Can fecal microbiota transplantations modulate autoimmune responses in type 1 diabetes?

Type 1 diabetes (T1D) is a chronic autoimmune disease targeting insulin-producing pancreatic beta cells. T1D is a multifactorial disease incorporating genetic and environmental factors. In recent years, the advances in high-throughput sequencing have allowed researchers to elucidate the changes in the gut microbiota taxonomy and functional capacity that accompany T1D development. An increasing number of studies have shown a role of the gut microbiota in mediating immune responses in health and disease, including autoimmunity. Fecal microbiota transplantations (FMT) have been largely used in murine models to prove a causal role of the gut microbiome in disease progression and have been shown to be a safe and effective treatment in inflammatory human diseases. In this review, we summarize and discuss recent research regarding the gut microbiota-host interactions in T1D, the current advancement in therapies for T1D, and the usefulness of FMT studies to explore microbiota-host immunity encounters in murine models and to shape the course of human type 1 diabetes.

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.

Atorvastatin lowers 68Ga-DOTATATE uptake in coronary arteries, bone marrow and spleen in individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Inflammation is a core component of residual cardiovascular risk in type 2 diabetes. With new anti-inflammatory therapeutics entering the field, accurate markers to evaluate their effectiveness in reducing cardiovascular disease are paramount. Gallium-68-labelled DOTATATE (68Ga-DOTATATE) has recently been proposed as a more specific marker of arterial wall inflammation than 18F-fluorodeoxyglucose (18F-FDG). This study set out to investigate whether 68Ga-DOTATATE uptake is amenable to therapeutic intervention in individuals with type 2 diabetes. METHODS: Individuals aged >50 years with type 2 diabetes underwent 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) at baseline and after 3 months treatment with atorvastatin 40 mg once daily. Primary outcome was the difference in coronary 68Ga-DOTATATE uptake, expressed as target-to-background ratio (TBR). The secondary outcome was difference in bone marrow and splenic uptake, expressed as the standardised uptake value (SUV). RESULTS: Twenty-two individuals with type 2 diabetes (mean age 63.2±6.4 years, 82% male, LDL-cholesterol 3.42±0.81 mmol/l, HbA1c 55±12 mmol/mol [7.2%±3.2%]) completed both 68Ga-DOTATATE PET/CT scans. The maximum TBR was -31% (95% CI -50, -12) lower in the coronary arteries, and bone marrow and splenic 68Ga-DOTATATE uptake was also significantly lower post statin treatment, with a mean percentage reduction of -15% (95% CI -27, -4) and -17% (95% CI -32, -2), respectively. CONCLUSIONS/INTERPRETATION: 68Ga-DOTATATE uptake across the cardio-haematopoietic axis was lower after statin therapy in individuals with type 2 diabetes. Therefore, 68Ga-DOTATATE is promising as a metric for vascular and haematopoietic inflammation in intervention studies using anti-inflammatory therapeutics in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05730634.

Pyridoxamine reduces methylglyoxal and markers of glycation and endothelial dysfunction, but does not improve insulin sensitivity or vascular function in abdominally obese individuals: A randomized double-blind placebo-controlled trial.

AIM: To investigate the effects of pyridoxamine (PM), a B6 vitamer and dicarbonyl scavenger, on glycation and a large panel of metabolic and vascular measurements in a randomized double-blind placebo-controlled trial in abdominally obese individuals. MATERIALS AND METHODS: Individuals (54% female; mean age 50 years; mean body mass index 32 kg/m2 ) were randomized to an 8-week intervention with either placebo (n = 36), 25 mg PM (n = 36) or 200 mg PM (n = 36). We assessed insulin sensitivity, ß-cell function, insulin-mediated microvascular recruitment, skin microvascular function, flow-mediated dilation, and plasma inflammation and endothelial function markers. PM metabolites, dicarbonyls and advanced glycation endproducts (AGEs) were measured using ultra-performance liquid chromatography tandem mass spectrometry. Treatment effects were evaluated by one-way ANCOVA. RESULTS: In the high PM dose group, we found a reduction of plasma methylglyoxal (MGO) and protein-bound Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), as compared to placebo. We found a reduction of the endothelial dysfunction marker soluble vascular cell adhesion molecule-1 (sVCAM-1) in the low and high PM dose group and of soluble intercellular adhesion molecule-1 (sICAM-1) in the high PM dose, as compared to placebo. We found no treatment effects on insulin sensitivity, vascular function or other functional outcome measurements. CONCLUSIONS: This study shows that PM is metabolically active and reduces MGO, AGEs, sVCAM-1 and sICAM-1, but does not affect insulin sensitivity and vascular function in abdominally obese individuals. The reduction in adhesion markers is promising because these are important in the pathogenesis of endothelial damage and atherosclerosis.

Microbial influencers: treating diabetes through the gut.

A recently published study by Bell et al. shows altered immunotolerance in people with type 1 diabetes by dietary supplementation of modified resistant starch fibre.

Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis.

RATIONALE: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. OBJECTIVE: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. METHODS AND RESULTS: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8, or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. CONCLUSIONS: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.

Apoptotic Ablation of Platelets Reduces Atherosclerosis in Mice With Diabetes.

OBJECTIVE: People with diabetes are at a significantly higher risk of cardiovascular disease, in part, due to accelerated atherosclerosis. Diabetic subjects have increased number of platelets that are activated, more reactive, and respond suboptimally to antiplatelet therapies. We hypothesized that reducing platelet numbers by inducing their premature apoptotic death would decrease atherosclerosis. Approach and Results: This was achieved by targeting the antiapoptotic protein Bcl-xL (B-cell lymphoma-extra large; which is essential for platelet viability) via distinct genetic and pharmacological approaches. In the former, we transplanted bone marrow from mice carrying the Tyr15 to Cys loss of function allele of Bcl-x (known as Bcl-xPlt20) or wild-type littermate controls into atherosclerotic-prone Ldlr+/- mice made diabetic with streptozotocin and fed a Western diet. Reduced Bcl-xL function in hematopoietic cells significantly decreased platelet numbers, exclusive of other hematologic changes. This led to a significant reduction in atherosclerotic lesion formation in Bcl-xPlt20 bone marrow transplanted Ldlr+/- mice. To assess the potential therapeutic relevance of reducing platelets in atherosclerosis, we next targeted Bcl-xL with a pharmacological strategy. This was achieved by low-dose administration of the BH3 (B-cell lymphoma-2 homology domain 3) mimetic, ABT-737 triweekly, in diabetic Apoe-/- mice for the final 6 weeks of a 12-week study. ABT-737 normalized platelet numbers along with platelet and leukocyte activation to that of nondiabetic controls, significantly reducing atherosclerosis while promoting a more stable plaque phenotype. CONCLUSIONS: These studies suggest that selectively reducing circulating platelets, by targeting Bcl-xL to promote platelet apoptosis, can reduce atherosclerosis and lower cardiovascular disease risk in diabetes. Graphic Abstract: A graphic abstract is available for this article.

Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial.

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.

Physical activity and markers of glycation in older individuals: data from a combined cross-sectional and randomized controlled trial (EXAMIN AGE).

BACKGROUND: Advanced glycation end products (AGEs) are protein modifications that are predominantly formed from dicarbonyl compounds that arise from glucose and lipid metabolism. AGEs and sedentary behavior have been identified as a driver of accelerated (vascular) aging. The effect of physical activity on AGE accumulation is unknown. Therefore, we investigated whether plasma AGEs and dicarbonyl levels are different across older individuals that were active or sedentary and whether plasma AGEs are affected by high-intensity interval training (HIIT). METHODS: We included healthy older active (HA, n=38, 44.7% female, 60.1 ± 7.7 years old) and healthy older sedentary (HS, n=36, 72.2% female, 60.0 ± 7.3 years old) individuals as well as older sedentary individuals with increased cardiovascular risk (SR, n=84, 50% female, 58.7 ± 6.6 years old). The SR group was randomized into a 12-week walking-based HIIT program or control group. We measured protein-bound and free plasma AGEs and dicarbonyls by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) at baseline and after the HIIT intervention. RESULTS: Protein-bound AGE Nε-(carboxymethyl)lysine (CML) was lower in SR (2.6 ± 0.5 µmol/l) and HS (3.1 ± 0.5 µmol/l) than in HA (3.6 ± 0.6 µmol/l; P<0.05) and remained significantly lower after adjustment for several potential confounders. None of the other glycation markers were different between HS and HA. HIIT did not change plasma AGEs and dicarbonyls in SR. DISCUSSION: Although lifestyle interventions may act as important modulators of cardiovascular risk, HIIT is not a potent short-term intervention to reduce glycation in older individuals, underlining the need for other approaches, such as pharmacological agents, to reduce AGEs and lower cardiovascular risk in this population.

Methylglyoxal stress, the glyoxalase system, and diabetic chronic kidney disease.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) remains a serious diabetic complication despite the use of widely employed interventions such as angiotensin-converting enzyme inhibitors and glucose-lowering treatments. Accumulation of methylglyoxal, a highly reactive glucose metabolite and a major precursor in the formation of advanced glycation end products, may link the hemodynamic, inflammatory, metabolic, and structural changes that drive diabetic CKD. Therefore, methylglyoxal may serve as a potential therapeutic target to prevent diabetic CKD. RECENT FINDINGS: Higher plasma methylglyoxal levels were shown to be associated with a decline in the estimated glomerular filtration rate. Furthermore, interventions that lower methylglyoxal levels reduced albuminuria in rodent models of diabetes. In addition, the glyoxalase system, which detoxifies methylglyoxal into D-lactate, has been identified as a key protective enzymatic system against diabetic CKD in both human and rodent studies. Recently, several promising treatments to lower methylglyoxal directly or to boost the glyoxalase system have been identified. SUMMARY: The review highlights the mechanisms through which methylglyoxal is formed in diabetes, and how methylglyoxal contributes to the mechanisms that drive CKD in diabetes. Furthermore, we discuss the role of glyoxalase-1 in diabetic CKD. Finally, we discuss recent data about treatments that lower methylglyoxal stress.

Quercetin, but Not Epicatechin, Decreases Plasma Concentrations of Methylglyoxal in Adults in a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial with Pure Flavonoids.

Background: Methylglyoxal (MGO) is the most potent precursor of advanced glycation end products (AGEs). MGO and AGEs have been associated with diabetes, its complications, and other age-related diseases. Experimental studies have shown that the flavonoids quercetin and epicatechin are able to scavenge MGO and lower AGE formation. Objective: Data on the effects of these flavonoids on MGO and AGE concentrations in humans are not yet available. We therefore investigated the effect of quercetin and epicatechin on the concentrations of MGO and AGEs in a post hoc analysis. Methods: Thirty-seven apparently healthy, nonsmoking adults with a systolic blood pressure between 125 and 160 mm Hg at screening were included in a randomized, double-blind, placebo-controlled crossover trial. Participants ingested (-)-epicatechin (100 mg/d), quercetin 3-glucoside (160 mg/d), or placebo capsules for periods of 4 wk separated by 4-wk washout periods. Fasting blood samples were collected at the start and end of each intervention period. Liquid chromatography-tandem mass spectrometry was used to determine plasma concentrations of the dicarbonyl compounds MGO, glyoxal (GO), and 3-deoxyglucosone (3-DG) and free and protein-bound AGEs. Gene expression of glyoxalase 1 (GLO1), the enzyme involved in the degradation of MGO, was determined by either microarray or quantitative reverse transcriptase-polymerase chain reaction. Results: The treatment effect (Δtreatment - Δplacebo) of quercetin on MGO was -40.2 nmol/L (95% CI: -73.6, -6.8 nmol/L; P = 0.019), a decrease of 11% from baseline values, whereas GO, 3-DG, and free and protein-bound AGEs did not change significantly. Epicatechin did not affect the concentrations of dicarbonyls and free and protein-bound AGEs. We did not find a significant change in expression of GLO1. Conclusions: In apparently healthy (pre)hypertensive men and women, quercetin but not epicatechin decreased plasma MGO concentrations. Quercetin may potentially form a new treatment strategy for diseases in which MGO plays a pivotal role. This study was registered at clinicaltrials.gov as NCT01691404.

Energy restriction and Roux-en-Y gastric bypass reduce postprandial α-dicarbonyl stress in obese women with type 2 diabetes.

AIMS/HYPOTHESIS: Dicarbonyl compounds are formed as byproducts of glycolysis and are key mediators of diabetic complications. However, evidence of postprandial α-dicarbonyl formation in humans is lacking, and interventions to reduce α-dicarbonyls have not yet been investigated. Therefore, we investigated postprandial α-dicarbonyl levels in obese women without and with type 2 diabetes. Furthermore, we evaluated whether a diet very low in energy (very low calorie diet [VLCD]) or Roux-en-Y gastric bypass (RYGB) reduces α-dicarbonyl stress in obese women with type 2 diabetes. METHODS: In lean (n = 12) and obese women without (n = 27) or with type 2 diabetes (n = 27), we measured the α-dicarbonyls, methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), and glucose in fasting and postprandial plasma samples obtained during a mixed meal test. Obese women with type 2 diabetes underwent either a VLCD or RYGB. Three weeks after the intervention, individuals underwent a second mixed meal test. RESULTS: Obese women with type 2 diabetes had higher fasting and particularly higher postprandial plasma α-dicarbonyl levels, compared with those without diabetes. After three weeks of a VLCD, postprandial α-dicarbonyl levels in diabetic women were significantly reduced (AUC MGO -14%, GO -16%, 3-DG -25%), mainly through reduction of fasting plasma α-dicarbonyls (MGO -13%, GO -13%, 3-DG -33%). Similar results were found after RYGB. CONCLUSIONS/INTERPRETATION: This study shows that type 2 diabetes is characterised by increased fasting and postprandial plasma α-dicarbonyl stress, which can be reduced by improving glucose metabolism through a VLCD or RYGB. These data highlight the potential to reduce reactive α-dicarbonyls in obese individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01167959.

Higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques are associated with a rupture-prone phenotype.

AIMS: Rupture-prone atherosclerotic plaques are characterized by inflammation and a large necrotic core. Inflammation is linked to high metabolic activity. Advanced glycation endproducts (AGEs) and their major precursor methylglyoxal are formed during high metabolic activity and can have detrimental effects on cellular function and may induce cell death. Therefore, we investigated whether plaque AGEs are increased in human carotid rupture-prone plaques and are associated with plaque inflammation and necrotic core formation. METHODS AND RESULTS: The protein-bound major methylglyoxal-derived AGE 5-hydro-5-methylimidazolone (MG-H1) and N(ε)-(carboxymethyl)lysine (CML) were measured in human carotid endarterectomy specimens (n = 75) with tandem mass spectrometry. MG-H1 and CML levels were associated with rupture-prone plaques, increased protein levels of the inflammatory mediators IL-8 and MCP-1 and with higher MMP-9 activity. Immunohistochemistry showed that AGEs accumulated predominantly in macrophages surrounding the necrotic core and co-localized with cleaved caspase-3. Intra-plaque comparison revealed that glyoxalase-1 (GLO-1), the major methylglyoxal-detoxifying enzyme, mRNA was decreased (-13%, P < 0.05) in ruptured compared with stable plaque segments. In line, in U937 monoctyes, we found reduced (GLO-1) activity (-38%, P < 0.05) and increased MGO (346%, P < 0.05) production after stimulation with the inflammatory mediator TNF. Direct incubation with methylglyoxal increased apoptosis up to two-fold. CONCLUSION: This is the first study showing that AGEs are associated with human rupture-prone plaques. Furthermore, this study suggests a cascade linking inflammation, reduced GLO-1, methylglyoxal- and AGE-accumulation, and subsequent apoptosis. Thereby, AGEs may act as mediators of the progression of stable to rupture-prone plaques, opening a window towards novel treatments and biomarkers to treat cardiovascular diseases.

Methylglyoxal and glyoxalase I in atherosclerosis.

Cardiovascular disease, caused predominantly by atherosclerotic plaque rupture, remains one of the leading causes of death. However, the mechanism of plaque rupture remains largely unknown. Recent studies have linked high metabolic activity in inflamed atherosclerotic plaques to the development of plaque rupture. AGEs (advanced glycation end-products) are known to be formed as a result of high metabolic activity and are higher in rupture-prone than stable plaques. Furthermore, AGEs seem to be more than mere markers of metabolic activity, as recent studies have elucidated that AGEs and their major precursor, MG (methylglyoxal), may have an important role in the progression of atherosclerosis and plaque rupture. MG can be detoxified by Glo1 (glyoxalase I), thereby preventing the accumulation of MG and MG-derived AGEs. In the present review, data concerning MG, Glo1 and AGEs in the context of plaque phenotype are discussed.

Prevalence and predictive features of metabolic dysfunction-associated steatotic liver disease in type 1 diabetes.

AIMS/HYPOTHESIS: The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in type 1 diabetes remain unclear. Therefore, we investigated the prevalence and severity of MASLD in type 1 diabetes and assessed which clinical features are most important in predicting MASLD severity. METHODS: A total of 453 individuals with type 1 diabetes (41.6 ± 15.0 years, 64% female, body mass index [BMI] 25.4 ± 4.2 kg/m2, and HbA1c 55.6 ± 12 mmol/mol) underwent vibration-controlled transient elastography (VCTE), with a controlled attenuation parameter (CAP) score for steatosis (≥280.0 dB/m) and a liver stiffness measurement (LMS) for fibrosis (≥8.0 kPa). A machine learning Extra-Trees classification model was performed to assess the predictive power of the clinical features associated with type 1 diabetes with respect to steatosis and fibrosis. RESULTS: The prevalence of hepatic steatosis and fibrosis was 9.5% (95% CI, 6.8-12.2) and 3.5% (95% CI, 1.8-5.2). Higher LMS was associated with a longer duration of type 1 diabetes (median 30.5 [IQR 18.0-39.3] years vs 15.0 [IQR 6.0-27.0] years), and individuals were older, had a higher BMI (mean 27.8 ± 5.2 vs 25.3 ± 4.1 kg/m2), and a higher CAP score (mean 211.4 ± 51.7 dB/m vs 241.4 ± 75.6 dB/m). The most important predictive features of fibrosis were duration of type 1 diabetes, age, and systolic blood pressure, with a mean ± SD area under the curve of 0.73 ± 0.03. CONCLUSION: Individuals with type 1 diabetes and high blood pressure, older age, higher BMI, and longer duration of disease could be considered at high-risk for developing MASLD.

Evidence for the contribution of the gut microbiome to obesity and its reversal.

Obesity has become a worldwide pandemic affecting more than 650 million people and is associated with a high burden of morbidity. Alongside traditional risk factors for obesity, the gut microbiome has been identified as a potential factor in weight regulation. Although rodent studies suggest a link between the gut microbiome and body weight, human evidence for causality remains scarce. In this Review, we postulate that existing evidence remains to establish a contribution of the gut microbiome to the development of obesity in humans but that modified probiotic strains and supraphysiological dosages of microbial metabolites may be beneficial in combatting obesity.

Pyridoxamine prevents increased atherosclerosis by intermittent methylglyoxal spikes in the aortic arches of ApoE-/- mice.

Methylglyoxal (MGO) is a reactive glucose metabolite linked to diabetic cardiovascular disease (CVD). MGO levels surge during intermittent hyperglycemia. We hypothesize that these MGO spikes contribute to atherosclerosis, and that pyridoxamine as a MGO quencher prevents this injury. To study this, we intravenously injected normoglycemic 8-week old male C57Bl6 ApoE-/- mice with normal saline (NS, n = 10) or 25 µg MGO for 10 consecutive weeks (MGOiv, n = 11) with or without 1 g/L pyridoxamine (MGOiv+PD, n = 11) in the drinking water. We measured circulating immune cells by flow cytometry. We quantified aortic arch lesion area in aortic roots after Sudan-black staining. We quantified the expression of inflammatory genes in the aorta by qPCR. Intermittent MGO spikes weekly increased atherosclerotic burden in the arch 1.8-fold (NS: 0.9 ± 0.1 vs 1.6 ± 0.2 %), and this was prevented by pyridoxamine (0.8 ± 0.1 %). MGOiv spikes increased circulating neutrophils and monocytes (2-fold relative to NS) and the expression of ICAM (3-fold), RAGE (5-fold), S100A9 (2-fold) and MCP1 (2-fold). All these changes were attenuated by pyridoxamine. This study suggests that MGO spikes damages the vasculature independently of plasma glucose levels. Pyridoxamine and potentially other approaches to reduce MGO may prevent excess cardiovascular risk in diabetes.

Ancestral and environmental patterns in the association between triglycerides and other cardiometabolic risk factors.

BACKGROUND: West Africans and African Americans with substantial (∼80%) West African ancestry are characterized by low levels of triglycerides (TG) compared to East Africans and Europeans. The impact of these varying TG levels on other cardiometabolic risk factors is unclear. We compared the strength of association between TG with hypertension, blood pressure, BMI, waist circumference, type 2 diabetes (T2D), and fasting glucose across West African (WA), East African (EA), and European (EU) ancestry populations residing in three vastly different environmental settings: sub-Saharan Africa, United States, and Europe. METHODS: We analysed data from four cross-sectional studies that included WA in sub-Saharan Africa (n = 7201), the U.S. (n = 4390), and Europe (n = 6436), EA in sub-Saharan Africa (n = 781), and EU in the U.S. (n = 8670) and Europe (n = 4541). Linear regression analyses were used to test the association between TG and cardiometabolic risk factors. FINDINGS: Higher adjusted regression coefficients were observed in EU compared with WA ancestry for TG on hypertension (EU ß [95% CI]: 0.179 [0.156, 0.203], WA ß [95% CI]: 0.102 [0.086, 0.118]), BMI (EU ß [95% CI]: 0.028 [0.027, 0.030], WA ß [95% CI]: 0.015 [0.014, 0.016]), and waist circumference (EU ß [95% CI]: 0.013 [0.013, 0.014], WA ß [95% CI]: 0.009 [0.008, 0.009) (all ancestry × trait interaction P-values <0.05), irrespective of environmental differences within ancestry groups. Less consistency was observed among EA. Associations of TG with T2D did not follow ancestry patterns, with substantial variation observed between environments. INTERPRETATION: TG may not be an equally strong associated with other established cardiometabolic risk factors in West and East Africans in contrast to European ancestry populations. The value of TG for identifying individuals at high risk for developing metabolic disorders needs to be re-evaluated for African ancestry populations. FUNDING: National Institutes of Health, European Commission, Dutch Heart Foundation, Netherlands Organization for Health Research and Development, Centers for Disease Control and Prevention.

Tryptophan metabolites and incident cardiovascular disease: The EPIC-Norfolk prospective population study.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) remains the largest cause of death globally due to various risk factors. One novel potential contributor to CVD might be the metabolism of the essential amino acid tryptophan (Trp), which through many pathways can produce immunomodulatory metabolites such as kynurenine, indole-3-propionate and serotonin. We aim to identify the metabolites with the strongest association with cardiovascular disease, utilizing a substantial and diverse cohort of individuals. In our pursuit of this aim, our primary focus is to validate and reinforce the findings from previous cross-sectional studies. METHODS: We used the community-based EPIC-Norfolk cohort (46.3 % men, age 59.8 ± 9.0) with a median follow-up of 22.1 (17.6-23.3) years to study associations between the relative levels of Trp metabolites measured with untargeted metabolomics and incident development of CVD. Serum from n = 11,972 apparently healthy subjects was analysed, of which 6982 individuals had developed CVD at the end of follow-up. Cox proportional hazard models were used to study associations, adjusted for sex, age, conventional cardiovascular risk factors and CRP. All metabolites were Ln-normalised prior to analysis. RESULTS: Higher levels of Trp were inversely associated with mortality (HR 0.73; CI 0.64-0.83) and fatal CVD (HR 0.76; CI 0.59-0.99). Higher levels of kynurenine (HR 1.33; CI 1.19-1.49) and the [Kynurenine]/[Tryptophan]-ratio (HR 1.24; CI 1.14-1.35) were associated with a higher incident development of CVD. Serotonin was not associated with overall CVD, but we did find associations for myocardial infarction and stroke. Adjustment for CRP did not yield any discernible differences in effect size. CONCLUSIONS: Tryptophan levels were inversely correlated with CVD, while several of its major metabolites (especially kynurenine and serotonin) were positively correlated. These findings indicate that mechanistic studies are required to understand the role of Trp metabolism in CVD with the goal to identify new therapeutic targets.