Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study.
ABSTRACT: Environmental factors driving the development of type 1 diabetes (T1D) are still largely unknown. Both animal and human studies have shown an association between altered fecal microbiota composition, impaired production of short-chain fatty acids (SCFA) and T1D onset. However, observational evidence on SCFA and fecal and oral microbiota in adults with longstanding T1D vs healthy controls (HC) is lacking.We included 53 T1D patients without complications or medication and 50 HC matched for age, sex and BMI. Oral and fecal microbiota, fecal and plasma SCFA levels, markers of intestinal inflammation (fecal IgA and calprotectin) and markers of low-grade systemic inflammation were measured.Oral microbiota were markedly different in T1D (eg abundance of Streptococci) compared to HC. Fecal analysis showed decreased butyrate producing species in T1D and less butyryl-CoA transferase genes. Also, plasma levels of acetate and propionate were lower in T1D, with similar fecal SCFA. Finally, fecal strains Christensenella and Subdoligranulum correlated with glycemic control, inflammatory parameters and SCFA.We conclude that T1D patients harbor a different amount of intestinal SCFA (butyrate) producers and different plasma acetate and propionate levels. Future research should disentangle cause and effect and whether supplementation of SCFA-producing bacteria or SCFA alone can have disease-modifying effects in T1D.
Project description:<h4>Objective</h4>To explore alterations in fecal short-chain fatty acids (SCFA) and gut microbiota in patients with diarrhea-predominant irritable bowel disease (IBS-D) and their relationships with clinical manifestations.<h4>Methods</h4>We recruited 162 patients with IBS-D and 66 healthy controls (HC). Their manifestations and psychological status were evaluated using the IBS severity scoring system and the Hospital Anxiety and Depression Scale (HADS). Colorectal visceral sensitivity was evaluated using a barostat. Systemic inflammation was evaluated using plasma cytokine levels. Fecal SCFA were quantified using ultra-performance liquid chromatography-tandem mass spectrometry, and fecal microbiota communities were analyzed using 16S rRNA sequencing.<h4>Results</h4>More men presented with IBS-D than women in our patient cohort. Patients with IBS-D had more severe manifestations, higher HADS score, and a higher rate of previous infectious enteritis than HC. Notably, female patients had significantly higher HADS scores than male patients. Male patients had significantly higher levels of plasma interleukin (IL)-12, fecal propionate and colorectal visceral sensitivity than male HC, while no differences were observed between female patients and female HC. Fecal acetate, butyrate and valerate correlated with the initial visceral sensory threshold, stressors, and IL-10 and IL-12 levels. The propionate-producing Prevotella 9 genus was significantly increased in male patients and positively correlated with fecal propionate.<h4>Conclusion</h4>Distinct sex-based differences in clinical manifestations, fecal SCFA and microbiota richness are found in Chinese patients with IBS-D, which may be used to diagnose dysbiosis in these patients.
Project description:<h4>Background</h4>Short-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial anti-inflammatory and gut homeostasis effects and prevent type 1 diabetes (T1D) in mice. Reduced SCFA production indicates a loss of beneficial bacteria, commonly associated with chronic autoimmune and inflammatory diseases, including T1D and type 2 diabetes. Here, we addressed whether a metabolite-based dietary supplement has an impact on humans with T1D. We conducted a single-arm pilot-and-feasibility trial with high-amylose maize-resistant starch modified with acetate and butyrate (HAMSAB) to assess safety, while monitoring changes in the gut microbiota in alignment with modulation of the immune system status.<h4>Results</h4>HAMSAB supplement was administered for 6 weeks with follow-up at 12 weeks in adults with long-standing T1D. Increased concentrations of SCFA acetate, propionate, and butyrate in stools and plasma were in concert with a shift in the composition and function of the gut microbiota. While glucose control and insulin requirements did not change, subjects with the highest SCFA concentrations exhibited the best glycemic control. Bifidobacterium longum, Bifidobacterium adolescentis, and vitamin B7 production correlated with lower HbA1c and basal insulin requirements. Circulating B and T cells developed a more regulatory phenotype post-intervention.<h4>Conclusion</h4>Changes in gut microbiota composition, function, and immune profile following 6 weeks of HAMSAB supplementation were associated with increased SCFAs in stools and plasma. The persistence of these effects suggests that targeting dietary SCFAs may be a mechanism to alter immune profiles, promote immune tolerance, and improve glycemic control for the treatment of T1D.<h4>Trial registration</h4>ACTRN12618001391268. Registered 20 August 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375792 Video Abstract.
Project description:<h4>Objective</h4>Short-chain fatty acids (SCFAs) are produced by the gut microbiota and may reflect health. Gut symptoms are common in individuals with depressive disorders, and recent data indicate relationships between gut microbiota and psychiatric health. We aimed to investigate potential associations between SCFAs and self-reported depressive and gut symptoms in young adults.<h4>Methods</h4>Fecal samples from 164 individuals (125 were patients with psychiatric disorders: mean [standard deviation] age = 21.9 [2.6] years, 14% men; 39 nonpsychiatric controls: age = 28.5 [9.5] years, 38% men) were analyzed for the SCFA acetate, butyrate, and propionate by nuclear magnetic resonance spectroscopy. We then compared SCFA ratios with dimensional measures of self-reported depressive and gut symptoms.<h4>Results</h4>Depressive symptoms showed a positive association with acetate levels (ρ = 0.235, p = .003) and negative associations with both butyrate (ρ = -0.195, p = .014) and propionate levels (ρ = -0.201, p = .009) in relation to total SCFA levels. Furthermore, symptoms of diarrhea showed positive associations with acetate (ρ = 0.217, p = .010) and negative associations with propionate in relation to total SCFA levels (ρ = 0.229, p = 0-007). Cluster analysis revealed a heterogeneous pattern where shifts in SCFA ratios were observed in individuals with elevated levels of depressive symptoms, elevated levels of gut symptoms, or both.<h4>Conclusions</h4>Shifts in SCFAs are associated with both depressive symptoms and gut symptoms in young adults and may have of relevance for treatment.
Project description:Fiber fermentation by gut microbiota yields short-chain fatty acids (SCFAs) that are either absorbed by the gut or excreted in feces. Studies are conflicting as to whether SCFAs are beneficial or detrimental to cardiometabolic health, and how gut microbiota associated with SCFAs is unclear. In this study of 441 community-dwelling adults, we examined associations of fecal SCFAs, gut microbiota diversity and composition, gut permeability, and cardiometabolic outcomes, including obesity and hypertension. We assessed fecal microbiota by 16S rRNA gene sequencing, and SCFA concentrations by gas chromatography/mass spectrometry. Fecal SCFA concentrations were inversely associated with microbiota diversity, and 70 unique microbial taxa were differentially associated with at least one SCFA (acetate, butyrate or propionate). Higher SCFA concentrations were associated with a measure of gut permeability, markers of metabolic dysregulation, obesity and hypertension. Microbial diversity showed association with these outcomes in the opposite direction. Associations were significant after adjusting for measured confounders. In conclusion, higher SCFA excretion was associated with evidence of gut dysbiosis, gut permeability, excess adiposity, and cardiometabolic risk factors. Studies assessing both fecal and circulating SCFAs are needed to test the hypothesis that the association of higher fecal SCFAs with obesity and cardiometabolic dysregulation is due to less efficient SCFA absorption.
Project description:<h4>Background</h4>Recent studies indicate that gut microbiota disorders potentially contribute to the pathogenesis of irritable bowel syndrome (IBS), which can be partly reflected by fecal short-chain fatty acids (SCFAs) generated from gut microbiota. Previous studies on SCFA alterations in patients with IBS have yielded conflicting results. No prior systematic review has been conducted on the alterations in fecal SCFAs in IBS patients.<h4>Aims</h4>We performed a meta-analysis to explore and clarify alterations in fecal SCFAs in IBS patients.<h4>Methods</h4>Case-control studies, randomized controlled trials (RCTs), and self-controlled studies were identified through electronic database searches. The standardized mean difference (SMD) with 95% confidence interval (CI) in fecal SCFA levels between different groups was calculated.<h4>Results</h4>The proportion of fecal propionate in patients with IBS was significantly higher than in healthy controls (HCs) (SMD?=?0.44, 95% CI?=?0.12, 0.76). A subgroup analysis showed that the concentration of fecal propionate (SMD?=?-0.91, 95% CI?=?-1.41, -0.41) and butyrate (SMD?=?-0.53, 95% CI?=?-1.01, -0.04) in patients with constipation-predominant IBS (IBS-C) was significantly lower than that in HCs, and the concentration of fecal butyrate in patients with diarrhea-predominant IBS (IBS-D) was higher than that in HCs (SMD?=?0.34, 95% CI?=?0.00, 0.67). Finally, we found that restricted diets correlated with fecal butyrate reduction in IBS (SMD?=?-0.26, 95% CI?=?-0.51, -0.01).<h4>Conclusions</h4>In terms of fecal SCFAs, there were differences between patients with IBS and HCs. In IBS-C patients, propionate and butyrate were reduced, whereas butyrate was increased in IBS-D patients in comparison to HCs. Propionate and butyrate could be used as biomarkers for IBS diagnosis.
Project description:The gut microbiota is essential for human health and plays an important role in the pathogenesis of several diseases. Short-chain fatty acids (SCFA), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients that distribute systemically via the blood. The aim of this study was to investigate the transcriptional response of immature and LPS-matured human monocyte-derived DC to SCFA. Our data revealed distinct effects exerted by each individual SCFA on gene expression in human monocyte-derived DC, especially in the mature ones. Acetate only exerted negligible effects, while both butyrate and propionate strongly modulated gene expression in both immature and mature human monocyte-derived DC. An Ingenuity pathway analysis based on the differentially expressed genes suggested that propionate and butyrate modulate leukocyte trafficking, as SCFA strongly reduced the release of several pro-inflammatory chemokines including CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11. Additionally, butyrate and propionate inhibited the expression of lipopolysaccharide (LPS)-induced cytokines such as IL-6 and IL-12p40 showing a strong anti-inflammatory effect. This work illustrates that bacterial metabolites far from the site of their production can differentially modulate the inflammatory response and generally provides new insights into host-microbiome interactions.
Project description:Short chain fatty acids (SCFA), including acetate, propionate, and butyrate, are produced during bacterial fermentation of undigested carbohydrates in the human colon. In this study, we applied a stable-isotope dilution method to quantify the in vivo colonic production of SCFA in healthy humans after consumption of inulin. Twelve healthy subjects performed a test day during which a primed continuous intravenous infusion with [1-(13)C]acetate, [1-(13)C]propionate and [1-(13)C]butyrate (12, 1.2 and 0.6 ?mol·kg(-1)·min(-1), respectively) was applied. They consumed 15 g of inulin with a standard breakfast. Breath and blood samples were collected at regular times during the day over a 12 h period. The endogenous rate of appearance of acetate, propionate, and butyrate was 13.3 ± 4.8, 0.27 ± 0.09, and 0.28 ± 0.12 ?mol·kg(-1)·min(-1), respectively. Colonic inulin fermentation was estimated to be 137 ± 75 mmol acetate, 11 ± 9 mmol propionate, and 20 ± 17 mmol butyrate over 12 h, assuming that 40%, 10%, and 5% of colonic derived acetate, propionate, and butyrate enter the systemic circulation. In conclusion, inulin is mainly fermented into acetate and, to lesser extents, into butyrate and propionate. Stable isotope technology allows quantifying the production of the three main SCFA in vivo and proved to be a practical tool to investigate the extent and pattern of SCFA production.
Project description:There have been mixed results regarding the relationship among short chain fatty acids (SCFAs), microbiota, and obesity in human studies. We selected studies that provided data on SCFA levels or fecal microbiota abundance in obese and nonobese individuals and then combined the published estimates using a random-effects meta-analysis. Obese individuals had significantly higher fecal concentrations of acetate (SMD (standardized mean differences) = 0.87, 95% CI (confidence interva) = 0.24-1.50, I2 (I-squared) = 88.5), propionate (SMD = 0.86, 95% CI = 0.35-1.36, I2 = 82.3%), and butyrate (SMD = 0.78, 95% CI = 0.29-1.27, I2 = 81.7%) than nonobese controls. The subgroup analyses showed no evidence of heterogeneity among obese individuals with a BMI >30 kg/m2 (I2 = 0.0%). At the phylum level, the abundance of fecal microbiota was reduced in obese compared to nonobese individuals, but the difference was not statistically significant (Bacteroidetes phylum, SMD = -0.36, 95% CI = -0.73-0.01; Firmicutes phylum, SMD = -0.10, 95% CI = -0.31-0.10). The currently available human case-control studies show that obesity is associated with high levels of SCFA but not gut microbiota richness at the phylum level. Additional well-designed studies with a considerable sample size are needed to clarify whether this association is causal, but it is also necessary to identify additional contributors to SCFA production, absorption, and excretion in humans.
Project description:Microbial-derived short-chain fatty acids (SCFA) acetate, propionate and butyrate may provide a link between gut microbiota and whole-body insulin sensitivity (IS). In this cross-sectional study (160 participants, 64% male, BMI: 19.2-41.0?kg/m2, normal or impaired glucose metabolism), associations between SCFA (faecal and fasting circulating) and circulating metabolites, substrate oxidation and IS were investigated. In a subgroup (n?=?93), IS was determined using a hyperinsulinemic-euglycemic clamp. Data were analyzed using multiple linear regression analysis adjusted for sex, age and BMI. Fasting circulating acetate, propionate and butyrate concentrations were positively associated with fasting GLP-1 concentrations. Additionally, circulating SCFA were negatively related to whole-body lipolysis (glycerol), triacylglycerols and free fatty acids levels (standardized (std) ? adjusted (adj) -0.190, P?=?0.023; std ? adj -0.202, P?=?0.010; std ? adj -0.306, P?=?0.001, respectively). Circulating acetate and propionate were, respectively, negatively and positively correlated with IS (M-value: std ? adj -0.294, P?<?0.001; std ? adj 0.161, P?=?0.033, respectively). We show that circulating rather than faecal SCFA were associated with GLP-1 concentrations, whole-body lipolysis and peripheral IS in humans. Therefore, circulating SCFA are more directly linked to metabolic health, which indicates the need to measure circulating SCFA in human prebiotic/probiotic intervention studies as a biomarker/mediator of effects on host metabolism.
Project description:Kestose, a fructooligosaccharide (FOS) with one fructose monomer linked to sucrose, is a key component of the prebiotic activity of FOS. This study aimed to evaluate the prebiotic potential of Kestose in terms of the impact on population change in the intestinal microbiota and fecal short-chain fatty acid (SCFA) concentration in dogs. Kestose 2 g per dog was administered daily with conventional diet to 6 healthy, adult beagle dogs for 8 weeks followed by 4 weeks of follow-up period without Kestose supplementation. Fresh fecal samples were obtained before and every 4 weeks until the end of the follow-up period. Genomic DNA extracted from the fecal samples was subjected to 16S rRNA gene analysis using next generation sequencer and to quantitative polymerase chain reaction (qPCR). Fecal acetate, propionate, butyrate, lactate and ethanol concentrations were measured by high-performance liquid chromatography. 16S rRNA gene analysis and qPCR showed increasing trend of genus Bifidobacterium after Kestose supplementation while genera Bacteroides and Sutterella decreased. Clostridium perfringens decreased below the detection limit within first 4 weeks after starting Kestose supplementation. Fecal butyrate concentration was significantly increased at week 8 and returned to the base level after 4 weeks of the washing period. To the best of our knowledge, this is the first study to reveal effect of Kestose on the populational changes in fecal microbiota and fecal butyrate concentration in dogs.