Metagenomic analysis reveals crosstalk between gut microbiota and glucose-lowering drugs targeting the gastrointestinal tract in Chinese patients with type 2 diabetes: a 6 month, two-arm randomised trial.

AIMS/HYPOTHESIS: The use of oral glucose-lowering drugs, particularly those designed to target the gut ecosystem, is often observed in association with altered gut microbial composition or functional capacity in individuals with type 2 diabetes. The gut microbiota, in turn, plays crucial roles in the modulation of drug efficacy. We aimed to assess the impacts of acarbose and vildagliptin on human gut microbiota and the relationships between pre-treatment gut microbiota and therapeutic responses. METHODS: This was a randomised, open-labelled, two-arm trial in treatment-naive type 2 diabetes patients conducted in Beijing between December 2016 and December 2017. One hundred participants with overweight/obesity and newly diagnosed type 2 diabetes were recruited from the Pinggu Hospital and randomly assigned to the acarbose (n=50) or vildagliptin (n=50) group using sealed envelopes. The treatment period was 6 months. Blood, faecal samples and visceral fat data from computed tomography images were collected before and after treatments to measure therapeutic outcomes and gut microbiota. Metagenomic datasets from a previous type 2 diabetes cohort receiving acarbose or glipizide for 3 months were downloaded and processed. Statistical analyses were applied to identify the treatment-related changes in clinical variables, gut microbiota and associations. RESULTS: Ninety-two participants were analysed. After 6 months of acarbose (n=44) or vildagliptin (n=48) monotherapy, both groups achieved significant reductions in HbA1c (from 60 to 46 mmol/mol [from 7.65% to 6.40%] in the acarbose group and from 59 to 44 mmol/mol [from 7.55% to 6.20%] in the vildagliptin group) and visceral fat areas (all adjusted p values for pre-post comparisons <0.05). Both arms showed drug-specific and shared changes in relative abundances of multiple gut microbial species and pathways, especially the common reductions in Bacteroidetes species. Three months and 6 months of acarbose-induced changes in microbial composition were highly similar in type 2 diabetes patients from the two independent studies. Vildagliptin treatment significantly enhanced fasting active glucagon-like peptide-1 (GLP-1) levels. Baseline gut microbiota, rather than baseline GLP-1 levels, were strongly associated with GLP-1 response to vildagliptin, and to a lesser extent with GLP-1 response to acarbose. CONCLUSIONS/INTERPRETATION: This study reveals common microbial responses in type 2 diabetes patients treated with two glucose-lowering drugs targeting the gut differently and acceptable performance of baseline gut microbiota in classifying individuals with different GLP-1 responses to vildagliptin. Our findings highlight bidirectional interactions between gut microbiota and glucose-lowering drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02999841 FUNDING: National Key Research and Development Project: 2016YFC1304901.

Appoptosin interacts with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology.

Mitochondrial morphology is regulated by fusion and fission machinery. Impaired mitochondria dynamics cause various diseases, including Alzheimer's disease. Appoptosin (encoded by SLC25A38) is a mitochondrial carrier protein that is located in the mitochondrial inner membrane. Appoptosin overexpression causes overproduction of reactive oxygen species (ROS) and caspase-dependent apoptosis, whereas appoptosin downregulation abolishes ß-amyloid-induced mitochondrial fragmentation and neuronal death during Alzheimer's disease. Herein, we found that overexpression of appoptosin resulted in mitochondrial fragmentation in a manner independent of its carrier function, ROS production or caspase activation. Although appoptosin did not affect levels of mitochondrial outer-membrane fusion (MFN1 and MFN2), inner-membrane fusion (OPA1) and fission [DRP1 (also known as DNM1L) and FIS1] proteins, appoptosin interacted with MFN1 and MFN2, as well as with the mitochondrial ubiquitin ligase MITOL (also known as MARCH5) but not OPA1, FIS1 or DRP1. Appoptosin overexpression impaired the interaction between MFN1 and MFN2, and mitochondrial fusion. By contrast, co-expression of MFN1, MITOL and a dominant-negative form of DRP1, DRP1(K38A), partially rescued appoptosin-induced mitochondrial fragmentation and apoptosis, whereas co-expression of FIS1 aggravated appoptosin-induced apoptosis. Together, our results demonstrate that appoptosin can interact with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology.

N-Terminal Pro-Brain Natriuretic Peptide Concentrations After Hypertensive Intracerebral Hemorrhage: Relationship With Hematoma Size, Hyponatremia, and Intracranial Pressure.

INTRODUCTION:: The role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with hypertensive intracerebral hemorrhage (HICH) is poorly understood. This study aimed to investigate the secretion pattern of NT-proBNP in patients with HICH and to assess its relationship with hematoma size, hyponatremia, and intracranial pressure (ICP). METHODS:: This prospective study enrolled 147 isolated patients with HICH. Blood samples were obtained from each patient, and values of serum NT-proBNP, hematoma size, blood sodium, and ICP were collected for each patient. RESULTS:: The peak-to-mean concentration of NT-proBNP was 666.8 ± 355.1 pg/mL observed on day 4. The NT-proBNP levels in patients with hematoma volume >30 mL were significantly higher than those in patients with hematoma volume <30 mL ( P < .05). In patients with severe HICH, the mean concentration of NT-proBNP was statistically higher than that in patients with mild-moderate HICH ( P < .05), and the mean level of NT-proBNP in hyponatremia group was significantly higher than that in normonatremic group ( P < .05). In addition, the linear regression analysis indicated that serum NT-proBNP concentrations were positively correlated with ICP ( r = .703, P < .05) but negatively with blood sodium levels only in patients with severe HICH ( r = -.704, P < .05). The serum NT-proBNP levels on day 4 after admission were positively correlated with hematoma size ( r = .702, P < .05). CONCLUSION:: The NT-proBNP concentrations were elevated progressively and markedly at least in the first 4 days after HICH and reached a peak level on the fourth day. The NT-proBNP levels on day 4 were positively correlated with hematoma size. There was a notable positive correlation between plasma NT-proBNP levels and ICP in patients with severe HICH. Furthermore, only in patients with severe HICH, the plasma NT-proBNP levels presented a significant correlation with hyponatremia, which did not occur in patients with mild-moderate HICH.

Deciphering unique and shared interactions between the human gut microbiota and oral antidiabetic drugs.

The administration of oral antidiabetic drugs (OADs) to patients with type 2 diabetes elicits distinct and shared changes in the gut microbiota, with acarbose and berberine exhibiting greater impacts on the gut microbiota than metformin, vildagliptin, and glipizide. The baseline gut microbiota strongly associates with treatment responses of OADs.

Divergent age-associated and metabolism-associated gut microbiome signatures modulate cardiovascular disease risk.

Insight into associations between the gut microbiome with metabolism and aging is crucial for tailoring interventions to promote healthy longevity. In a discovery cohort of 10,207 individuals aged 40-93 years, we used 21 metabolic parameters to classify individuals into five clusters, termed metabolic multimorbidity clusters (MCs), that represent different metabolic subphenotypes. Compared to the cluster classified as metabolically healthy (MC1), clusters classified as 'obesity-related mixed' (MC4) and 'hyperglycemia' (MC5) exhibited an increased 11.1-year cardiovascular disease (CVD) risk by 75% (multivariable-adjusted hazard ratio (HR): 1.75, 95% confidence interval (CI): 1.43-2.14) and by 117% (2.17, 1.72-2.74), respectively. These associations were replicated in a second cohort of 9,061 individuals with a 10.0-year follow-up. Based on analysis of 4,491 shotgun fecal metagenomes from the discovery cohort, we found that gut microbial composition was associated with both MCs and age. Next, using 55 age-specific microbial species to capture biological age, we developed a gut microbial age (MA) metric, which was validated in four external cohorts comprising 4,425 metagenomic samples. Among individuals aged 60 years or older, the increased CVD risk associated with MC4 or MC5, as compared to MC1, MC2 or MC3, was exacerbated in individuals with high MA but diminished in individuals with low MA, independent of age, sex and other lifestyle and dietary factors. This pattern, in which younger MA appears to counteract the CVD risk attributable to metabolic dysfunction, implies a modulating role of MA in cardiovascular health for metabolically unhealthy older people.

Cushing Syndrome Is Associated With Gut Microbial Dysbiosis and Cortisol-Degrading Bacteria.

CONTEXT: Cushing syndrome (CS) is a severe endocrine disease characterized by excessive secretion of cortisol with multiple metabolic disorders. While gut microbial dysbiosis plays a vital role in metabolic disorders, the role of gut microbiota in CS remains unclear. OBJECTIVE: The objective of this work is to examine the alteration of gut microbiota in patients with CS. METHODS: We performed shotgun metagenomic sequencing of fecal samples from 78 patients with CS and 78 healthy controls matched for age and body mass index. Furthermore, we verify the cortisol degradation capacity of Ruminococcus gnavus in vitro and identify the potential metabolite by LC-MC/MS. RESULTS: We observed significant differences in microbial composition between CS and controls in both sexes, with CS showing reduced Bacteroidetes (Bacteroides vulgatus) and elevated Firmicutes (Erysipelotrichaceae_bacterium_6_1_45) and Proteobacteria (Enterobacter cloacae). Despite distinct causes of hypercortisolism in ACTH-dependent and ACTH-independent CS, we found no significant differences in metabolic profiles or gut microbiota between the 2 subgroups. Furthermore, we identified a group of gut species, including R. gnavus, that were positively correlated with cortisol levels in CS. These bacteria were found to harbor cortisol-degrading desAB genes and were consistently enriched in CS. Moreover, we demonstrated the efficient capacity of R. gnavus to degrade cortisol to 11-oxygenated androgens in vitro. CONCLUSION: This study provides evidence of gut microbial dysbiosis in patients with CS and identifies a group of CS-enriched bacteria capable of degrading cortisol. These findings highlight the potential role of gut microbiota in regulating host steroid hormone levels, and consequently host health.

Obesity-enriched gut microbe degrades myo-inositol and promotes lipid absorption.

Numerous studies have reported critical roles for the gut microbiota in obesity. However, the specific microbes that causally contribute to obesity and the underlying mechanisms remain undetermined. Here, we conducted shotgun metagenomic sequencing in a Chinese cohort of 631 obese subjects and 374 normal-weight controls and identified a Megamonas-dominated, enterotype-like cluster enriched in obese subjects. Among this cohort, the presence of Megamonas and polygenic risk exhibited an additive impact on obesity. Megamonas rupellensis possessed genes for myo-inositol degradation, as demonstrated in vitro and in vivo, and the addition of myo-inositol effectively inhibited fatty acid absorption in intestinal organoids. Furthermore, mice colonized with M. rupellensis or E. coli heterologously expressing the myo-inositol-degrading iolG gene exhibited enhanced intestinal lipid absorption, thereby leading to obesity. Altogether, our findings uncover roles for M. rupellensis as a myo-inositol degrader that enhances lipid absorption and obesity, suggesting potential strategies for future obesity management.

Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study.

Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.

BiOBr/Ag/AgBr heterojunctions decorated carbon fiber cloth with broad-spectral photoresponse as filter-membrane-shaped photocatalyst for the efficient purification of flowing wastewater.

The development of recyclable photocatalysts with broad-spectral photoresponse has drawn much attention for the practical application in flowing wastewater treatment. Herein, we have reported the construction of BiOBr/Ag/AgBr junctions on carbon fiber cloth (CFC) as broad-spectral-response filter-membrane-shaped photocatalyst that is efficient and easily recyclable. With CFC as the substrate, BiOBr nanosheets (diameter: 0.5-1 µm) were firstly synthesized by a hydrothermal method, and then Ag/AgBr nanoparticles (size: 100-300 nm) were prepared on the surface of CFC/BiOBr by using a chemical bath deposition route. CFC/BiOBr/Ag/AgBr presents superior flexibility and wide UV-Vis-NIR photoabsorption (from 200 to 1000 nm). Under visible light irradiation, CFC/BiOBr/Ag/AgBr (area: 4 × 4 cm2) can remove 99.8% rhodamine B (RhB), 99.0% acid orange 7 (AO7), and 93.0% tetracycline (TC) after 120 min, better than CFC/BiOBr (95.4% RhB, 55.0% AO7 and 91.2% TC). Interestingly, when CFC/BiOBr/Ag/AgBr is served as a filter-membrane in a photoreactor to purify the flowing sewage (RhB, rate: ~1.5 L h-1), the degradation rate of RhB goes up to 90.0% after ten filtering grades. Therefore, CFC/BiOBr/Ag/AgBr has great potential to purify the flowing wastewater as a novel filter-membrane-shaped photocatalyst.

Sex- and age-related trajectories of the adult human gut microbiota shared across populations of different ethnicities.

Lifelong sex- and age-related trajectories of the human gut microbiota remain largely unexplored. Using metagenomics, we derived the gut microbial composition of 2,338 adults (26-76 years) from a Han Chinese population-based cohort where metabolic health, hormone levels and aspects of their lifestyles were also recorded. In this cohort, and in three independent cohorts distributed across China, Israel and the Netherlands, we observed sex differences in the gut microbial composition and a shared age-related decrease in sex-dependent differences in gut microbiota. Compared to men, the gut microbiota of premenopausal women exhibited higher microbial diversity and higher abundances of multiple species known to have beneficial effects on host metabolism. We also found consistent sex-independent, age-related gut microbial characteristics across all populations, with the presence of members of the oral microbiota being the strongest indicator of older chronological age. Our findings highlight the existence of sex- and age-related trajectories in the human gut microbiota that are shared between populations of different ethnicities and emphasize the pivotal links between sex hormones, gut microbiota and host metabolism.

Characterization of respiratory microbial dysbiosis in hospitalized COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus disease 2019 (COVID-19). However, the microbial composition of the respiratory tract and other infected tissues as well as their possible pathogenic contributions to varying degrees of disease severity in COVID-19 patients remain unclear. Between 27 January and 26 February 2020, serial clinical specimens (sputum, nasal and throat swab, anal swab and feces) were collected from a cohort of hospitalized COVID-19 patients, including 8 mildly and 15 severely ill patients in Guangdong province, China. Total RNA was extracted and ultra-deep metatranscriptomic sequencing was performed in combination with laboratory diagnostic assays. We identified distinct signatures of microbial dysbiosis among severely ill COVID-19 patients on broad spectrum antimicrobial therapy. Co-detection of other human respiratory viruses (including human alphaherpesvirus 1, rhinovirus B, and human orthopneumovirus) was demonstrated in 30.8% (4/13) of the severely ill patients, but not in any of the mildly affected patients. Notably, the predominant respiratory microbial taxa of severely ill patients were Burkholderia cepacia complex (BCC), Staphylococcus epidermidis, or Mycoplasma spp. (including M. hominis and M. orale). The presence of the former two bacterial taxa was also confirmed by clinical cultures of respiratory specimens (expectorated sputum or nasal secretions) in 23.1% (3/13) of the severe cases. Finally, a time-dependent, secondary infection of B. cenocepacia with expressions of multiple virulence genes was demonstrated in one severely ill patient, which might accelerate his disease deterioration and death occurring one month after ICU admission. Our findings point to SARS-CoV-2-related microbial dysbiosis and various antibiotic-resistant respiratory microbes/pathogens in hospitalized COVID-19 patients in relation to disease severity. Detection and tracking strategies are needed to prevent the spread of antimicrobial resistance, improve the treatment regimen and clinical outcomes of hospitalized, severely ill COVID-19 patients.

Spontaneous growth of free-standing polypyrrole films at an air/ionic liquid interface.

A novel strategy for the one-pot fabrication of free-standing polypyrrole films is presented in this work. The films are spontaneously formed at an air/ionic liquid interface through interface oxypolymerization. The thicknesses of the films are finely controlled from tens to hundreds of nanometers, and the films are uniform and compact. Asymmetrical films with different smoothness on the two sides of the film are also obtained and exhibit different water wettability. This method is extremely simple and does not need any equipment. It may bring about a general methodology for forming free-standing conducting polymer films.

Synthesis of BiOBr/Ag3PO4 heterojunctions on carbon-fiber cloth as filter-membrane-shaped photocatalyst for treating the flowing antibiotic wastewater.

Numerous nanosized photocatalysts have been demonstrated to treat antibiotic solutions efficiently in beakers, but plenty of antibiotics have been discharged to the flowing rivers. For photocatalytically degrading the flowing antibiotic wastewater, the prerequisite is to develop flexible large-scale filter-membrane with high photocatalytic activity. To solve this issue, with carbon fiber (CF) cloth as a flexible porous substrate, herein we have reported the in-situ growth of BiOBr/Ag3PO4 heterostructures. BiOBr nanosheets (thickness: ~10 nm, diameter: 0.5-1 µm) and Ag3PO4 particles (size: 50-200 nm) are synthesized on CF cloth successively via a solvothermal-chemical deposition two-step strategy. CF/BiOBr/Ag3PO4 cloth displays excellent visible photoabsorption (edge: ~520 nm). Under visible-light illumination, CF/BiOBr/Ag3PO4 cloth (4 × 4 cm2) could degrade ~90.0% tetracycline hydrochloride (TCH) as a model of antibiotics in 30 min in a beaker. Especially, CF/BiOBr/Ag3PO4 cloth can be used as the filter-membrane to construct multiple photocatalytic-setup for degrading the flowing antibiotic wastewater. The removal efficiency of TCH goes up from 12.8% at the first grade to 89.6% at the sixth grade. Furthermore, the photocatalytic mechanism of CF/BiOBr/Ag3PO4 cloth and the possible decomposition pathway of TCH have been proposed based on simulation and experiment results. Therefore, the present work provides some insight for developing flexible filter-membrane-shaped photocatalysts for degrading the flowing wastewater.

Is addition of reductive metals (Mo, W) a panacea for accelerating transition metals-mediated peroxymonosulfate activation?

The interaction of reductive metal ions and peroxymonosulfate (PMS) is necessary for the generation of sulfate radials (SO4-), however, this process is greatly restrained by the sluggish reduction of high-valent metal ions. Here we report that commercially available reductive metal (Mo or W) powders are capable of unlocking this kinetic constraint. The reduction of Fe(III) to Fe(II), decomposition of PMS, and degradation/mineralization of 4-chlorophenol (4-CP) are all accelerated in the Mo/Fe2+/PMS process at a very low Fe2+/PMS ratio (Fe2+/PMS = 1/10). In such an accelerated system, common adverse effects of natural water constituents such as chloride and humic acid are largely mitigated. According to the fluorescence measurement and scavenging tests, sulfate and hydroxyl radicals dominate in Mo/Fe2+/PMS process. The addition of Mo or W is further confirmed to favor Cu2+/PMS process, but this is not the case for other metal ions (Mn2+, Ni2+, Ce3+ and Co2+). Reductive zero-valence and four-valence active sites (Mo0 and Mo4+; W0 and W4+) play key roles in overall redox reaction. Overall, our present work provides an alternative route for expediting redox cycling of transition metals in advanced oxidation processes, without useless consumption of PMS and increase of total organic carbon.

Construction of TiO2/Ag3PO4 nanojunctions on carbon fiber cloth for photocatalytically removing various organic pollutants in static or flowing wastewater.

Plenty of power-shaped semiconductor nanomaterials have been used to photocatalytically degrade various pollutant wastewater in beakers, but they are difficult to be applied in the practical wastewater that is flowing in river or pipeline. Thus, the key to photocatalytically degrading the flowing wastewater is to develop flexible large-scale filter-membrane with high photocatalytic activity. To address the issue, with carbon fiber cloth (CFC) as the porous substrate and TiO2/Ag3PO4 as ultraviolet/visible (UV/Vis) responsed components, we reported the in-situ growth of TiO2/Ag3PO4 nanojunctions on CFC as filter-membrane-shaped photocatalyst. The resulting CFC/TiO2/Ag3PO4 is composed of CFC whose surface is decorated with TiO2 nanorods (length: 1 ± 0.5 µm, diameter: 150 ± 50 nm) and Ag3PO4 nanoparticles (diameter: 20-100 nm). CFC/TiO2/Ag3PO4 displays a broad absorption region with two edges (~410 and ~510 nm), owing to the bandgaps of TiO2 and Ag3PO4. Under Vis or UV-Vis light illumination, CFC/TiO2/Ag3PO4 (4 × 4 cm2) can efficiently degrade more phenol (80.6%/89.4%), tetracycline (TC, 91.7%/94.2%), rhodamine B (RhB, 98.4%/99.5%) and acid orange 7 (AO7, 97.6%/98.3%) in the beaker than CFC/TiO2 or CFC/Ag3PO4. Especially, CFC/TiO2/Ag3PO4 (diameter: ~10 cm) as the filter-membrane was used to construct multiple device for degrading the flowing RhB wastewater. The removal efficiency of RhB increases from 19.6% at the 1st pool to 96.8% at the 8th pool. Therefore, this study brings some insights for purifying organic pollutants in static or flowing wastewater by using filter-membrane-shaped photocatalysts.

Construction of titanium dioxide/cadmium sulfide heterojunction on carbon fibers as weavable photocatalyst for eliminating various contaminants.

Semiconductor heterojunction powders have exhibited the enhanced photocatalytic activities, but their practical applications have been limited due to their poor recycling performance from flowing wastewater. To solve these problems, with carbon fibers (CFs) as the fixing substrate, we constructed TiO2/CdS heterojunction as a model on CF surface by utilizing a hydrothermal-chemical bath deposition method. CFs/TiO2/CdS bundles display a wide photoabsorption with two photoabsorption edges (~410 and 520 nm). Furthermore, CFs/TiO2/CdS bundles can be weaved into macroscopical cloth (such as weight: 0.1 g, area: 4 × 4 cm2) which have considerable photocurrent density of 5.75 × 10-6 A/cm2. Under visible light irradiation (λ > 400 nm), macroscopic CFs/TiO2/CdS cloth can degrade 95.44% methylene blue (MB), 64.95% acid orange 7 (AO7), 91.37% tetracycline hydrochloride (TC) and remove 90.70% hexavalent chromium (Cr(VI)) after 120 min, higher than those by CFs/CdS (43.42% MB, 37.42% AO7, 31.76% TC and 30.45% Cr(VI)) or CFs/TiO2 (12.84% MB, 10.48% AO7, 11.85% TC and 15.58% Cr(VI)). Thus, CFs/TiO2/CdS can act as a weavable and efficient photocatalyst for eliminating various pollutants from wastewater.

Effect of Caloric Restriction on BMI, Gut Microbiota, and Blood Amino Acid Levels in Non-Obese Adults.

Adequate calorie restriction (CR) as a healthy lifestyle is recommended not only for people with metabolic disorders but also for healthy adults. Previous studies have mainly focused on the beneficial metabolic effects of CR on obese subjects, while its effects on non-obese subjects are still scarce. Here, we conducted a three-week non-controlled CR intervention in 41 subjects, with approximately 40% fewer calories than the recommended daily energy intake. We measured BMI, and applied targeted metabolic profiling on fasting blood samples and shotgun metagenomic sequencing on fecal samples, before and after intervention. Subjects were stratified into two enterotypes according to their baseline microbial composition, including 28 enterotype Bacteroides (ETB) subjects and 13 enterotype Prevotella (ETP) subjects. CR decreased BMI in most subjects, and ETP subjects exhibited a significantly higher BMI loss ratio than the ETB subjects. Additionally, CR induced limited changes in gut microbial composition but substantial microbial-independent changes in blood AAs, including a significant increase in 3-methylhistidine, a biomarker of the skeletal muscle protein turnover. Finally, baseline abundances of seven microbial species, rather than baseline AA levels, could well predict CR-induced BMI loss. This non-controlled intervention study revealed associations between baseline gut microbiota and CR-induced BMI loss and provided evidence to accelerate the application of microbiome stratification in future personalized nutrition intervention.

Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study).

Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], -1.04[-1.19, -0.89]%) and BBR-alone group (-0.99[-1.16, -0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (-0.59[-0.75, -0.44]%, -0.53[-0.68, -0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).

SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aß Accumulation and Memory Deficits in an AD Mouse.

Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer's disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered and its contribution to AD onset is currently unknown. Here, we observe decreased expression of SNX8 in human AD and AD mouse brain. SNX8 predominantly localized to early and late endosomes, where SNX8 overexpression enhanced total APP levels, cell surface APP distribution and consequent soluble APPα cleavage. SNX8 depletion resulted in elevated ß-amyloid (Aß) levels, while SNX8 overexpression reduced Aß levels in cells and in an APP/PS1 AD mouse model. Importantly, SNX8 overexpression rescued cognitive impairment in APP/PS1 mice. Together, these results implicate a neuroprotective role for SNX8 in enhancing non-amyloidogenic APP trafficking and processing pathways. Given that endosomal dysfunction is an early event in AD, restoration of dysfunctional endosomal components such as SNX8 may be beneficial in future therapeutic strategies.

Impact of early events and lifestyle on the gut microbiota and metabolic phenotypes in young school-age children.

BACKGROUND: The gut microbiota evolves from birth and is in early life influenced by events such as birth mode, type of infant feeding, and maternal and infant antibiotics use. However, we still have a gap in our understanding of gut microbiota development in older children, and to what extent early events and pre-school lifestyle modulate the composition of the gut microbiota, and how this impinges on whole body metabolic regulation in school-age children. RESULTS: Taking advantage of the KOALA Birth Cohort Study, a long-term prospective birth cohort in the Netherlands with extensive collection of high-quality host metadata, we applied shotgun metagenomics sequencing and systematically investigated the gut microbiota of children at 6-9 years of age. We demonstrated an overall adult-like gut microbiota in the 281 Dutch school-age children and identified 3 enterotypes dominated by the genera Bacteroides, Prevotella, and Bifidobacterium, respectively. Importantly, we found that breastfeeding duration in early life and pre-school dietary lifestyle correlated with the composition and functional competences of the gut microbiota in the children at school age. The correlations between pre-school dietary lifestyle and metabolic phenotypes exhibited a striking enterotype dependency. Thus, an inverse correlation between high dietary fiber consumption and low plasma insulin levels was only observed in individuals with the Bacteroides and Prevotella enterotypes, but not in Bifidobacterium enterotype individuals in whom the gut microbiota displayed overall lower microbial gene richness, alpha-diversity, functional potential for complex carbohydrate fermentation, and butyrate and succinate production. High total fat consumption and elevated plasma free fatty acid levels in the Bifidobacterium enterotype are associated with the co-occurrence of Streptococcus. CONCLUSIONS: Our work highlights the persistent effects of breastfeeding duration and pre-school dietary lifestyle in affecting the gut microbiota in school-age children and reveals distinct compositional and functional potential in children according to enterotypes. The findings underscore enterotype-specific links between the host metabolic phenotypes and dietary patterns, emphasizing the importance of microbiome-based stratification when investigating metabolic responses to diets. Future diet intervention studies are clearly warranted to examine gut microbe-diet-host relationships to promote knowledge-based recommendations in relation to improving metabolic health in children.