Background Microbiota-derived short-chain fatty acid acetate has improved glucose metabolism and reduced appetite in animal studies and some preliminary human trials. However, other experiments show contradicting results, with acetate inducing hyperphagia and insulin resistance. Objective Study the effects of acute intravenous acetate infusion on postprandial insulin and glucose responses and on central responsivity in fasted state. Design We performed a randomised placebo-controlled crossover trial, including 18 lean individuals and 19 individuals with metabolic syndrome. We administered sodium acetate intravenously for 3 hours. We performed a standardised mixed meal test and employed a functional MRI (fMRI) paradigm, including a food-cue task and a food-receipt task. Results Acetate infusion did not significantly affect postprandial glucose or insulin levels or fasted fMRI results. Remarkably, plasma acetate levels decreased significantly after meal ingestion despite the constant acetate infusion rate. Fractional urinary acetate excretion significantly increased upon infusion but contained only 1–2% of the total amount of acetate infused. Conclusion Our data do not support effects of increased plasma acetate levels on glucose metabolism or blood oxygen level-dependent signal response to food-related stimuli in humans. These findings suggest that previously established positive effects of acetate are not dependent on acute rises in plasma acetate and may be primarily mediated through intestinal hormone release and the gut–brain axis—a route of effect that is bypassed in this current study. Finally, the decreasing acetate concentrations upon meal ingestion raise the question what tissues absorb or metabolise acetate in the postprandial phase. Trial registration number NL8381.

Background Obesity is an important risk factor for cardiometabolic disease, including dyslipidemia and atherosclerotic cardiovascular disease. Although the role of the liver in dyslipidemia is established, the contribution of adipose tissue is less clear. This study aims to clarify the role of adipose tissue in lipid metabolism and dyslipidemia. Methods We conducted a cross‐sectional analysis of 125 patients from the BARIA (The Immune System and Microbial Tone in Relation to NAFLD/NASH Before and After Bariatric Surgery in the Morbidly Obese in Amsterdam) longitudinal cohort study undergoing bariatric surgery. Comprehensive phenotyping included fasting untargeted plasma metabolomics, lipid, lipoprotein, adipokine profiling, RNA sequencing, and fecal shotgun metagenomics. Tissue transcriptomic and plasma metabolites were compared between individuals with and without dyslipidemia. Results Dyslipidemia was present in 43 of 125 individuals (34.4%), with higher triglycerides (1.62 versus 1.24 mmol/L), apoB (apolipoprotein B; 93.15 versus 81.81 mg/dL), and lower high‐density lipoprotein (1.02 versus 1.35 mmol/L) and apoAI (136.40 versus 161.35 mg/dL). Plasma adipokines showed limited differences: leptin concentrations were lower in dyslipidemia in unadjusted analysis but reduced after adjustment for age, sex, and body weight (adjusted P=0.057). RNA sequencing identified altered gene expression of liver, jejunum, visceral and subcutaneous adipose tissue, most pronounced in subcutaneous adipose tissue. Dyslipidemia was associated with adipose tissue pathways related to inflammation, oxidative stress, and adipogenesis. Plasma metabolomics revealed associations with endocannabinoid‐like, secondary bile acid, plasmalogen, butyrate, and sphingolipid metabolites. Gut metagenome analysis found modest differences. Conclusions Dyslipidemia in obesity is associated with transcriptomic alterations in adipose tissue, including subcutaneous adipose tissue, involving inflammation, oxidative stress, and adipogenesis. These findings support a role of adipose tissue in lipid regulation beyond hepatic pathways.

OBJECTIVES:To assess the feasibility and efficacy of fecal microbiota transplantation (FMT) in adolescents (16-21 years) with refractory irritable bowel syndrome (IBS). METHODS:Randomized controlled pilot trial. Thirty-two patients were included and randomized to receive two allogeneic or autologous FMTs. At baseline and after 6 weeks, two allogeneic or autologous FMTs were administered via a nasoduodenal tube. Feasibility outcomes included dropout rate. Clinical efficacy was evaluated by the proportion of responders (≥50 points reduction in total score of the IBS severity-scoring-system) at 12, 24, and 48 weeks follow-up. Secondary outcomes included health-related quality of life (QoL), depression and anxiety scores, and school/work absenteeism. RESULTS:One patient (3%) withdrew after randomization, due to lack of effect after the first FMT. Response rates 12 weeks after allogeneic and autologous FMTs were 40% and 38% (p = 0.886). At 24 weeks, significantly more patients responded after allogeneic FMTs (60% vs. 25% autologous, p = 0.048), without significant differences at 48 weeks (60% vs. 50%, p = 0.576). Total QoL score was significantly better after allogeneic than autologous FMTs at 12, 24, and 48 weeks (p = 0.028, p = 0.007, p = 0.011). In the allogeneic FMTs group, school/work absenteeism was 7% at 24 weeks (vs. 41% autologous, p = 0.037). CONCLUSIONS:Allogeneic FMTs were feasible and resulted in high response rates and better QoL compared to autologous FMTs. These results provide preliminary evidence for the use of allogeneic FMTs in adolescents with refractory IBS. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT03074227 (https://clinicaltrials.gov/study/NCT03074227?id=NCT03074227&rank=1).

Background: Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies (aPL), mainly targeted against β2 glycoprotein 1 (β2GP1). The autoimmune response to β2GP1 is aimed at several B cell and T cell epitopes. Molecular mimicry of these epitopes by gut commensal proteins, so-called mimotopes, causing cross-immunization might contribute to the formation of aPL. Objective: To study the potential role of gut microbiome cross-immunization in APS by examining cross-reactivity of aPL with gut commensal mimotope containing proteins. Methods: Fecal microbial metagenome of APS patients was determined using shotgun sequencing. An in-house developed in silico pipeline was used to identify gut commensal proteins that show sequence homology with known β2GP1 B and T cell epitopes in the metagenomic data. An enzyme-linked immunosorbent assay was used to test the identified microbial proteins for IgG cross-reactivity, with plasma of 21 APS patients and 17 control participants. Results: The in silico pipeline resulted in the identification of six gut commensals with a B cell and T cell β2GP1 epitope homologue. Of these, YjjG family noncanonical pyrimidine nucleotidase, one of the candidate-β2GP1 B cell mimicking proteins, showed significantly increased IgG reactivity in APS patients compared to control participants, as well as higher binding of a specific anti-β2GP1 monoclonal antibody than a negative control. Conclusion: Our study shows reactivity of IgG antibodies to YjjG family noncanonical pyrimidine nucleotidase from Roseburia amylophila in APS patients. Insights into the origins of antibody formation may yield new therapeutic targets for improvement of APS treatment.

Although exocrine pancreatic insufficiency (EPI) is thought to be common in type 1 diabetes, little is known about the relationship of EPI with type 1 diabetes parameters or food intake and abdominal complaints. Characterising individuals with EPI could help prevent EPI-related complications such as malabsorption and osteoporosis. In a cross-sectional cohort of 443 individuals with type 1 diabetes (62

INTRODUCTION:Obesity and cancer cachexia represent two seemingly contrasting yet interrelated ends of the metabolic disorder spectrum, both characterized by disrupted energy homeostasis, inflammation and neuroendocrine dysfunction, and associated with increased morbidity and mortality. Existing treatments often fail to address the complex underlying pathophysiological mechanisms. Emerging research highlights the role of the gut microbiome in the pathophysiology of both conditions and how it can serve as a novel therapeutic target. AREAS COVERED:This review explores shared and distinct pathways linking obesity and cancer cachexia. Key systems discussed include the gut-brain axis as well as skeletal muscle and adipose tissue metabolism. We discuss how the gut microbiota influences these processes through (diet-derived) gut microbial metabolites that affect specific signaling pathways. The review evaluates the efficacy and limitations of current anti-obesity and cachexia therapies and summarizes clinical and preclinical interventions targeting the gut microbiome, including pre-, pro-, postbiotics and fecal microbiota transplantation. EXPERT OPINION:The gut microbiota holds potential as a therapeutic target in metabolic diseases, offering opportunities for precision medicine based on microbial and metabolic profiles. While early microbiota-based therapies show promise, further investigation into mechanistic pathways and novel engineered microbiota is essential to develop effective treatments for obesity and cachexia.

Obesity is a major health concern, affecting over 1 in 8 people worldwide. Bariatric surgery (BS) is currently the most effective long-term treatment for morbid obesity. In addition to sustained weight loss, BS is beneficial in treating obesity related comorbidities including dyslipidemia and type 2 diabetes (T2DM). The beneficial effects of BS are a result of weight loss and surgery-induced shifts in the gut microbiota and its metabolites. At the same time, BS may also lead to complications and side effects. Abdominal pain is one of the most frequently reported complaints after BS with a prevalence of 33.8–54.4

Gut microbiota are disrupted in patients hospitalized for COVID-19, with a loss of anaerobic bacteria-producing butyrate. Yet, these disruptions could either be a consequence of the infection itself or increase susceptibility from the outset. Here, we investigated whether gut microbiota influence the risk of future COVID-19 hospitalization and mortality. In 5084 participants of a population-based cohort, gut microbiota composition was associated with the risk of future severe COVID-19. Specifically, increased abundances of butyrate-producing bacteria were associated with a lower risk of severe COVID-19. Together, gut microbiota alterations precede severe COVID-19 and may represent a novel target for prevention.

The human gut microbiome has been suggested to be linked with the risk of developing sepsis, a life-threatening medical emergency. However, it remains unclear whether the gut microbiome is an independent predictor of long-term sepsis risk in the general adult population. Here, we investigated for the first time the prospective association between the gut microbiome and incident sepsis in the general population. The study sample (FINRISK) consisted of 6,372 individuals who underwent fecal sampling in 2002 and were followed for incident sepsis. We used multivariable-adjusted models to study the associations of microbial alpha-diversity, beta-diversity, taxa, butyrate producers, and predicted pathways with incident sepsis. Two hundred and forty participants developed sepsis over a follow-up of 19.8 years. A 1-SD increase in Faecalibacterium prausnitzii_C_71351 abundance was associated with 21% (95% CI, 10%-30%; FDR = 0.03) lower risk of sepsis. Higher abundances of six other species were associated with higher sepsis risk (FDR < 0.05 for all). Five of these species were positively associated with C-reactive protein. The species-sepsis associations were consistent across various subgroups. Moreover, in an independent validation cohort of 4,248 individuals, we found a similar association between Faecalibacterium and a lower risk of future sepsis. Additionally, overall pathways related to carbohydrate degradation, energy production, and sulfur metabolism were positively linked to incident sepsis. We did not detect any associations of alpha-diversity, beta-diversity, or butyrate producers with incident sepsis. Future studies should investigate the causality of these associations and the mechanisms by which the identified species may influence sepsis development.IMPORTANCEPrevious cross-sectional and case-control studies have linked changes in the gut microbiome with the occurrence of sepsis. However, the relationship between the gut microbiome and the risk of incident sepsis in the general adult population remains unexplored. Here, we found clear evidence on the association of gut microbiome species with incident sepsis in a large population cohort. In particular, we provided an in-depth analysis of the negative link between F. prausnitzii and sepsis risk, which was robust across independent cohorts. This finding supports a potential protective role of F. prausnitzii, but further experimental investigation is required. We also show that six species, including Clostridium symbiosum-a causative agent of bacteremia/sepsis in few cases-are positively linked to incident sepsis. Most of these species were also positively linked to an inflammatory marker. Our research provides the groundwork for future experimental analysis of the detected associations to understand their role in infection.

Vascular ageing (VA) is a major risk factor for cardiovascular disease. Its early identification is particularly challenging in migrant populations, who experience higher cardiovascular risk. Emerging evidence links gut microbiota (GM) to vascular health, but population-based studies in ethnically diverse groups remain limited. Therefore, we evaluated the association between GM and VA markers in a multi-ethnic population while exploring sex and ethnic differences. This cross-sectional analysis included 2,446 adults from the HELIUS cohort in Amsterdam, the Netherlands. VA markers, including aortic pulse wave velocity, central systolic blood pressure, and augmentation index, were measured using validated techniques. GM was profiled via 16S rRNA sequencing. Differentially abundant taxa were identified using ANCOM-BC2 and further evaluated in adjusted linear and logistic regression models incorporating sex and ethnicity interactions. VA profiles differ substantially across ethnic groups, with the highest vascular burden among Surinamese and Ghanaian participants. Higher abundance of Faecalibacterium (OR = 0.89, 95% CI: 0.81, 0.99), Bacteroides (OR = 0.89, 95% CI: 0.81, 0.98), and Ruminococcaceae UCG-013 (OR = 0.92, 95% CI: 0.84, 0.99) is associated with lower odds of arterial stiffness. Coprococcus 3, Fusicatenibacter, and members of the Ruminococcaceae and Lachnospiraceae families are also linked to better vascular health, whereas Streptococcus and Sutterella are associated with poorer vascular profiles. Several associations differ by sex and ethnicity, particularly among Surinamese and Ghanaian participants. Our findings support a link between GM composition and VA markers, with sex- and ethnic-specific differences that may inform future research on microbiota-targeted strategies for cardiovascular prevention. Vascular ageing includes early changes in blood vessels that increase cardiovascular risk. Recent studies suggest that gut bacteria may influence vascular ageing, but evidence from ethnically diverse populations remains limited. We investigated whether gut microbiota was associated with vascular ageing markers and explored sex and ethnic differences in 2,446 adults in the multi-ethnic HELIUS study. We found the highest vascular ageing among Surinamese and Ghanaians. Higher abundance of beneficial bacteria, including Faecalibacterium and Bacteroides, was associated with favourable vascular profiles, whereas Streptococcus and Sutterella showed adverse results. Some associations also differed by sex and ethnicity. Our results suggest that gut microbes may contribute to vascular ageing and support the need for future longitudinal and mechanistic studies in diverse populations. Hernández Vargas et al., investigate associations between gut microbiota and vascular ageing markers in 2,446 adults from Amsterdam’s multi-ethnic HELIUS cohort. Several bacterial taxa are associated with better vascular health, with associations varying by sex and ethnicity.

Associations between the gut microbiota and cardiometabolic health are well established, but evidence from longitudinal studies remains limited. In the prospective multi-ethnic HELIUS cohort, we investigated whether baseline gut microbiota composition was associated with long-term cardiometabolic outcomes. Fecal samples from 4792 participants were collected at baseline and analyzed using 16S rRNA sequencing. At follow-up, new diagnoses of hypertension, dyslipidemia, and diabetes were assessed, and major adverse cardiovascular events (MACE and MACE + , including angina pectoris) were obtained from hospital and mortality registries. Logistic regression was used to study associations with incident cardiometabolic disease, while Cox regression evaluated associations with MACE among participants without cardiovascular disease at baseline. During follow-up, 129 participants experienced MACE (2.7%) and 180 MACE+ (3.8%). Higher abundance of Eubacterium xylanophilum group spp. and Akkermansia muciniphila was associated with lower MACE+ risk, whereas Ruminococcus gnavus group spp. was associated with higher MACE risk, although only Eubacterium xylanophilum group spp. remained significant after full adjustment. Several taxa were associated with incident cardiometabolic disease, and exploratory metabolomics linked Ruminococcus gnavus group spp. to bile acid and acylcarnitine metabolites. These findings suggest that gut microbiota composition is longitudinally associated with cardiometabolic disease.

Thyroid disorders are among the most common endocrine disorders worldwide and are classified as noncommunicable diseases. These disorders are associated with significant morbidity, impaired quality of life, and considerable socioeconomic burden. Like other noncommunicable diseases, thyroid disorders arise from complex interactions between genetic susceptibility and environmental factors, including diet and lifestyle. Despite growing interest in lifestyle-based approaches to noncommunicable disease prevention and management, thyroid disorders have received comparatively limited attention in this context. Graves' disease, the most common cause of hyperthyroidism, is a relevant condition for exploring dietary interventions. Current treatment strategies-anti-thyroid drugs, radioactive iodine and thyroidectomy-have remained largely unchanged for decades. Long-term remission following drug therapy is achieved in no more than approximately 50% of patients, while all treatment modalities carry potential adverse effects. These limitations underscore the need for alternative or adjunctive therapeutic strategies. Iodine intake plays a central role in thyroid hormone synthesis. Indeed, observational studies have shown inverse associations between iodine intake and remission rates, as well as achievement of euthyroidism, medication requirements and thyroid autoantibody titers. These findings suggest that dietary iodine restriction may enhance treatment efficacy and reduce medication-related risks. Beyond its direct effects on thyroid hormone synthesis, iodine may influence Graves' disease through indirect mechanisms involving the lipid profile and the gut-thyroid axis. Autoimmune thyroid diseases are associated with a dyslipidemic profile and with gut microbiota dysbiosis; the latter characterized by increased potentially pathogenic bacteria and reduced beneficial bacteria such as Lactobacillus and Bifidobacterium.

Introduction Sodium-glucose cotransporter (SGLT) inhibitors have shown substantial benefit in reducing cardiovascular and kidney events across diverse clinical populations, but the underlying physiological mechanisms remain unclear. However, existing mechanistic studies on renal and cardiovascular haemodynamics show variability in design, have limited statistical power and yield inconsistent outcomes, thus limiting the ability to draw generalisable conclusions. To address this gap, we conducted a systematic review and proposed the first meta-analysis to aggregate individual participant-level data from mechanistic studies to identify consistent physiological patterns and enhance understanding of the therapeutic effects of SGLT inhibition.Methods and analysis Gold-standard measured glomerular filtration rate (mGFR) was selected as the primary outcome for this systematic review, which aimed to identify all completed mechanistic studies investigating the effects of SGLT inhibition. Electronic databases including Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; and Cochrane Central Register of Controlled Trials were searched using a detailed search strategy. In total, 24 studies (n=1296) were identified. This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Key variables including demographics, medical history, concomitant medications, vital signs, mGFR, renal haemodynamics, urine and plasma biochemistry, tubular sodium handling, echocardiography, cardiac output monitoring, arterial stiffness and fluid volume will be extracted. A one-stage individual participant data meta-analysis under a Bayesian framework will be conducted, using hierarchical models to simultaneously analyse data from all eligible studies. The risk of bias due to missing results will be assessed. Sensitivity analyses and subgroup evaluations will be incorporated to explore sources of heterogeneity and assess robustness of findings.Ethics and dissemination Ethics approval was obtained from University Health Network, Toronto, Canada. Findings from the Mechanisms of SGLT Inhibitor Action and Physiological Mediators (MOSAIC) meta-analysis will be published in peer-reviewed journals and results will be disseminated at scientific conferences.PROSPERO registration number CRD420251001413.

Short-chain fatty acids (SCFAs), including acetate, butyrate and propionate, have been linked to depression. It remains unclear whether fecal SCFA levels or predicted SCFA synthesis and degradation are associated with depressive symptoms. We explored these relationships in a Dutch, non-clinical adult sample, considering systolic blood pressure (SBP) as a potential moderator. We studied 200 adults (<50 years old) from the HELIUS cohort with high or low SBP, matched on age, sex and BMI. Fecal SCFA concentrations were quantified by HPLC. SCFA synthesis and degradation pathways were inferred from 16S rRNA gene sequencing using PICRUSt and mapped to gut-brain modules. Depressive symptoms were assessed using the Patient Health Questionnaire-9. Negative binomial regression was used to explore associations between depressive symptoms and SCFA measures, adjusting for demographic, lifestyle, and clinical covariates, with SBP as a potential moderator. In the high SBP group, higher depressive symptom severity was associated with lower acetate concentrations, but this association did not survive multiple-testing (IRR = 0.82, 95% CI [0.69–0.96], p = 0.016, p-adjusted = 0.063). No significant associations were observed in the low SBP group, and similarly no association was found in either group for other fecal SCFA ratios or predicted SCFA pathways. Our exploratory analyses do not provide conclusive evidence for associations between fecal SCFA concentrations or ratios, or SCFA pathways, and depressive symptoms in this non-clinical subsample, although the acetate finding suggests a potential signal influenced by metabolic status. Future research in clinical populations is needed to inform gut-targeted interventions in depression.

Background & aims Proton pump inhibitor (PPI) use has been associated with metabolic dysfunction associated with steatotic liver disease (MASLD) in multiple studies. While the association is confounded by various risk factors, such as BMI and age, a potential mediating factor of the microbiome has been suggested. In this study, we aimed to identify bacterial clades with the highest mediating potential and evaluate the serially mediated path through microbially derived endogenous ethanol.Methods Microbiome mediation analysis of PPI use and MASLD was conducted in two cohorts. In a bariatric surgery cohort (n = 122), liver biopsy-proven steatosis grade and postprandial ethanol concentrations were used as outcomes. In the HELIUS cohort (n = 2440), a general population cohort study, mediation was performed using the Fatty Liver Index (FLI) score. The strongest associations were validated in the FINRISK cohort (n = 7066).Results Several bacterial taxa, which are predominantly found in the small intestine, showed a potential role in mediating the effects of PPIs on MASLD, postprandial ethanol levels, and FLI score. The Lactobacillales order showed the strongest mediating potential across the outcomes tested in both discovery cohorts. A notable serial mediation pathway was identified, linking PPI use to MASLD via Lactobacillales abundance and postprandial plasma ethanol concentrations. The mediating role of Lactobacillales in the association between PPI use and FLI scores was confirmed in the final study cohort.Conclusions Data from multiple cross-sectional cohort studies support a mediating potential of the microbiome in the association between PPI use and hepatic steatosis, independent of alcohol consumption. The effect of PPIs on MASLD appears to be mediated mainly by increased lactic acid bacteria abundance, and is potentially, in part, serially mediated by endogenous ethanol production.