (>95%) short-chain galactooligosaccharide (GOS), designated “RP-G28,” significantly improved clinical outcomes for lactose digestion and tolerance. In these individuals, stool samples were collected pretreatment (day 0), after GOS treatment (day 36), and 30 d after GOS feeding stopped and consumption of dairy products was encouraged (day 66). In this study, changes in the fecal microbiome were investigated using 16S rRNA amplicon pyrosequencing and high-throughput quantitative PCR. At day 36, bifidobacterial populations were increased in 27 of 30 of GOS subjects (90%), demonstrating a bifidogenic response in vivo. Relative abundance of lactose-fermenting Bifidobacterium, Faecalibacterium, and Lactobacillus were significantly increased in response to GOS. When dairy was introduced into the diet, lactose-fermenting Roseburia species increased from day 36 to day 66. The results indicated a definitive change in the fecal microbiome of lactose-intolerant individuals, increasing the abundance of lactose-metabolizing bacteria that were responsive to dietary adaptation to GOS. This change correlated with clinical outcomes of improved lactose tolerance.

Background and aims:Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis.Methods:Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data.Results:For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity.Conclusion:Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis.ClinicalTrials.gov number, NCT00639821.

Certain purified indigestible carbohydrates such as inulin have been shown to stimulate gut-derived hormones involved in glycaemic regulation and appetite regulation, and to counteract systemic inflammation through a gut microbiota-mediated mechanism. Less is known about the properties of indigestible carbohydrates intrinsic to food. The aim of this study was to investigate the possibility to affect release of endogenous gut hormones and ameliorate appetite control and glycaemic control by ingestion of a whole-grain cereal food product rich in NSP and resistant starch in healthy humans. In all, twenty middle-aged subjects were provided with a barley kernel-based bread (BB) or a reference white wheat bread during 3 consecutive days, respectively, in a randomised cross-over design study. At a standardised breakfast the following day (day 4), blood was collected for the analysis of blood (b) glucose regulation, gastrointestinal hormones, markers of inflammation and markers of colonic fermentation; 3 d of intervention with BB increased gut hormones in plasma (p) the next morning at fasting (p-glucagon-like peptide-1; 56 %) and postprandially (p-glucagon-like peptide-2; 13 % and p-peptide YY; 18 %). Breath H2 excretion and fasting serum (s) SCFA concentrations were increased (363 and 18 %, respectively), and b-glucose (22 %) and s-insulin responses (17 %) were decreased after BB intervention. Insulin sensitivity index (ISIcomposite) was also improved (25 %) after BB. In conclusion, 3 d of intervention with BB increased systemic levels of gut hormones involved in appetite regulation, metabolic control and maintenance of gut barrier function, as well as improved markers of glucose homoeostasis in middle-aged subjects, altogether relevant for the prevention of obesity and the metabolic syndrome.

The mechanisms underlying diarrhea-predominant irritable bowel syndrome (IBS-D) are poorly understood, but increased intestinal permeability is thought to contribute to symptoms. A recent clinical trial of gluten-free diet (GFD) demonstrated symptomatic improvement, relative to gluten-containing diet (GCD), which was associated with reduced intestinal permeability in non-celiac disease IBS-D patients. The aim of this study was to characterize intestinal epithelial tight junction composition in IBS-D before and after dietary gluten challenge. Biopsies from 27 IBS-D patients (13 GFD and 14 GCD) were examined by H&E staining and semiquantitative immunohistochemistry for phosphorylated myosin II regulatory light chain (MLC), MLC kinase, claudin-2, claudin-8 and claudin-15. Diet-induced changes were assessed and correlated with urinary mannitol excretion (after oral administration). In the small intestine, epithelial MLC phosphorylation was increased or decreased by GCD or GFD, respectively, and this correlated with increased intestinal permeability (P<0.03). Colonocyte expression of the paracellular Na+ channel claudin-15 was also markedly augmented following GCD challenge (P<0.05). Conversely, colonic claudin-2 expression correlated with reduced intestinal permeability (P<0.03). Claudin-8 expression was not affected by dietary challenge. These data show that alterations in MLC phosphorylation and claudin-15 and claudin-2 expression are associated with gluten-induced symptomatology and intestinal permeability changes in IBS-D. The results provide new insight into IBS-D mechanisms and can explain permeability responses to gluten challenge in these patients.

Despite antiretroviral therapy (ART), some HIV-infected persons maintain lower than normal CD4(+) T-cell counts in peripheral blood and in the gut mucosa. This incomplete immune restoration is associated with higher levels of immune activation manifested by high systemic levels of biomarkers, including sCD14 and D-dimer, that are independent predictors of morbidity and mortality in HIV infection. In this 12-week, single-arm, open-label study, we tested the efficacy of IL-7 adjunctive therapy on T-cell reconstitution in peripheral blood and gut mucosa in 23 ART suppressed HIV-infected patients with incomplete CD4(+) T-cell recovery, using one cycle (consisting of three subcutaneous injections) of recombinant human IL-7 (r-hIL-7) at 20 µg/kg. IL-7 administration led to increases of both CD4(+) and CD8(+) T-cells in peripheral blood, and importantly an expansion of T-cells expressing the gut homing integrin α4β7. Participants who underwent rectosigmoid biopsies at study baseline and after treatment had T-cell increases in the gut mucosa measured by both flow cytometry and immunohistochemistry. IL-7 therapy also resulted in apparent improvement in gut barrier integrity as measured by decreased neutrophil infiltration in the rectosigmoid lamina propria 12 weeks after IL-7 administration. This was also accompanied by decreased TNF and increased FOXP3 expression in the lamina propria. Plasma levels of sCD14 and D-dimer, indicative of systemic inflammation, decreased after r-hIL-7. Increases of colonic mucosal T-cells correlated strongly with the decreased systemic levels of sCD14, the LPS coreceptor - a marker of monocyte activation. Furthermore, the proportion of inflammatory monocytes expressing CCR2 was decreased, as was the basal IL-1β production of peripheral blood monocytes. These data suggest that administration of r-hIL-7 improves the gut mucosal abnormalities of chronic HIV infection and attenuates the systemic inflammatory and coagulation abnormalities that have been linked to it.

Liver oxygen stress is one of the main extraintestinal manifestations of colitis and 5% of cases develop into a further liver injury and metabolic disease. 2′-fucosyllactose (2′-FL), a main member of human milk oligosaccharides (HMOs), has been found to exert efficient impacts on remitting colitis. However, whether 2′-FL exerts the function to alleviate colitis-induced liver injury and how 2′-FL influences the metabolism via regulating gut microbiota remain unknown. Herein, in our study, liver oxygen stress was measured by measuring liver weight and oxygen-stress-related indicators. Then, 16S full-length sequencing analysis and non-target metabolome in feces were performed to evaluate the overall responses of metabolites and intestinal bacteria after being treated with 2′-FL (400 mg/kg b.w.) in colitis mice. The results showed that, compared with the control group, the liver weight of colitis mice was significantly decreased by 18.30% (p < 0.05). After 2′-FL treatment, the liver weight was significantly increased by 12.65% compared with colitis mice (p < 0.05). Meanwhile, they exhibited higher levels of oxidation in liver tissue with decreasing total antioxidant capacity (T-AOC) (decreased by 17.15%) and glutathione (GSH) levels (dropped by 22.68%) and an increasing malondialdehyde (MDA) level (increased by 36.24%), and 2′-FL treatment could reverse those tendencies. Full-length 16S rRNA sequencing revealed that there were 39 species/genera differentially enriched in the control, dextran sulphate sodium (DSS), and DSS + 2′-FL groups. After treatment with 2′-FL, the intestinal metabolic patterns, especially glycometabolism and the lipid-metabolism-related process, in DSS mice were strikingly altered with 33 metabolites significantly down-regulated and 26 metabolites up-regulated. Further analysis found DSS induced a 40.01%, 41.12%, 43.81%, and 39.86% decline in acetic acid, propionic acid, butyric acid, and total short chain fatty acids (SCFAs) in colitis mice (all p < 0.05), respectively, while these were up-regulated to different degrees in the DSS + 2′-FL group. By co-analyzing the data of gut microbiota and metabolites, glycometabolism and lipid-metabolism-associated metabolites exhibited strong positive/negative relationships with Akkermansia_muciniphila (all p < 0.01) and Paraprevotella spp. (all p < 0.01), suggesting that the two species might play crucial roles in the process of 2′-FL alleviating colitis-induced liver oxygen stress. In conclusion, in the gut–liver–microbiotas axis, 2′-FL mediated in glucose and lipid-related metabolism and alleviated liver oxygen stress via regulating gut microbiota in the DSS-induced colitis model. The above results provide a new perspective to understand the probiotic function of 2′-FL.

Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P ), 4h (P ) and 12h (P ). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit -S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P , P and P were 10.1%, 28.60% and 65.45%. Significant ( < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in T (from 2.5h to 6h), a prolongation in MRT (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). E-M14C is a potential system for possible colon targeting of etoricoxib.