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.

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.

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.

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.

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.

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.

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.

Glycodeoxycholic acid inhibits primary bile acid synthesis with minor effects on glucose- and lipid homeostasis in humans.

BACKGROUND: Bile acids play vital roles in control of lipid-, glucose-, and energy metabolism by activating Takeda G protein-coupled receptor 5 (TGR5) and Farnesoid X receptor (FXR), the latter promoting production of the endocrine-acting fibroblast growth factor 19 (FGF19). Short-term administration of single bile acids has been reported to enhance plasma levels of GLP-1 and to enhance energy expenditure. However, prolonged bile acid supplementation, e.g. of chenodeoxycholic acid (CDCA) for gallstone dissolution, has been reported to have adverse effects. STUDY DESIGN: In this proof-of-concept study, we assessed the safety and metabolic effects of oral glycine-conjugated deoxycholic acid (GDCA) administration at 10 mg/kg/day using regular and slow-release capsules (mimicking physiological bile acid release) over 30 days in two groups of each 10 healthy lean men respectively. MAIN FINDINGS: GDCA increased postprandial total bile acid and FGF19 concentrations while suppressing those of the primary bile acids CDCA and cholic acid. Plasma levels of 7α-hydroxy-4-cholesten-3-one were reduced, indicating repressed hepatic bile acid synthesis. There were minimal effects on indices of lipid-, glucose-, and energy metabolism. No serious adverse events were reported during GDCA administration in either capsule types, although 50% of participants showed mild increases in plasma levels of liver transaminases and 80% (regular capsules) and 50% (slow-release capsules) of participants experienced gastrointestinal adverse events. CONCLUSION: GDCA administration leads to elevated FGF19 levels and effectively inhibits primary bile acid synthesis, supporting therapy compliance and its effectiveness. However, effects on lipid, glucose- and energy metabolism were minimal, indicating that expanding the pool of this relatively hydrophobic bile acid does not impact energy metabolism in healthy subjects.

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.

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.

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.

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.

Re-Cellularization via Electroporation Therapy of the duodenum combined with GPL-1 receptor agonist to replace insulin therapy in patients with type 2 diabetes; 12 months results of a first-in-human study.

BACKGROUND AND AIMS: Studies have shown that hydrothermal duodenal mucosal ablation results in improved glycemic control. Re-Cellularization via Electroporation Therapy (ReCET) is a novel endoscopic procedure that uses electroporation to induce cellular apoptosis and subsequent reepithelization. In this study, we aimed to eliminate exogenous insulin treatment in T2D patients through a single ReCET procedure combined with a GLP-1 receptor agonist (GLP-1RA). Feasibility, safety, and (dose) efficacy of ReCET were assessed. METHODS: First-in-human study including patients with T2D on basal insulin (28-75years; BMI 24-40kg/m2, HbA1c ≤64mmol/mol; C-peptide ≥0.2nmol/L). The electroporation dose was optimized during the study, starting with single 600V and ending with double 750V treatments. All patients underwent ReCET, after which insulin was discontinued and semaglutide (GLP-1RA) was initiated. Primary endpoints were: feasibility (procedure time [catheter in-out], technical success rate), safety, and efficacy (patients off insulin at 6 months; HbA1c ≤58mmol/mol). RESULTS: Fourteen patients underwent endoscopic ReCET. Median procedure time was 58 (IQR 49-73) minutes. ReCET demonstrated a technical success rate of 100%. No device related SAEs or severe hypoglycemic events were observed. At 12 months follow up, 12 (86%) patients remained off exogenous insulin therapy with significant improvements in glycemic control, metabolic parameters. The 2 patients in whom insulin therapy was reintroduced both received ReCET at the lowest voltage (single 600V). CONCLUSION: These results suggest that ReCET is feasible and safe. In combination with semaglutide, ReCET may be a promising therapeutic option to replace insulin therapy in selected T2D patients, while improving glycemic control and metabolic health.

Advanced microbiome therapeutics as a novel modality for oral delivery of peptides to manage metabolic diseases.

The rising prevalence of metabolic diseases calls for innovative treatments. Peptide-based drugs have transformed the management of conditions such as obesity and type 2 diabetes. Yet, challenges persist in oral delivery of these peptides. This review explores the potential of 'advanced microbiome therapeutics' (AMTs), which involve engineered microbes for delivery of peptides in situ, thereby enhancing their bioavailability. Preclinical work on AMTs has shown promise in treating animal models of metabolic diseases, including obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease. Outstanding challenges toward realizing the potential of AMTs involve improving peptide expression, ensuring predictable colonization control, enhancing stability, and managing safety and biocontainment concerns. Still, AMTs have potential for revolutionizing the treatment of metabolic diseases, potentially offering dynamic and personalized novel therapeutic approaches.

The gut microbiome modulates the impact of Anaerobutyricum soehngenii supplementation on glucose homeostasis in mice.

Background: There is growing interest in the development of next-generation probiotics to prevent or treat metabolic syndrome. Previous studies suggested that Anaerobutyricum soehngenii may represent a promising probiotic candidate. A recent human study showed that while A. soehngenii supplementation is well tolerated and safe, it resulted in variable responses among individuals with a subset of the subjects significantly benefiting from the treatment. We hypothesized that gut microbiome variation is linked to the heterogeneous responses to A. soehngenii treatment observed in humans. Results: We colonized germ-free mice with fecal microbiota from human subjects that responded to A. soehngenii treatment (R65 and R55) and non-responder subjects (N96 and N40). Colonized mice were fed a high-fat diet (45% kcal from fat) to induce insulin resistance, and orally treated with either live A. soehngenii culture or heat-killed culture. We found that R65-colonized mice received a benefit in glycemic control with live A. soehngenii treatment while mice colonized with microbiota from the other donors did not. The glucose homeostasis improvements observed in R65-colonized mice were positively correlated with levels of cecal propionate, an association that was reversed in N40-colonized mice. To test whether the microbiome modulates the effects of propionate, R65- or N40-colonized mice were treated with tripropionin (TP, glycerol tripropionate), a pro-drug of propionate, or glycerol (control). TP supplementation showed a similar response pattern as that observed in live A. soehngenii treatment, suggesting that propionate may mediate the effects of A. soehngenii. We also found that TP supplementation to conventional mice reduces adiposity, improves glycemic control, and reduces plasma insulin compared to control animals supplemented with glycerol. Conclusions: These findings highlight the importance of the microbiome on glycemic control and underscore the need to better understand personal microbiome-by-therapeutic interactions to develop more effective treatment strategies.

Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD.

Accurate non-invasive biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis are urgently needed. This study applies a translational approach to develop a blood-based biomarker panel for fibrosis detection in MASLD. A molecular gene expression signature identified from a diet-induced MASLD mouse model (LDLr-/-.Leiden) is translated into human blood-based biomarkers based on liver biopsy transcriptomic profiles and protein levels in MASLD patient serum samples. The resulting biomarker panel consists of IGFBP7, SSc5D and Sema4D. LightGBM modeling using this panel demonstrates high accuracy in predicting MASLD fibrosis stage (F0/F1: AUC = 0.82; F2: AUC = 0.89; F3/F4: AUC = 0.87), which is replicated in an independent validation cohort. The overall accuracy of the model outperforms predictions by the existing markers Fib-4, APRI and FibroScan. In conclusion, here we show a disease mechanism-related blood-based biomarker panel with three biomarkers which is able to identify MASLD patients with mild or advanced hepatic fibrosis with high accuracy.

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.