Bovine milk contains bioactive proteins, carbohydrates, and phospholipids with immunomodulatory properties impacting human immunity, potentially contributing to resistance to infections and allergies through diverse mechanisms. One such mechanism is the enhancing of the innate immune response to secondary pathogen-related stimuli, termed innate immune training. Although in vitro studies demonstrate that milk immunoglobulin G (IgG) can train human monocytes, evidence for in vivo immune training is limited. To explore the potential of bovine IgG for inducing innate immune training in vivo, this human study utilized an IgG-rich whey protein concentrate (WPC). Healthy male volunteers were assigned to a high dose WPC, low dose WPC, or placebo group. Blood was collected pre- and post-two weeks of WPC consumption. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with TLR ligands, evaluating IL-6 and TNF-α production by monocytes, myeloid DCs, and plasmacytoid DCs. Additionally, RNA was isolated for differential gene expression (DGE) analysis. Results indicated that the two-week WPC intervention did not influence the ex vivo response of studied cells to TLR agonists. Furthermore, PBMC gene expression patterns showed no significant differences between the placebo and high dose WPC groups. The data suggests that oral WPC ingestion did not enhance immune responses in young, healthy male participants.

Animal studies suggest that short-chain fatty acids acetate and butyrate are key players in the gut-brain axis and may affect insulin sensitivity. We investigated the association of intestinal acetate and butyrate availability (measured by butyryl-coenzyme A transferase (ButCoA) gene amount) with insulin sensitivity and secretion in healthy subjects from the HELIUS cohort study from the highest 15% (N = 30) and the lowest 15% (N = 30) intestinal ButCoA gene amount. The groups did not differ in insulin sensitivity or secretion. However, the high ButCoA group showed lower glucose and insulin peaks during the first 60 min after a meal and a higher nadir during the second 60 min (p < 0.01), suggesting delayed glucose adsorption from the small intestine. Our data suggest that chronically increased acetate and butyrate availability may improve glucose metabolism by delaying gastric emptying and intestinal adsorption. Future studies should further investigate the effect of acetate and butyrate interventions.

Objective Type 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota–immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT). Design Patients with recent-onset (<6 weeks) T1D (18–30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition. Results Stimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=−0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics. Conclusion FMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D. Trial registration number NTR3697.

Abstract Purpose: Cachexia is a multifactorial syndrome, associated with poor survival in patients with cancer, and is influenced by the gut microbiota. We investigated the effects of fecal microbiota transplantation (FMT) on cachexia and treatment response in patients with advanced gastroesophageal cancer. Experimental Design: In a double-blind randomized placebo-controlled trial performed in the Amsterdam University Medical Center, we assigned 24 cachectic patients with metastatic HER2-negative gastroesophageal cancer to either allogenic FMT (healthy obese donor) or autologous FMT, prior to palliative chemotherapy (capecitabine and oxaliplatin). Primary objective was to assess the effect of allogenic FMT on satiety. Secondary outcomes were other features of cachexia, along with disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity. Finally, exploratory analyses were performed on the effect of FMT on gut microbiota composition (metagenomic sequencing) and metabolites (untargeted metabolomics). Results: Allogenic FMT did not improve any of the cachexia outcomes. Patients in the allogenic group (n = 12) had a higher DCR at 12 weeks (P = 0.035) compared with the autologous group (n = 12), longer median OS of 365 versus 227 days [HR = 0.38; 95% confidence interval (CI), 0.14–1.05; P = 0.057] and PFS of 204 versus 93 days (HR = 0.50; 95% CI, 0.21–1.20; P = 0.092). Patients in the allogenic group showed a significant shift in fecal microbiota composition after FMT (P = 0.010) indicating proper engraftment of the donor microbiota. Conclusions: FMT from a healthy obese donor prior to first-line chemotherapy did not affect cachexia, but may have improved response and survival in patients with metastatic gastroesophageal cancer. These results provide a rational for larger FMT trials.

OBJECTIVE:Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic Anaerobutyricum soehngenii to be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of A. soehngenii L2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS.DESIGN:In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of A. soehngenii/ placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring.RESULTS:A. soehngenii treatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, A. soehngenii treatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B (REG1B)-encoding gene. Strikingly, duodenal REG1B expression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following A. soehngenii intake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, A. soehngenii duodenal administration was safe and well tolerated.CONCLUSIONS:A single dose of A. soehngenii improves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and REG1B expression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity.TRIAL REGISTRATION NUMBER:NTR-NL6630.

Microbial amplicon sequencing studies are an important tool in biological and biomedical research. Widespread 16S rRNA gene microbial surveys have shed light on the structure of many ecosystems inhabited by bacteria, including the human body. However, specialized software and algorithms are needed to convert raw sequencing data into biologically meaningful information (i.e. tables of bacterial counts). While different bioinformatic pipelines are available in a rapidly changing and improving field, users are often unaware of limitations and biases associated with individual pipelines and there is a lack of agreement regarding best practices. Here, we compared six bioinformatic pipelines for the analysis of amplicon sequence data: three OTU-level flows (QIIME-uclust, MOTHUR, and USEARCH-UPARSE) and three ASV-level (DADA2, Qiime2-Deblur, and USEARCH-UNOISE3). We tested workflows with different quality control options, clustering algorithms, and cutoff parameters on a mock community as well as on a large (N = 2170) recently published fecal sample dataset from the multi-ethnic HELIUS study. We assessed the sensitivity, specificity, and degree of consensus of the different outputs. DADA2 offered the best sensitivity, at the expense of decreased specificity compared to USEARCH-UNOISE3 and Qiime2-Deblur. USEARCH-UNOISE3 showed the best balance between resolution and specificity. OTU-level USEARCH-UPARSE and MOTHUR performed well, but with lower specificity than ASV-level pipelines. QIIME-uclust produced large number of spurious OTUs as well as inflated alpha-diversity measures and should be avoided in future studies. This study provides guidance for researchers using amplicon sequencing to gain biological insights.

Several proteins and peptides in saliva were shown to stimulate gingival wound repair, but the role of salivary metabolites in this process remains unexplored. In vitro gingival re-epithelialization kinetics were determined using unstimulated saliva samples from healthy individuals collected during an experimental gingivitis study. Elastic net regression with stability selection identified a specific metabolite signature in a training dataset that was associated with the observed re-epithelialization kinetics and enabled its prediction for all saliva samples obtained in the clinical study. This signature encompassed ten metabolites, including plasmalogens, diacylglycerol and amino acid derivatives, which reflect enhanced host-microbe interactions. This association is in agreement with the positive correlation of the metabolite signature with the individual’s gingival bleeding index. Remarkably, intra-individual signature-variation over time was associated with elevated risk for gingivitis development. Unravelling how these metabolites stimulate wound repair could provide novel avenues towards therapeutic approaches in patients with impaired wound healing capacity.

OBJECTIVE:Bariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects.DESIGN:Subjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks.RESULTS:We observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa.CONCLUSION:Allogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects.TRIAL REGISTRATION NUMBER:NTR4327.

Plasma metabolites affect a range of metabolic functions in humans, including insulin sensitivity (IS). A subset of these plasma metabolites is modified by the gut microbiota. To identify potential microbial–metabolite pathways involved in IS, we investigated the link between plasma metabolites, gut microbiota composition, and IS, using the gold-standard for peripheral and hepatic IS measurement in a group of participants with metabolic syndrome (MetSyn). In a cross-sectional study with 115 MetSyn participants, fasting plasma samples were collected for untargeted metabolomics analysis and fecal samples for 16S rRNA gene amplicon sequencing. A two-step hyperinsulinemic euglycemic clamp was performed to assess peripheral and hepatic IS. Collected data were integrated and potential interdependence between metabolites, gut microbiota, and IS was analyzed using machine learning prediction models. Plasma metabolites explained 13.2% and 16.7% of variance in peripheral and hepatic IS, respectively. Fecal microbiota composition explained 4.2% of variance in peripheral IS and was not related to hepatic IS. Although metabolites could partially explain the variances in IS, the top metabolites related to peripheral and hepatic IS did not significantly correlate with gut microbiota composition (both on taxonomical level and alpha-diversity). However, all plasma metabolites could explain 18.5% of the variance in microbial alpha-diversity (Shannon); the top 20 metabolites could even explain 44.5% of gut microbial alpha-diversity. In conclusion, plasma metabolites could partially explain the variance in peripheral and hepatic IS; however, these metabolites were not directly linked to the gut microbiota composition, underscoring the intricate relation between plasma metabolites, the gut microbiota, and IS in MetSyn

OBJECTIVE:Increasing evidence indicates that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Human bariatric surgery data suggest that the gut-brain axis is also involved in this process, but the underlying mechanisms remain unknown.METHODS:We compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors vs oral butyrate supplementation on (123I-FP-CIT-determined) brain dopamine transporter (DAT) and serotonin transporter (SERT) binding as well as stable isotope-determined insulin sensitivity at baseline and after 4 weeks in 24 male and female treatment-naïve metabolic syndrome subjects. Plasma metabolites and fecal microbiota were also determined at these time points.RESULTS:We observed an increase in brain DAT after donor FMT compared to oral butyrate that reduced this binding. However, no effect on body weight and insulin sensitivity was demonstrated after post-RYGB donor feces transfer in humans with metabolic syndrome. Increases in fecal levels of Bacteroides uniformis were significantly associated with an increase in DAT, whereas increases in Prevotella spp. showed an inverse association. Changes in the plasma metabolites glycine, betaine, methionine, and lysine (associated with the S-adenosylmethionine cycle) were also associated with altered striatal DAT expression.CONCLUSIONS:Although more and larger studies are needed, our data suggest a potential gut microbiota-driven modulation of brain dopamine and serotonin transporters in human subjects with obese metabolic syndrome. These data also suggest the presence of a gut-brain axis in humans that can be modulated.NTR REGISTRATION:4488.

Introduction The gut microbiome may contribute to the development of obesity. So far, the extent of microbiome variation in people with obesity has not been determined in large cohorts and for a wide range of body mass index (BMI). Here, we aimed to investigate whether the faecal microbial metagenome can explain the variance in several clinical phenotypes associated with morbid obesity. Methods Caucasian subjects were recruited at our hospital. Blood pressure and anthropometric measurements were taken. Dietary intake was determined using questionnaires. Shotgun metagenomic sequencing was performed on faecal samples from 177 subjects. Results Subjects without obesity (n = 82, BMI 24.7 +/- 2.9 kg m(-2)) and subjects with obesity (n = 95, BMI 38.6 +/- 5.1 kg m(-2)) could be clearly distinguished based on microbial composition and microbial metabolic pathways. A total number of 52 bacterial species differed significantly in people with and without obesity. Independent of dietary intake, we found that microbial pathways involved in biosynthesis of amino acids were enriched in subjects with obesity, whereas pathways involved in the degradation of amino acids were depleted. Machine learning models showed that more than half of the variance in body fat composition followed by BMI could be explained by the gut microbiome composition and microbial metabolic pathways, compared to 6% of variation explained in triglycerides and 9% in HDL. Conclusion Based on the faecal microbiota composition, we were able to separate subjects with and without obesity. In addition, we found strong associations between gut microbial amino acid metabolism and specific microbial species in relation to clinical features of obesity.

AbstractRecently, increased attention has been drawn to the composition of the intestinal microbiota and its possible role in metabolic syndrome and type 2 diabetes (T2DM). However, potential variation in gut microbiota composition across ethnic groups is rarely considered despite observed unequal prevalence for these diseases. Our objective was therefore to study the gut microbiota composition across health, metabolic syndrome and T2DM in a multi-ethnic population residing in the same geographical area. 16S rRNA gene sequencing was performed on fecal samples from 3926 participants to the HELIUS cohort (Amsterdam, The Netherlands), representing 6 ethnic groups (Dutch, Ghanaians, Moroccans, Turks, Surinamese of either African or South-Asian descent). Included participants completed a questionnaire and underwent a physical examination and overnight fasted blood sampling. Gut microbiota composition was compared across metabolic status (diabetes with and without metformin use, metabolic syndrome and its subsequent components, health) and ethnicities using Wilcoxon-Mann-Withney tests and logistic regressions. Overall, the gut microbiota alpha-diversity (richness, Shannon index and phylogenetic diversity) decreased with worsening of the metabolic state (comparing health to metabolic syndrome to T2DM) but this was only partially reproduced in ethnic-specific analyses. In line, a lower alpha-diversity was found in relation to all metabolic syndrome components as well as in T2DM subjects using metformin compared to non-users. Alterations, mainly decreased abundances, were also observed at the genus level (many Clostridiales) in metabolic syndrome subjects and more strongly in T2DM subjects with differences across ethnic groups. In particular, we observed decreased abundances of members of the Peptostreptococcaceae family and of Turicibacter and an increased abundance of a member of the Enterobacteriaceae family. Our data highlight several compositional differences in the gut microbiota of individuals with metabolic syndrome or T2DM. These features, confirming prior observations, give some insights into potential key intestinal bacteria related to a worsening of metabolic state. Our results also underscore possible ethnic-specific profiles associated with these microbiota alterations that should be further explored.

Gut microbiota and its metabolites such as short chain fatty acids (SCFA), lipopolysaccharides (LPS), and trimethylamine-N-oxide (TMAO) impact cardiovascular health. In this review, we discuss how gut microbiota and gut metabolites can affect hypertension and atherosclerosis. Hypertensive patients were shown to have lower alpha diversity, lower abundance of SCFA-producing microbiota, and higher abundance of gram-negative bacteria, which are a source of LPS. Animal studies point towards a direct role for SCFAs in blood pressure regulation and show that LPS has pro-inflammatory effects. Translocation of LPS into the systemic circulation is a consequence of increased gut permeability. Atherosclerosis, a multifactorial disease, is influenced by the gut microbiota through multiple pathways. Many studies have focused on the pro-atherogenic role of TMAO, however, it is not clear if this is a causal factor. In addition, gut microbiota play a key role in bile acid metabolism and some interventions targeting bile acid receptors tend to decrease atherosclerosis. Concluding, gut microbiota affect hypertension and atherosclerosis through many pathways, providing a wide range of potential therapeutic targets. Challenges ahead include translation of findings and mechanisms to humans and development of therapeutic interventions that target cardiovascular risk by modulation of gut microbes and metabolites.

The intestinal microbiota has been linked to the development and prevalence of steatohepatitis in humans. Interestingly, steatohepatitis is significantly lower in individuals taking a plant-based, low-animal-protein diet, which is thought to be mediated by gut microbiota. However, data on causality between these observations in humans is scarce. In this regard, fecal microbiota transplantation (FMT) using healthy donors is safe and is capable of changing microbial composition in human disease. We therefore performed a double-blind randomized controlled proof-of-principle study in which individuals with hepatic steatosis on ultrasound were randomized to two study arms: lean vegan donor (allogenic n = 10) or own (autologous n = 11) FMT. Both were performed three times at 8-week intervals. A liver biopsy was performed at baseline and after 24 weeks in every subject to determine histopathology (Nonalcoholic Steatohepatitis Clinical Research Network) classification and changes in hepatic gene expression based on RNA sequencing. Secondary outcome parameters were changes in intestinal microbiota composition and fasting plasma metabolomics. We observed a trend toward improved necro-inflammatory histology, and found significant changes in expression of hepatic genes involved in inflammation and lipid metabolism following allogenic FMT. Intestinal microbial community structure changed following allogenic FMT, which was associated with changes in plasma metabolites as well as markers of . Conclusion: Allogenic FMT using lean vegan donors in individuals with hepatic steatosis shows an effect on intestinal microbiota composition, which is associated with beneficial changes in plasma metabolites and markers of steatohepatitis.

Dysbiosis of the intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We performed a phase I/II dose-finding and safety study on the effect of oral intake of the anaerobic butyrogenic strain Anaerobutyricum soehngenii on glucose metabolism in 24 subjects with metabolic syndrome. We found that treatment with A. soehngenii was safe and observed a significant correlation between the measured fecal abundance of administered A. soehngenii and improvement in peripheral insulin sensitivity after 4 weeks of treatment. This was accompanied by an altered microbiota composition and a change in bile acid metabolism. Finally, we show that metabolic response upon administration of A. soehngenii (defined as improved insulin sensitivity 4 weeks after A. soehngenii intake) is dependent on microbiota composition at baseline. These data in humans are promising, but additional studies are needed to reproduce our findings and to investigate long-term effects, as well as other modes of delivery.

Aims Preliminary evidence from animal and human studies shows that gut microbiota composition and levels of microbiota-derived metabolites, including short-chain fatty acids (SCFAs), are associated with blood pressure (BP). We hypothesized that faecal microbiota composition and derived metabolites may be differently associated with BP across ethnic groups Methods and results We included 4672 subjects (mean age 49.8 +/- 11.7 years, 52% women) from six different ethnic groups participating in the HEalthy Life In an Urban Setting (HELIUS) study. The gut microbiota was profiled using 16S rRNA gene amplicon sequencing. Associations between microbiota composition and office BP were assessed using machine learning prediction models. In the subgroups with the largest associations, faecal SCFA levels were compared in 200 subjects with lower or higher systolic BP. Faecal microbiota composition explained 4.4% of the total systolic BP variance. Best predictors for systolic BP included Roseburia spp., Clostridium spp., Romboutsia spp., and Ruminococcaceae spp. Explained variance of the microbiota composition was highest in Dutch subjects (4.8%), but very low in South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan and Turkish descent groups (explained variance <0.8%). Faecal SCFA levels, including acetate (P < 0.05) and propionate (P < 0.01), were lower in young Dutch participants with low systolic BP Conclusions Faecal microbiota composition is associated with BP, but with strongly divergent associations between ethnic groups. Intriguingly, while Dutch participants with lower BP had higher abundances of several SCFA-producing microbes, they had lower faecal SCFA levels. Intervention studies with SCFAs could provide more insight in the effects of these metabolites on BP.

4556 Background: Both human and rodent studies provide evidence for a role of the microbiome in patients who respond to checkpoint inhibition (CI). So far, no study has unraveled the physiological link between intestinal and tumor microbiome composition in relation to response to CI. The PERFECT trial was a single-arm phase II feasibility study investigating the addition of atezolizumab (PD-L1 inhibitor) to neoadjuvant chemoradiotherapy (nCRT) for resectable esophageal adenocarcinoma (NCT03087864). An exploratory objective of this trial was to evaluate intestinal and tumor microbiome composition including plasma metabolomics as potential biomarkers for immunological and pathological response. Methods: Using 16S rRNA gene sequencing, we analyzed fecal, duodenal and tumor samples at baseline (V0), 3 weeks after start of atezolizumab (V1), and 1 week before surgery (V2). We compared microbiome composition and metabolomics from patients with pathological complete response (pCR; ypT0N0) to patients with a pathological incomplete response. Differences in alpha diversity metrics were tested using mixed linear models. Beta-diversity associations were assessed using permutational MANOVA (adonis) and multilevel PCA (mixOmics). Biomarkers were identified using a machine learning model (XGboost) feature selection. Plasma metabolomics (Metabolon) were determined with liquid chromatography mass spectrometry (LC-MS). Results: Microbiome profiles were significantly altered after start of treatment in all sample types. None of the sample types showed a relation between alpha or beta diversity and pCR. On taxonomical level, we found that the tumor and duodenal baseline samples were weak predictors for response (AUC 0.60 and 0.62, respectively), but better compared to fecal microbiome composition (AUC = 0.49). We identified the top 20 microbes that predicted pCR best in tumor and fecal samples and found significant correlations with metabolites involved in bile acid metabolism. Conclusions: Both tumor and duodenal baseline biopsies were better predictors of pathological response compared to fecal microbiome. Microbes predictive of pCR showed significant correlations with metabolites involved in bile acid metabolism, which is known to indirectly influence immunosurveillance in cancer. Data on immune response in relation to the microbiome and metabolomics are expected Spring 2020. Clinical trial information: NCT03087864 .

The gut microbiota constitutes an important modulator of metabolic heath and an unbalanced microbiota is increasingly recognized as an important risk factor for metabolic disorders, such as obesity, insulin resistance and type 2 diabetes. Seeking for novel treatments to counteract insulin resistance and metabolic disturbances in obese subjects, we explore whether delivering a protective commensal bacteria (Anaerobutyricum soehngenii L2-7) directly into the small intestine of treatment-naïve subjects with metabolic syndrome would ameliorate glucose metabolism (NTR NL6630). We previously identified this butyrate-producing intestinal commensal to be associated with improved insulin sensitivity in metabolic syndrome subjects. Herein, we found that a single-dose of duodenal infusion containing A. soehngenii improved peripheral glucose control and stimulated the secretion of the hormone GLP-1, which is reported to positively act on both insulin secretion and sensitivity. Moreover, by RNA-seq, we found that A. soehngenii-treatment triggered a prominent alteration of the duodenal transcriptome with 73 genes being differentially expressed. Among these, the expression of regenerating islet-protein 1B-encoding gene (REG1B) was the most significantly unregulated by A. soehngenii administration. Strikingly, duodenal REG1B expression negatively correlated with peripheral glucose variability, which was significantly diminished by A. soehngeniiduodenal infusion. Altogether our findings disclose that a single-dose of A. soehngenii is sufficient to greatly impact the duodenal transcriptional profile and ameliorate glucose metabolism in metabolic syndrome individuals, likely through induction of intestinal GLP-1 production. Nonetheless, further studies are needed to delineate the specific pathways involved in induction of REG1B and GLP-1. Notably, duodenal administration of A. soehngenii was also safe and well-tolerated.

Oral bacteria colonize the gut more frequently than previously thought.

The Christmas season can have a major impact on human health. Especially increased contact with in-laws during the holiday season is an important environmental factor known to affect both physical and mental health (Mirza et al., 2004). However, the mechanism through which in-laws influence host health is not yet understood. Emerging evidence has identified the intestinal microbiota as an important mediator for both physical and mental health. Here, we performed a prospective observational study to examine the impact of contact with in-laws on the gut microbiome during the Christmas season. We conducted 16S ribosomal DNA sequencing of fecal samples collected at two separate time points (December 23rd and December 27th 2016) from a group of 28 healthy volunteers celebrating Christmas. To discriminate between participants who visited their own family versus their in-laws, we built a multivariate statistical model that identified microbial biomarker species. We observed two distinct microbial-biomarker signatures discriminating the participants that visited their in-laws versus their own family over the Christmas season. We identified seven bacterial species whose relative-change profile differed significantly among these two groups. In participants visiting in-laws, there was a significant decrease in all Ruminococcus species, known to be associated with psychological stress and depression. A larger randomized controlled study is needed to reproduce these findings before we can recognize in-laws as a potential risk factor for the gut microbiota composition and subsequently host health.