Short-chain Fatty Acids Levels In Plasma Research Articles

MO099REPROGRAMMING HYPERTENSION PROGRAMMED BY HIGH-FAT DIET: THE ROLE OF GARLIC OIL

Abstract Background and Aims Perinatal high-fat (HF) diet programs high blood pressure (BP) in adult offspring. Hydrogen sulfide (H2S) has shown benefits in hypertension by restoration of nitric oxide (NO) bioavailability and alterations of gut microbiota. Garlic, a naturally dietary source of H2S donors, supplementation has shown benefits in hypertension. We aimed to examine whether maternal garlic oil supplementation can prevent hypertension programmed by maternal and post-weaning high-fat diet in adult offspring and whether its protective effects are related to mediation of H2S-genetaing system, alterations of gut microbiota composition, and microbiota metabolite short chain fatty acids (SCFAs). Method Pregnant rats received either a normal diet (ND) or HF diet (D12331, Research Diets, Inc.) Garlic oil (GO) or vesicle was administered daily by oral gavage at 100 mg/kg/day during pregnancy and lactation. Male offspring were weaned at 3 weeks of age, and onto either ND or HF diet to 16 weeks of age. Male offspring were assigned to four groups (n=8/group): ND, HF, ND+GO, and HF+GO. Garlic supplementation during pregnancy and lactation protected against programmed hypertension in adult male offspring fed with HF diet. All offspring were killed at 16 weeks of age. NO-related parameters were analyzed by HPLC. Plasma levels of SCFA were determined using GC-MS method. Fecal microbial community was analyzed using a combination of 16S rRNA gene and fecal metagenome sequence analysis. Results Garlic supplementation during pregnancy and lactation protected against programmed hypertension in adult male offspring fed with HF diet. Garlic oil supplementation caused a significant increase in plasma levels of acetate, propionate, and butyrate. NO bioavailability was augmented by garlic oil supplementation, represented by decreases of plasma levels of asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels, and increased plasma L-arginine-to-ADMA ratio (AAR). HF intake associated with decreased α-diversity was quantified by Shannon diversity index. The Analysis of similarities (ANOSIM) demonstrated the difference in the gut microbiota among the four groups existed (All p < 0.05), indicating that four groups had distinct enterotypes. Additionally, garlic oil supplementation increased abundance of genus Lactobacillus, but decreased genera Turicibacter and Staphylococcus. Moreover, the linear discriminant analysis effect size (LEfSe) algorithm analysis identified several microbial markers including genera Lactobacillus, Staphylococcus, and Turicibacter. Conclusion The beneficial effects of garlic oil were associated with increased renal mRNA expression and activity of H2S-generating enzymes, increased NO bioavailability, increased plasma SCFA levels, and alterations of gut microbiota composition. Our data revealed associations between H2S-generating pathway in the gut and kidneys, NO system, gut microbiota, and microbiota-derived metabolites in hypertension programmed by HF intake and provided insight to garlic oil as a hypertension reprogramming strategy for further translational research.

Probiotic Supplementation with Lactobacillus plantarum 299v Lowers Systemic Inflammation, Reduces Islet ER Stress and Prevents Type 1 Diabetes in BioBreeding Rats

Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of the pancreatic β-cells. T1D pathogenesis has a strong genetic basis. However, in recent decades, the prevalence of high-risk HLA haplotypes among new diagnoses has declined, the age of onset has decreased, and T1D incidence has increased. These changes are consistent with increased environmental pressure and coincide with introduction of the Western diet, widespread antibiotic use and reduced breast feeding. These factors are thought to drive intestinal dysbiosis, increased gut permeability and systemic inflammation. Notably, our studies of T1D families and the BioBreeding (BB) rat have identified a peripheral inflammatory state associated with diabetes susceptibility that is consistent with microbial antigen exposure and pattern recognition receptor ligation. Lactobacillus plantarum 299v (Lp299v), a probiotic strain, is reported to increase plasma and stool levels of anti-inflammatory short chain fatty acids (SCFA) and promote IL-10 signaling in colonic derived macrophages and T-cells. Here we investigated the effect of Lp299v supplement on T1D progression and inflammatory phenotypes in diabetes prone BB DRlyp/lyp rats. Rats were weaned at 21 days onto a normal cereal diet (ND) or a gluten-free hydrolyzed casein diet (HCD), with and without daily Lp299v supplementation. All DRlyp/lyp ND rats developed T1D by day 83 (mean time to onset of 62.8+/-7.9 days). DRlyp/lyp ND+Lp299v rats exhibited an insignificant delay in T1D onset (62.6+/-6.5 days), however 8% remained diabetes-free to day 130. Providing DRlyp/lyp rats HCD prevented T1D in 17% of rats (to age 130 days) and significantly delayed onset (mean time to onset 72.8+/-7.3 days, p<0.001). Providing DRlyp/lyp rats HCD+Lp299v prevented T1D in 25% of rats and more robustly delayed onset (mean time to onset 84.9 +/-14.3 days, p<0.001). While multiplex ELISA failed to detect significantly altered plasma cytokine/chemokine levels at 40 days of life, plasma induced transcription revealed the greatest normalization of systemic inflammation in the HCD+Lp299v group. Plasma SCFA levels (propionate and butyrate, p<0.01) were elevated in the HCD+Lp299v group compared to the ND group. Global gene expression analysis of pancreatic islets was conducted at 40 days, prior to insulitis. Endoplasmic reticulum (ER) stress has been implicated in the formation of islet neoantigens that may underlie the initial loss of immune tolerance in T1D. Under one or both diets, Lp299v favorably modulated islet expression levels of pathways and transcripts related to inflammation and innate immunity (Cxcl9, Cxcl10), oxidative stress (Gsta1, Gsta4, Gstp1, Gstk1), as well as ER stress and unfolded protein response (Cirbp, Edem1, Hspa1a, Atf4). These ongoing studies add to a growing understanding that inherited susceptibility can be modulated by diet and microbiota.

Short-chain fatty acids combined with intronic DNA methylation of HIF3A: Potential predictors for diabetic cardiomyopathy

Hyperglycemia can induce the heart to enter an oxygen-restricted environment, which results in diabetic cardiomyopathy (DCM). Microbiota-derived short-chain fatty acids (SCFAs) affect O2 consumption and play crucial roles in modulating metabolic and cardiovascular health. The epigenetic regulation of the hypoxia-inducible factor 3A (HIF3A) gene is implicated in oxidative metabolism in the pathogenesis of diabetes. Identifying the associations between plasma SCFA levels and intronic DNA methylation of HIF3A may reveal useful predictors or provide insights into the disease processes of DCM. In this cross-sectional study, we analyzed plasma SCFA levels, HIF3A expression, and CpG methylation of HIF3A intron 1 in peripheral blood from patients with type 2 diabetes presenting with (n=92) and without (n=105) cardiomyopathy. Plasma butyric acid levels and HIF3A mRNA expression in peripheral blood were decreased in DCM patients, whereas 3 CpGs in HIF3A intron 1 (CpG 6, CpG 7 and CpG 11) were highly methylated in DCM patients. Interestingly, butyric acid levels positively correlated with HIF3A levels, while a negative association was identified between butyric acid levels and the methylation rates of HIF3A intron 1at CpG 6. Butyric acid levels also correlated with several clinical/echocardiographic factors in DCM patients. Additionally, the combination of plasma butyric acid levels and HIF3A intron 1 methylation at CpG 6 discriminated DCM patients from type2 diabetes mellitus (T2DM) patients. The novel associations between plasma butyric acid levels and HIF3A intron 1 methylation at CpG 6 may highlight an underlying mechanism by which the "microbial-myocardial" axis and host-microbe interactions may participate in the pathogenesis of DCM.

Nutritional combinatorial impact on the gut microbiota and plasma short-chain fatty acids levels in the prevention of mammary cancer in Her2/neu estrogen receptor-negative transgenic mice.

Breast cancer is the second leading cause of cancer-related mortality in women. Various nutritional compounds possess anti-carcinogenic properties which may be mediated through their effects on the gut microbiota and its production of short-chain fatty acids (SCFAs) for the prevention of breast cancer. We evaluated the impact of broccoli sprouts (BSp), green tea polyphenols (GTPs) and their combination on the gut microbiota and SCFAs metabolism from the microbiota in Her2/neu transgenic mice that spontaneously develop estrogen receptor-negative [ER(-)] mammary tumors. The mice were grouped based on the dietary treatment: control, BSp, GTPs or their combination from beginning in early life (BE) or life-long from conception (LC). We found that the combination group showed the strongest inhibiting effect on tumor growth volume and a significant increase in tumor latency. BSp treatment was integrally more efficacious than the GTPs group when compared to the control group. There was similar clustering of microbiota of BSp-fed mice with combination-fed mice, and GTPs-fed mice with control-fed mice at pre-tumor in the BE group and at pre-tumor and post-tumor in the LC group. The mice on all dietary treatment groups incurred a significant increase of Adlercreutzia, Lactobacillus genus and Lachnospiraceae, S24-7 family in the both BE and LC groups. We found no change in SCFAs levels in the plasma of BSp-fed, GTPs-fed and combination-fed mice of the BE group. Marked changes were observed in the mice of the LC group consisting of significant increases in propionate and isobutyrate in GTPs-fed and combination-fed mice. These studies indicate that nutrients such as BSp and GTPs differentially affect the gut microbial composition in both the BE and LC groups and the key metabolites (SCFAs) levels in the LC group. The findings also suggest that temporal factors related to different time windows of consumption during the life-span can have a promising influence on the gut microbial composition, SCFAs profiles and ER(-) breast cancer prevention.

Acetate correlates with disability and immune response in multiple sclerosis.

BackgroundGut microbiota has been related to multiple sclerosis (MS) etiopathogenesis. Short-chain fatty acids (SCFA) are compounds derived from microbial metabolism that have a role in gut-brain axis.ObjectivesTo analyse SCFA levels in plasma of MS patients and healthy donors (HD), and the possible link between these levels and both clinical data and immune cell populations.MethodsNinety-five MS patients and 54 HD were recruited. Patients were selected according to their score in the Expanded Disability Status Scale (EDSS) (49 EDSS ≤ 1.5, 46 EDSS ≥ 5.0). SCFA were studied in plasma samples by liquid chromatography-mass spectrometry. Peripheral blood mononuclear cells were studied by flow cytometry. Gender, age, treatments, EDSS and Multiple Sclerosis Severity Score (MSSS) were evaluated at the recruitment.ResultsPlasma acetate levels were higher in patients than in HD (p = 0.003). Patients with EDSS ≥ 5.0 had higher acetate levels than those with EDSS≤ 1.5 (p = 0.029), and HD (p = 2.97e–4). Acetate levels correlated with EDSS (r = 0.387; p = 1.08e–4) and MSSS (r = 0.265; p = 0.011). In untreated MS patients, acetate levels correlated inversely with CD4+ naïve T cells (r = − 0.550, p = 0.001) and directly with CD8+ IL-17+ cells (r = 0.557; p = 0.001).ConclusionsPlasma acetate levels are higher in MS patients than in HD. In MS there exists a correlation between plasma acetate levels, EDSS and increased IL-17+ T cells. Future studies will elucidate the role of SCFA in the disease.

Plasma Short Chain Fatty Acids As a Predictor of Response to Therapy for Life-Threatening Acute Graft-Versus-Host Disease

Introduction Minnesota High Risk and steroid-refractory acute graft-versus-host disease (aGVHD) are life-threatening complications of allogeneic hematopoietic cell transplantation (HCT). Recent data suggests dysbiosis may relate to GVHD outcomes. Bacteria in the lower gastrointestinal tract (LGI) produce short chain fatty acids (SCFAs) as fuel for enterocytes and modulators of mucosal immunity. LGI damage caused by aGVHD and antibiotic administration may be detrimental to SCFAs production and thus intestinal repair. However, limited data exists on how plasma SCFA levels vary between aGVHD patients who respond to treatment and those who do not. This study examined how aGVHD treatment response relates to plasma levels of five common SCFAs: acetate, propionate, butyrate, isovalerate, and valerate. Patients and Methods Serial plasma samples (n=221) were collected from 49 patients who underwent treatment for Minnesota High Risk or steroid-dependent/refractory aGVHD on NCT02525029 at study baseline and at 7, 14, 28 and 56 days post-treatment initiation. GVHD severity was graded using Minnesota criteria. Patients were categorized by their response to therapy at day 28 (complete/partial response [CR/PR], n=35 versus no response or death [NR], n=14). Plasma SCFA levels were quantified via liquid chromatography and cytokines measured by multiplex cytokine array. Changes in SCFA over time were assessed by repeated measures ANOVA. SCFA levels responders versus non-responders at individual time points were compared using Mann-Whitney testing and principal component analysis (PCA). SCFA, cytokines, and GVHD biomarkers including ST2, REG3a, and AREG were correlated using Spearman's rho with Bonferroni correction for multiple comparisons. Results Patients with CR/PR had higher levels of propionate (p=0.02) and butyrate (p=0.008) in comparison to NR among all samples analyzed (Figure 1a). Only butyrate levels varied significantly over time (p=0.018, with a significant difference in CR/PR vs NR at day 7, Figure 1b). The overall metabolomic profile of CR/PR patients was more stable than NR patients as determined by PCA. Neither initial clinical nor histologic grade of LGI aGVHD were associated with baseline plasma SCFA. Recent Clostridium difficile infection (n=5, p=NS) and total parenteral nutrition use (n=26, p=NS) did not influence baseline SCFA concentrations. Patients with high levels of butyrate also had high propionate (rho 0.9, p&amp;lt;0.001) and valerate (rho 0.84, p&amp;lt;0.001) and low isovalerate (rho -0.34, p&amp;lt;0.001). Plasma levels of interleukin-6 were higher in patients with low propionate and valerate (rho -0.33, p=0.008 and rho -0.36, p=0.002 respectively). Discussion Plasma SCFA profiles in patients with life-threatening GVHD suggest that differences in intestinal commensal microbe-derived SCFA production may relate to response to treatment. Patients responding to therapy have higher levels of plasma propionate and butyrate, especially early in the course of therapy. Patients with NR at day 28 appear to have increasing butyrate over time, possibly due to survival bias and/or stabilization on 2nd line therapy. Patients with higher concentrations of propionate and valerate have lower circulating IL-6 levels, which may indicate reduced systemic inflammation. Figure. (A) Comparison of short chain fatty acid (SCFA) plasma concentrations and clinical response (complete/partial response [CR/PR] vs no response [NR]) among all samples and (B) with butyrate over time. (C) Correlation of plasma SCFA, cytokines, and graft-versus-host disease biomarkers. Disclosures MacMillan: Equillium, Inc.: Consultancy; Mesoblast: Consultancy; Talaris Therapeutics, Inc: Consultancy; Fate Therapeutics, Inc.: Consultancy; Angiocrine Biosciences, Inc.: Consultancy. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Blazar:Tmunity: Other: Co-founder; Fate Therapeutics Inc.: Research Funding; KidsFirst Fund: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Magenta Therapeutics: Consultancy. Betts:Patent Pending: Patents &amp; Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Holtan:Incyte: Consultancy; Generon: Consultancy; CSL Behring: Other: Clinical trial data adjudication; BMS: Consultancy.

Effects of tetracycline on myocardial infarct size in obese rats with chemically-induced colitis

Recent evidence suggests that antibiotic-induced changes in the composition of intestinal microflora, as well as the systemic immunoendocrine effects that result from them, can modulate myocardial tolerance to ischemia-reperfusion injury. The aim of this study was to investigate the effects of tetracycline (TTC) on myocardial infarct size in the isolated hearts obtained from obese rats with chemically-induced colitis (CIC). The association between TTC-induced changes in infarct size and intestinal microbiome composition as well as plasma levels of cytokines and short-chain fatty acids (SCFAs) was also studied. Obesity was induced in Wistar rats by feeding them a high-fat, high-carbohydrate diet for five weeks. A single rectal administration of 3% acetic acid (2 mL) to the rats resulted in CIC. Healthy rats as well as obese rats with CIC received TTC (15 mg daily for 3 days) via gavage. The rats were euthanized, after which isolated heart perfusion with simulated global ischemia and reperfusion was performed. Infarct size was determined histochemically. Lipopolysaccharide (LPS) and cytokine levels in plasma were measured by enzyme-linked immunosorbent assay, whereas SCFA levels in plasma were measured by gas chromatography/mass spectrometry. The intestinal microbiome was analyzed using reverse transcription polymerase chain reaction. The treatment with TTC resulted in significant infarct size limitation (50 ± 7 vs. 62 ± 4% for the control mice, p < 0.05) in the hearts from intact animals. However, infarct size was not different between the control rats and the obese rats with CIC. Furthermore, infarct size was significantly larger in TTC-treated obese rats with CIC than it was in the control animals (77 ± 5%, p < 0.05). The concentrations of proinflammatory cytokines and LPS in serum were elevated in the obese rats with CIC. Compared to the control rats, the rats with both obesity and CIC had lower counts of Lactobacillus and Bifidobacterium spp. but higher counts of Escherichia coli. The effects of TTC on infarct size were not associated with specific changes in SCFA levels. TTC reduced infarct size in the healthy rats. However, this effect was reversed in the obese animals with CIC. Additionally, it was associated with specific changes in gut microbiota and significantly elevated levels of cytokines and LPS.

Successful elevation of circulating acetate and propionate by dietary modulation does not alter T-regulatory cell or cytokine profiles in healthy humans: a pilot study.

Increased circulating concentrations of short-chain fatty acids (SCFA) achieved by ingestion of high-fibre diets is associated with anti-inflammatory effects through promotion of FoxP3+ regulatory T(reg) cells in mouse models. This study aimed to determine whether similar increments in blood SCFA levels can be achieved in humans and whether these are associated with similar immune modulatory effects. In a pilot single-blinded, randomised, controlled cross-over study in ten healthy subjects, the effects were determined of high- (39g/day) and low-fibre (18g/day) intake (all food provided) on SCFA (gas chromatography), proportions of Treg cells (flow cytometry) and a panel of cytokines (multiplex methodology) measured in peripheral blood at day 5 of each diet. Actual fibre intake differed between the diets by 19 [16-21] g/day (P< 0.001). Median [range] total plasma SCFA levels with high-fibre intake were 174.5 [104.8-249.5] µmol/L, which were greater than those associated with low-fibre intake at 59.0 [26.5-79.9] (P < 0.001). Differences were significantly different for both acetate and propionate. The frequencies of total CD4 T cells and T-regulatory cells, and concentrations of inflammatory and anti-inflammatory cytokines were not significantly different between the dietary interventions. Plasma SCFA levels can be modulated by altering dietary fibre consumption in healthy individuals with increments similar to those achieved in murine studies. Five days of diet intervention did not result in changes in regulatory T-cell proportions and cytokine concentrations in peripheral blood, and may require longer duration of dietary change.

Soluble fibre supplementation with and without a probiotic in adults with asthma: A 7-day randomised, double blind, three way cross-over trial

SummaryBackgroundSoluble fibre modulates airway inflammation in animal models. The aim of this study was to investigate the effects of soluble fibre supplementation, with and without a probiotic, on plasma short chain fatty acids (SCFA), airway inflammation, asthma control and gut microbiome in adults with asthma.MethodsA randomised, double-blinded, placebo controlled 3-way cross-over trial in 17 subjects with stable asthma at the Hunter Medical Research Institute, Newcastle, Australia. Subjects received 3 × 7 day oral interventions in random order; soluble fibre (inulin 12 g/day), soluble fibre + probiotic (inulin 12 g/day + multi-strain probiotic >25 billion CFU) and placebo. Plasma SCFA, sputum cell counts and inflammatory gene expression, asthma control gut microbiota, adverse events including gastrointestinal symptoms were measured.FindingsThere was no difference in change in total plasma SCFA levels (μmol/L) in the placebo versus soluble fibre (Δmedian [95% CI] 16·3 [−16·9, 49·5], p = 0·335) or soluble fibre+probiotic (18·7 [−14·5, 51·9], p = 0·325) group. Following the soluble fibre intervention there was an improvement in the asthma control questionnaire (ACQ6) (∆median (IQR) -0·35 (−0·5, −0·13), p = 0·006), sputum %eosinophils decreased (−1.0 (−2·5, 0), p = 0·006) and sputum histone deacetylase 9 (HDAC9) gene expression decreased (−0.49 (−0.83, −0.27) 2-ΔCt, p = .008). Individual bacterial operational taxonomic units changed following both inulin and inulin+probiotic arms.InterpretationSoluble fibre supplementation for 7 days in adults with asthma did not change SCFA levels. Within group analysis showed improvements in airway inflammation, asthma control and gut microbiome composition following inulin supplementation and these changes warrant further investigation, in order to evaluate the potential of soluble fibre as a non-pharmacological addition to asthma management.FundJohn Hunter Hospital Charitable Trust.

1926-P: Regulation of Soluble Epoxide Hydrolase by Gut Bacteria and Acetate

Epoxyeicosatrienoic acids (EETs) are lipid mediators with beneficial effects on metabolic and cardiovascular (CV) health. EETs are metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EETs, has been shown to improve glucose homeostasis, blood pressure, and CV health in insulin-resistant or diabetic animals and proposed as an effective strategy to treat diabetes and CV diseases. Despite its importance to metabolic and CV health, little is known about mechanisms by which sEH is regulated in vivo. Our recent study demonstrated that in vivo sEH activity, assessed from plasma oxylipin levels, profoundly (3-fold) decreased after a meal in rats. Interestingly, this effect was completely abolished in rats with gut bacteria depleted by antibiotic treatment, suggesting that a gut-bacteria-derived factor(s) may be responsible for the postprandial effect. Gut bacteria produce short chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, from nutrients, and plasma SCFA levels rise during feeding. In the present study, we tested the possibility that SCFAs may be involved in the postprandial inhibition of sEH activity. For this, we examined the effects of SCFAs on sEH activity in vitro by measuring EET conversion to diol in liver homogenates. Acetate showed a profound effect to inhibit sEH activity (up to 91%) with EC50 of 39 ± 3 µM (n = 4). In contrast, propionate and butyrate had no significant effects (n = 4 and 5, respectively). The acetate effect occurred at physiological concentrations, suggesting acetate may be an endogenous inhibitor of sEH, and the postprandial inhibition of sEH activity may be mediated by acetate produced by gut bacteria after a meal. Because acetate is produced in vivo predominantly by gut bacteria, these data may explain why the postprandial effect to inhibit sEH was absent in gut-bacteria-depleted rats. Taken together, our data suggest sEH activity may be regulated in vivo by gut bacteria through the production of acetate. Disclosure J. Youn: None. Y. Oh: None. Funding American Diabetes Association (1-16-IBS-332 to J.Y.)

Diet-Independent Correlations between Bacteria and Dysfunction of Gut, Adipose Tissue, and Liver: A Comprehensive Microbiota Analysis in Feces and Mucosa of the Ileum and Colon in Obese Mice with NAFLD.

Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host health. We present a first systematic analysis of microbiota changes in the ileum and colon using multiple diets and investigating both fecal and mucosal samples. Ldlr−/−.Leiden mice received one of three different energy-dense (ED)-diets (n = 15/group) for 15 weeks. All of the ED diets induced obesity and metabolic risk factors, altered short-chain fatty acids (SCFA), and increased gut permeability and NAFLD to various extents. ED diets reduced the diversity of high-abundant bacteria and increased the diversity of low-abundant bacteria in all of the gut compartments. The ED groups showed highly variable, partially overlapping microbiota compositions that differed significantly from chow. Correlation analyses demonstrated that (1) specific groups of bacteria correlate with metabolic risk factors, organ dysfunction, and NAFLD endpoints, (2) colon mucosa had greater predictive value than other compartments, (3) correlating bacteria differed per compartment, and (4) some bacteria correlated with plasma SCFA levels. In conclusion, this comprehensive microbiota analysis demonstrates correlations between the microbiota and dysfunctions of gut, adipose tissue, and liver, independent of a specific disease-inducing diet.

Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study.

ObjectiveEnvironmental 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.Research design and methodsWe 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.ResultsOral 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.ConclusionsWe 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.