An Intestinal Microbiome Intervention Affects Biochemical Disease Activity in Patients with Antiphospholipid Syndrome.

Background The origin of autoantibodies in patients with antiphospholipid syndrome (APS) is unknown. The gut microbiome contributes to autoimmunity and contains peptide homologues to the main APS autoantigen, which affect disease activity in animal models. Alteration of the gut microbiota with vancomycin diminishes disease activity in mice but no data on the effect of gut microbiota alteration in APS patients are available to date. Objective To evaluate whether the gut microbiome affects disease activity in human APS. Methods This was a pre-post design intervention study in APS patients with stable disease and no gastrointestinal comorbidity. Subjects received oral vancomycin, 500 mg four times daily for 7 days, previously shown to alter gut microbiota composition without systemic effects. Disease activity was assessed at four time points by measuring a panel of clinical phenotype-related biomarkers: antiphospholipid antibodies (APLAs), complement and inflammation markers, and hemostatic parameters. The primary outcome was the composite of the biomarker panel determined by multilevel principal component analysis. Results A total of 15 subjects completed the study. The primary outcome, the first principal component of the biomarker panel data, was significantly different after 7 days of vancomycin treatment ( p = 0.03), but not at day 42. APLA titers were unaffected. Unexpectedly, 4 out of 15 patients were negative for APLAs at baseline. In a post-hoc analysis, there was a prolonged effect for subjects with positive antibodies at baseline ( p = 0.03). In subjects with negative APLAs at baseline, the intervention showed no effect. Conclusion The intestinal microbiome affects the biochemical disease activity in APS patients. The mechanism is yet unknown but appears to be APS-specific.

Oral Anaerobutyricum soehngenii augments glycemic control in type 2 diabetes.

This randomized, double-blind, placebo-controlled trial investigated the impact of 14-day Anaerobutyricum soehngenii L2-7 supplementation on postprandial glucose levels in 25 White Dutch males with type 2 diabetes (T2D) on stable metformin therapy. The primary endpoint was the effect of A. soehngenii versus placebo on glucose excursions and variability as determined by continuous glucose monitoring. Secondary endpoints were changes in ambulatory 24-h blood pressure, incretins, circulating metabolites and excursions of plasma short-chain fatty acids (SCFAs) and bile acids upon a standardized meal. Results showed that A. soehngenii supplementation for 14 days significantly improved glycemic variability and mean arterial blood pressure, without notable changes in SCFAs, bile acids, incretin levels, or anthropometric parameters as compared to placebo-treated controls. Although well-tolerated and effective in improving glycemic control in the intervention group, further research in larger and more diverse populations is needed to generalize these findings.

Alterations in bile acid kinetics after bariatric surgery in patients with obesity with or without type 2 diabetes.

BACKGROUND: Bariatric surgery is an effective treatment option for obesity and provides long-term weight loss and positive effects on metabolism, but the underlying mechanisms are poorly understood. Alterations in bile acid metabolism have been suggested as a potential contributing factor, but comprehensive studies in humans are lacking. METHODS: In this study, we analysed the postprandial responses of bile acids, C4 and FGF19 in plasma, and excretion of bile acids in faeces, before and after bariatric surgery in patients (n = 38; 74% females) with obesity with or without type 2 diabetes from the BARIA cohort. FINDINGS: We observed that total fasting plasma bile acid levels increased, and faecal excretion of bile acids decreased after surgery suggesting increased reabsorption of bile acids. Consistent with increased bile acid levels after surgery we observed increased postprandial levels of FGF19 and suppression of the bile acid synthesis marker C4, suggesting increased FXR activation in the gut. We also noted that a subset of bile acids had altered postprandial responses before and after surgery. Finally, fasting plasma levels of 6α-hydroxylated bile acids, which are TGR5 agonists and associated with improved glucose metabolism, were increased after surgery and one of them, HDCA, covaried with diabetes remission in an independent cohort. INTERPRETATION: Our findings provide new insights regarding bile acid kinetics and suggest that bariatric surgery in humans alters bile acid profiles leading to activation of FXR and TGR5, which may contribute to weight loss, improvements in glucose metabolism, and diabetes remission. FUNDING: Novo Nordisk Fonden, Leducq Foundation, Swedish Heart-Lung Foundation, Knut and Alice Wallenberg Foundation, the ALF-agreement, ZonMw.

Higher fibre and lower carbohydrate intake are associated with favourable CGM metrics in a cross-sectional cohort of 470 individuals with type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this work was to investigate the association between macronutrient intakes and continuous glucose monitoring (CGM) metrics in individuals with type 1 diabetes. METHODS: In 470 individuals with type 1 diabetes of the GUTDM1 cohort (65% female, median age 40 [IQR 28-53] years, median diabetes duration 15 [IQR 6-29] years), we used logistic regression to establish associations between macronutrient intakes and the CGM metrics time in range (TIR, time spent between 3.9-10.0 mmol/l blood glucose, optimally set at ≥70%) and time below range (TBR, <3.9 mmol/l blood glucose, optimally set at <4%). ORs were expressed per 1 SD intake of nutrient and were adjusted for other macronutrient intakes, age, sex, socioeconomic status, BMI, duration of type 1 diabetes, pump use, insulin dose and alcohol intake. RESULTS: The median (IQR) TIR was 67 (51-80)% and TBR was 2 (1-4)%; the mean ± SD energy intake was 6879±2001 kJ, fat intake 75±31 g, carbohydrate intake 162±63 g, fibre intake 20±9 g and protein intake 70±24 g. A higher fibre intake and a lower carbohydrate intake were associated with higher odds of having a TIR≥70% (OR [95% CI] 1.64 [1.22, 2.24] and 0.67 [0.51, 0.87], respectively), whereas solely a higher carbohydrate intake was associated with TBR<4% (OR 1.34 [95% CI 1.02, 1.78]). CONCLUSIONS/INTERPRETATION: A higher fibre intake is independently associated with a higher TIR. A higher carbohydrate intake is associated with less time spent in hypoglycaemia, a lower TIR and a higher time above range. These findings warrant confirmatory (interventional) investigations and may impact current nutritional guidelines for type 1 diabetes.

Effects of Oral Butyrate on Blood Pressure in Patients With Hypertension: A Randomized, Placebo-Controlled Trial.

BACKGROUND: The microbiota-derived short chain fatty acid butyrate has been shown to lower blood pressure (BP) in rodent studies. Nonetheless, the net effect of butyrate on hypertension in humans remains uncovered. In this study, for the first time, we aimed to determine the effect of oral butyrate on BP in patients with hypertension. METHODS: We performed a double-blind randomized placebo-controlled trial including 23 patients with hypertension. Antihypertensive medication was discontinued for the duration of the study with a washout period of 4 weeks before starting the intervention. Participants received daily oral capsules containing either sodium butyrate or placebo with an equivalent dosage of sodium chloride for 4 weeks. The primary outcome was daytime 24-hour systolic BP. Differences between groups over time were assessed using linear mixed models (group-by-time interaction). RESULTS: Study participants (59.0±3.7 years; 56.5% female) had an average baseline office systolic BP of 143.5±14.6 mm Hg and diastolic BP of 93.0±8.3 mm Hg. Daytime 24-hour systolic and diastolic BP significantly increased over the intervention period in the butyrate compared with the placebo group, with an increase of +9.63 (95% CI, 2.02-17.20) mm Hg in daytime 24-hour systolic BP and +5.08 (95% CI, 1.34-8.78) mm Hg in diastolic BP over 4 weeks. Butyrate levels significantly increased in plasma, but not in feces, upon butyrate intake, underscoring its absorption. CONCLUSIONS: Four-week treatment with oral butyrate increased daytime systolic and diastolic BP in subjects with hypertension. Our findings implicate that butyrate does not have beneficial effects on human hypertension, which warrants caution in future butyrate intervention studies. REGISTRATION: URL: https://clinicaltrialregister.nl/nl/trial/22936; Unique identifier: NL8924.

The Gut Microbiota and Diabetes: Research, Translation, and Clinical Applications-2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum.

This article summarizes the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organized by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: 1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g., genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomization in humans; 2) the highly individualized nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; 3) because single-time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and 4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.

An integrated analysis of bile acid metabolism in humans with severe obesity.

BACKGROUND AND AIMS: Bile acids (BA) are vital regulators of metabolism. BAs are AQ6 secreted in the small intestine, reabsorbed, and transported back to the liver, where they can modulate metabolic functions. There is a paucity of data regarding the portal BA composition in humans. This study aimed to address this knowledge gap by investigating portal BA composition and the relation with peripheral and fecal BA dynamics in conjunction with the gut microbiome. APPROACH AND RESULTS: Thirty-three individuals from the BARIA cohort were included. Portal plasma, peripheral plasma, and feces were collected. BA and C4 levels were measured employing mass spectrometry. FGF19 was measured using ELISA. Gut microbiota composition was determined through metagenomics analysis on stool samples. Considerable diversity in the portal BA composition was observed. The majority (n = 26) of individuals had a 9-fold higher portal than peripheral BA concentration. In contrast, 8 individuals showed lower portal BA concentration compared with peripheral and had higher levels of unconjugated and secondary BA in this compartment, suggesting more distal origin. The altered portal BA profile was associated with altered gut microbiota composition. In particular, taxa within Bacteroides were reduced in abundance in the feces of these individuals. CONCLUSIONS: Characterization of the portal BA composition in relation to peripheral and fecal BA increased insight into the dynamics of BA metabolism in individuals with obesity. Peripheral BA composition was much more diverse due to microbial metabolism. About 24% of the portal samples was surprisingly low in total BA; the underlying mechanism requires further exploration.

Plasma sphingolipids mediate the association between gut microbiome composition and type 2 diabetes risk in the HELIUS cohort: a case-cohort study.

INTRODUCTION: The association between the gut microbiome and incident type 2 diabetes (T2D) is potentially partly mediated through sphingolipids, however these possible mediating mechanisms have not been investigated. We examined whether sphingolipids mediate the association between gut microbiome and T2D, using data from the Healthy Life in an Urban Setting study. RESEARCH DESIGN AND METHODS: Participants were of Dutch or South-Asian Surinamese ethnicity, aged 18-70 years, and without T2D at baseline. A case-cohort design (subcohort n=176, cases incident T2D n=36) was used. The exposure was measured by 16S rRNA sequencing (gut microbiome) and mediator by targeted metabolomics (sphingolipids). Dimensionality reduction was achieved by principle component analysis and Shannon diversity. Cox regression and procrustes analyses were used to assess the association between gut microbiome and T2D and sphingolipids and T2D, and between gut microbiome and sphingolipids, respectively. Mediation was tested familywise using mediation analysis with permutation testing and Bonferroni correction. RESULTS: Our study confirmed associations between gut microbiome and T2D and sphingolipids and T2D. Additionally, we showed that the gut microbiome was associated with sphingolipids. The association between gut microbiome and T2D was partly mediated by a sphingolipid principal component, which represents a dominance of ceramide species over more complex sphingolipids (HR 1.17; 95% CI 1.08 to 1.28; proportional explained 48%), and by Shannon diversity (HR 0.97; 95% CI 0.95 to 0.99; proportional explained 24.8%). CONCLUSIONS: These data suggest that sphingolipids mediate the association between microbiome and T2D risk. Future research is needed to confirm observed findings and elucidate causality on a molecular level.

Oral histidine affects gut microbiota and MAIT cells improving glycemic control in type 2 diabetes patients.

Amino acids, metabolized by host cells as well as commensal gut bacteria, have signaling effects on host metabolism. Oral supplementation of the essential amino acid histidine has been shown to exert metabolic benefits. To investigate whether dietary histidine aids glycemic control, we performed a case-controlled parallel clinical intervention study in participants with type 2 diabetes (T2D) and healthy controls. Participants received oral histidine for seven weeks. After 2 weeks of histidine supplementation, the microbiome was depleted by antibiotics to determine the microbial contribution to histidine metabolism. We assessed glycemic control, immunophenotyping of peripheral blood mononucelar cells (PBMC), DNA methylation of PBMCs and fecal gut microbiota composition. Histidine improves several markers of glycemic control, including postprandial glucose levels with a concordant increase in the proportion of MAIT cells after two weeks of histidine supplementation. The increase in MAIT cells was associated with changes in gut microbial pathways such as riboflavin biosynthesis and epigenetic changes in the amino acid transporter SLC7A5. Associations between the microbiome and MAIT cells were replicated in the MetaCardis cohort. We propose a conceptual framework for how oral histidine may affect MAIT cells via altered gut microbiota composition and SLC7A5 expression in MAIT cells directly and thereby influencing glycemic control. Future studies should focus on the role of flavin biosynthesis intermediates and SLC7A5 modulation in MAIT cells to modulate glycemic control.

Mortality patterns in Dutch diabetes outpatients.

AIM: Diabetes mellitus is a major cause of death. Outpatients with diabetes have more complications than patients in general practice; mortality patterns have only been studied in the total diabetes population. This study aims to assess mortality, causes, and predictors in outpatients with diabetes. MATERIALS AND METHODS: A cohort study, included people with diabetes mellitus from the nationwide Dutch Paediatric and Adult Registry of Diabetes (DPARD) visiting diabetes outpatient clinics in 2016-2020. DPARD data were linked to Statistics Netherlands (CBS), comprising data on mortality, ethnicity and education. All-cause and cardiovascular mortality rates were estimated using Cox proportional hazard regression. RESULTS: During a median follow-up of 3.1 years among 12 992 people with diabetes, mortality rates per 10 000 person-years were 67.7 in adult type 1 diabetes and 324.2 in type 2 diabetes. The major cause of non-cardiovascular death was malignancy. During the pandemic years of influenza (2018) and COVID (2020), mortality rates peaked. Age, smoking and an estimated glomerular filtration rate of <60 ml/min were associated with all-cause mortality. In type 2 diabetes, additional factors were male sex, body mass index <20 kg/m2, diabetes duration <1 year and hypertension. CONCLUSIONS: Mortality among Dutch outpatients with diabetes is high. Smoking and renal failure were associated with mortality in both types. Further focus on early detection and treatment of mortality-associated factors may improve clinical outcomes.

Bacteriophages from treatment-naïve type 2 diabetes individuals drive an inflammatory response in human co-cultures of dendritic cells and T cells.

Individuals with type 2 diabetes (T2D) show signs of low-grade inflammation, which is related to the development of insulin resistance and beta-cell dysfunction. However, the underlying triggers remain unknown. The gut microbiota is a plausible source as it comprises pro-inflammatory bacteria, bacterial metabolites and viruses, including (bacterio)phages. These prokaryotic viruses have been shown to mediate inflammatory responses in gastrointestinal disease. Given the differences in phage populations in healthy individuals versus those with cardiometabolic diseases such as T2D, we here questioned whether phages from T2D individuals would have increased immunogenic potential. To address this, we isolated intestinal phages from a fresh stool sample of healthy controls and individuals with newly diagnosed, treatment-naive T2D. Phages were purified using cesium chloride ultracentrifugation and incubated with healthy donor dendritic cells (DCs) and autologous T cells. Donors with T2D had slightly higher free viral particle numbers compared to healthy controls (p = .1972), which has been previously associated with disease states. Further, phages from T2D induced a higher inflammatory response in DCs and T cells than phages from HC. For example, the expression of the co-stimulatory molecule CD86 on DCs (p < .001) and interferon-y secretion from T cells (p < .01) were increased when comparing the two groups. These results suggest that phages might play a role in low-grade inflammation in T2D individuals.

Phylogeny and disease associations of a widespread and ancient intestinal bacteriophage lineage.

Viruses are core components of the human microbiome, impacting health through interactions with gut bacteria and the immune system. Most human microbiome viruses are bacteriophages, which exclusively infect bacteria. Until recently, most gut virome studies focused on low taxonomic resolution (e.g., viral operational taxonomic units), hampering population-level analyses. We previously identified an expansive and widespread bacteriophage lineage in inhabitants of Amsterdam, the Netherlands. Here, we study their biodiversity and evolution in various human populations. Based on a phylogeny using sequences from six viral genome databases, we propose the Candidatus order Heliusvirales. We identify heliusviruses in 82% of 5441 individuals across 39 studies, and in nine metagenomes from humans that lived in Europe and North America between 1000 and 5000 years ago. We show that a large lineage started to diversify when Homo sapiens first appeared some 300,000 years ago. Ancient peoples and modern hunter-gatherers have distinct Ca. Heliusvirales populations with lower richness than modern urbanized people. Urbanized people suffering from type 1 and type 2 diabetes, as well as inflammatory bowel disease, have higher Ca. Heliusvirales richness than healthy controls. We thus conclude that these ancient core members of the human gut virome have thrived with increasingly westernized lifestyles.

Fecal, Duodenal and Tumor Microbiota Composition of Esophageal Carcinoma Patients, a Longitudinal Prospective Cohort.

BACKGROUND: The microbiome has been associated with chemotherapy and immune checkpoint inhibitor (ICI) efficacy. How this pertains to resectable esophageal carcinoma (EC) is unknown. Our aim was to identify microbial signatures in resectable EC associated with response to neoadjuvant chemoradiotherapy (nCRT) with or without ICI. METHODS: From two prospectively collected EC cohorts (n = 172 in total) treated with nCRT alone (n = 132) or a combination of nCRT and ICI (n = 40), fecal samples were available at baseline, during treatment, and pre-surgery. Additionally, in the ICI treated patients, tumor and duodenal snap frozen biopsies were collected over time. Fecal, tumor and duodenal DNA were extracted for 16S rRNA sequencing. Associations were investigated between microbiome composition pathological complete response (pCR) and progression-free survival (PFS). RESULTS: There was a significant shift in the microbiota profile of the fecal, tumor and duodenal microbiota over time. In the total cohort, patients with a pCR had a stable fecal alpha diversity, while the diversity of poor responders decreased during treatment, p = 0.036. Pre-surgery, lower alpha diversity (<4.12) was related to worse PFS, log-rank p = 0.025. Baseline tumor biopsies of patients with short PFS had more Fusobacterium. A low baseline duodenal alpha diversity (<3.96) was associated with worse PFS, log-rank p = 0.012. CONCLUSIONS: Lower intestinal alpha diversity was associated with worse response and survival of EC patients. In tumor biopsies Fusobacterium was more abundant in patients with poor PFS. After further mechanistic validation, these findings may aid in response prediction and the design of novel microbiome modulating treatments for EC patients.

Endogenous ethanol production in health and disease.

The gut microbiome exerts metabolic actions on distal tissues and organs outside the intestine, partly through microbial metabolites that diffuse into the circulation. The disruption of gut homeostasis results in changes to microbial metabolites, and more than half of the variance in the plasma metabolome can be explained by the gut microbiome. Ethanol is a major microbial metabolite that is produced in the intestine of nearly all individuals; however, elevated ethanol production is associated with pathological conditions such as metabolic dysfunction-associated steatotic liver disease and auto-brewery syndrome, in which the liver's capacity to metabolize ethanol is surpassed. In this Review, we describe the mechanisms underlying excessive ethanol production in the gut and the role of ethanol catabolism in mediating pathogenic effects of ethanol on the liver and host metabolism. We conclude by discussing approaches to target excessive ethanol production by gut bacteria.

Phytate metabolism is mediated by microbial cross-feeding in the gut microbiota.

Dietary intake of phytate has various reported health benefits. Previous work showed that the gut microbiota can convert phytate to short-chain fatty acids (SCFAs), but the microbial species and metabolic pathway are unclear. Here we identified Mitsuokella jalaludinii as an efficient phytate degrader, which works synergistically with Anaerostipes rhamnosivorans to produce the SCFA propionate. Analysis of published human gut taxonomic profiles revealed that Mitsuokella spp., in particular M. jalaludinii, are prevalent in human gut microbiomes. NMR spectroscopy using 13C-isotope labelling, metabolomic and transcriptomic analyses identified a complete phytate degradation pathway in M. jalaludinii, including production of the intermediate Ins(2)P/myo-inositol. The major end product, 3-hydroxypropionate, was converted into propionate via a synergistic interaction with Anaerostipes rhamnosivorans both in vitro and in mice. Upon [13C6]phytate administration, various 13C-labelled components were detected in mouse caecum in contrast with the absence of [13C6] InsPs or [13C6]myo-inositol in plasma. Caco-2 cells incubated with co-culture supernatants exhibited improved intestinal barrier integrity. These results suggest that the microbiome plays a major role in the metabolism of this phytochemical and that its fermentation to propionate by M. jalaludinii and A. rhamnosivorans may contribute to phytate-driven health benefits.

Novel Proteome Targets Marking Insulin Resistance in Metabolic Syndrome.

CONTEXT/OBJECTIVE: In order to better understand which metabolic differences are related to insulin resistance in metabolic syndrome (MetSyn), we used hyperinsulinemic-euglycemic (HE) clamps in individuals with MetSyn and related peripheral insulin resistance to circulating biomarkers. DESIGN/METHODS: In this cross-sectional study, HE-clamps were performed in treatment-naive men (n = 97) with MetSyn. Subjects were defined as insulin-resistant based on the rate of disappearance (Rd). Machine learning models and conventional statistics were used to identify biomarkers of insulin resistance. Findings were replicated in a cohort with n = 282 obese men and women with (n = 156) and without (n = 126) MetSyn. In addition to this, the relation between biomarkers and adipose tissue was assessed by nuclear magnetic resonance imaging. RESULTS: Peripheral insulin resistance is marked by changes in proteins related to inflammatory processes such as IL-1 and TNF-receptor and superfamily members. These proteins can distinguish between insulin-resistant and insulin-sensitive individuals (AUC = 0.72 ± 0.10) with MetSyn. These proteins were also associated with IFG, liver fat (rho 0.36, p = 1.79 × 10-9) and visceral adipose tissue (rho = 0.35, p = 6.80 × 10-9). Interestingly, these proteins had the strongest association in the MetSyn subgroup compared to individuals without MetSyn. CONCLUSIONS: MetSyn associated with insulin resistance is characterized by protein changes related to body fat content, insulin signaling and pro-inflammatory processes. These findings provide novel targets for intervention studies and should be the focus of future in vitro and in vivo studies.

Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes: the GUTDM1 study.

AIMS/HYPOTHESIS: Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease severity or progression after diagnosis. Therefore, we tested whether GRS are associated with residual beta cell function and glycaemic control in individuals with type 1 diabetes. METHODS: Immunochip arrays and TOPMed were used to genotype a cross-sectional cohort (n=479, age 41.7 ± 14.9 years, duration of diabetes 16.0 years [IQR 6.0-29.0], HbA1c 55.6 ± 12.2 mmol/mol). Several GRS, which were originally developed to assess genetic risk of type 1 diabetes (GRS-1, GRS-2) and type 2 diabetes (GRS-T2D), were calculated. GRS-C1 and GRS-C2 were based on SNPs that have previously been shown to be associated with residual beta cell function. Regression models were used to investigate the association between GRS and residual beta cell function, assessed using the urinary C-peptide/creatinine ratio, and the association between GRS and continuous glucose monitor metrics. RESULTS: Higher GRS-1 and higher GRS-2 both showed a significant association with undetectable UCPCR (OR 0.78; 95% CI 0.69, 0.89 and OR 0.84: 95% CI 0.75, 0.93, respectively), which were attenuated after correction for sex and age of onset (GRS-2) and disease duration (GRS-1). Higher GRS-C2 was associated with detectable urinary C-peptide/creatinine ratio (≥0.01 nmol/mmol) after correction for sex and age of onset (OR 6.95; 95% CI 1.19, 40.75). A higher GRS-T2D was associated with less time below range (TBR) (OR for TBR<4% 1.41; 95% CI 1.01 to 1.96) and lower glucose coefficient of variance (ß -1.53; 95% CI -2.76, -0.29). CONCLUSIONS/INTERPRETATION: Diabetes-related GRS are associated with residual beta cell function in individuals with type 1 diabetes. These findings suggest some genetic contribution to preservation of beta cell function.

Association between butyrate-producing gut bacteria and the risk of infectious disease hospitalisation: results from two observational, population-based microbiome studies.

BACKGROUND: Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria protect against systemic infections. However, the relationship between microbiota disruptions and increased susceptibility to severe infections in humans remains unclear. We investigated the relationship between gut microbiota and the risk of future infection-related hospitalisation in two large population-based cohorts. METHODS: In this observational microbiome study, gut microbiota were characterised using 16S rRNA gene sequencing in independent population-based cohorts from the Netherlands (HELIUS study; derivation cohort) and Finland (FINRISK 2002 study; validation cohort). HELIUS was conducted in Amsterdam, Netherlands, and included adults (aged 18-70 years at inclusion) who were randomly sampled from the municipality register of Amsterdam. FINRISK 2002 was conducted in six regions in Finland and is a population survey that included a random sample of adults (aged 25-74 years). In both cohorts, participants completed questionnaires, underwent a physical examination, and provided a faecal sample at inclusion (Jan 3, 2013, to Nov 27, 2015, for HELIUS participants and Jan 21 to April 19, 2002, for FINRISK participants. For inclusion in our study, a faecal sample needed to be provided and successfully sequenced, and national registry data needed to be available. Primary predictor variables were microbiota composition, diversity, and relative abundance of butyrate-producing bacteria. Our primary outcome was hospitalisation or mortality due to any infectious disease during 5-7-year follow-up after faecal sample collection, based on national registry data. We examined associations between microbiota and infection risk using microbial ecology and Cox proportional hazards. FINDINGS: We profiled gut microbiota from 10 699 participants (4248 [39·7%] from the derivation cohort and 6451 [60·3%] from the validation cohort). 602 (5·6%) participants (152 [3·6%] from the derivation cohort; 450 [7·0%] from the validation cohort) were hospitalised or died due to infections during follow-up. Gut microbiota composition of these participants differed from those without hospitalisation for infections (derivation p=0·041; validation p=0·0002). Specifically, higher relative abundance of butyrate-producing bacteria was associated with a reduced risk of hospitalisation for infections (derivation cohort cause-specific hazard ratio 0·75 [95% CI 0·60-0·94] per 10% increase in butyrate producers, p=0·013; validation cohort 0·86 [0·77-0·96] per 10% increase, p=0·0077). These associations remained unchanged following adjustment for demographics, lifestyle, antibiotic exposure, and comorbidities. INTERPRETATION: Gut microbiota composition, specifically colonisation with butyrate-producing bacteria, was associated with protection against hospitalisation for infectious diseases in the general population across two independent European cohorts. Further studies should investigate whether modulation of the microbiome can reduce the risk of severe infections. FUNDING: Amsterdam UMC, Porticus, National Institutes of Health, Netherlands Organisation for Health Research and Development (ZonMw), and Leducq Foundation.

The gut microbiota and diabetes: research, translation, and clinical applications - 2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum.

This article summarises the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organised by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: (1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g. genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomisation in humans; (2) the highly individualised nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; (3) because single time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and (4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.

Assessment of bone marrow edema on dual-energy CT scans in people with diabetes mellitus and suspected Charcot neuro-osteoarthropathy.

OBJECTIVE: This study aimed to quantitatively assess the diagnostic value of bone marrow edema (BME) detection on virtual non-calcium (VNCa) images calculated from dual-energy CT (DECT) in people with diabetes mellitus and suspected Charcot neuro-osteoarthropathy (CN). MATERIALS AND METHODS: People with diabetes mellitus and suspected CN who underwent DECT of the feet (80kVp/Sn150kVp) were included retrospectively. Two blinded observers independently measured CT values on VNCa images using circular regions of interest in five locations in the midfoot (cuneiforms, cuboid and navicular) and the calcaneus of the contralateral or (if one foot was available) the ipsilateral foot. Two clinical groups were formed, one with active CN and one without active CN (no-CN), based on the clinical diagnosis. RESULTS: Thirty-two people with diabetes mellitus and suspected CN were included. Eleven had clinically active CN. The mean CT value in the midfoot was significantly higher in the CN group (-55.6 ± 18.7 HU) compared to the no-CN group (-94.4 ± 23.5 HU; p < 0.001). In the CN group, the difference in CT value between the midfoot and calcaneus was statistically significant (p = 0.003); this was not the case in the no-CN group (p = 0.357). The overall observer agreement was good for the midfoot (ICC = 0.804) and moderate for the calcaneus (ICC = 0.712). Sensitivity was 100.0% and specificity was 71.4% using a cutoff value of -87.6 HU. CONCLUSION: The detection of BME on VNCa images has a potential value in people with diabetes mellitus and suspected active CN.