Metabolic changes enhance necroptosis of type 2 diabetes mellitus mice infected with Mycobacterium tuberculosis.

Previously, we found that Mycobacterium tuberculosis (Mtb) infection in type 2 diabetes mellitus (T2DM) mice enhances inflammatory cytokine production which drives pathological immune responses and mortality. In the current study, using a T2DM Mtb infection mice model, we determined the mechanisms that make T2DM mice alveolar macrophages (AMs) more inflammatory upon Mtb infection. Among various cell death pathways, necroptosis is a major pathway involved in inflammatory cytokine production by T2DM mice AMs. Anti-TNFR1 antibody treatment of Mtb-infected AMs from T2DM mice significantly reduced expression of receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) (necroptosis markers) and IL-6 production. Metabolic profile comparison of Mtb-infected AMs from T2DM mice and Mtb-infected AMs of nondiabetic control mice indicated that 2-ketohexanoic acid and deoxyadenosine monophosphate were significantly abundant, and acetylcholine and pyridoxine (Vitamin B6) were significantly less abundant in T2DM mice AMs infected with Mtb. 2-Ketohexanoic acid enhanced expression of TNFR1, RIPK3, MLKL and inflammatory cytokine production in the lungs of Mtb-infected nondiabetic mice. In contrast, pyridoxine inhibited RIPK3, MLKL and enhanced expression of Caspase 3 (apoptosis marker) in the lungs of Mtb-infected T2DM mice. Our findings demonstrate that metabolic changes in Mtb-infected T2DM mice enhance TNFR1-mediated necroptosis of AMs, which leads to excess inflammation and lung pathology.

The synchronized feature of Saururus chinensis and gut microbiota against T2DM, NAFLD, obesity and hypertension via integrated pharmacology.

Type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), obesity (OB) and hypertension (HT) are categorized as metabolic disorders (MDs), which develop independently without distinct borders. Herein, we examined the gut microbiota (GM) and Saururus chinensis (SC) to confirm their therapeutic effects via integrated pharmacology. The overlapping targets from the four diseases were determined to be key protein coding genes. The protein-protein interaction (PPI) networks, and the SC, GM, signalling pathway, target and metabolite (SGSTM) networks were analysed via RPackage. Additionally, molecular docking tests (MDTs) and density functional theory (DFT) analysis were conducted to determine the affinity and stability of the conformer(s). TNF was the main target in the PPI analysis, and equol derived from Lactobacillus paracasei JS1 was the most effective agent for the formation of the TNF complex. The SC agonism (PPAR signalling pathway), and antagonism (neurotrophin signalling pathway) by SC were identified as agonistic bioactives (aromadendrane, stigmasta-5,22-dien-3-ol, 3,6,6-trimethyl-3,4,5,7,8,9-hexahydro-1H-2-benzoxepine, 4α-5α-epoxycholestane and kinic acid), and antagonistic bioactives (STK734327 and piclamilast), respectively, via MDT. Finally, STK734327-MAPK1 was the most favourable conformer according to DFT. Overall, the seven bioactives from SC and equol that can be produced by Lactobacillus paracasei JS1 can exert synergistic effects on these four diseases.

Production of deoxycholic acid by low-abundant microbial species is associated with impaired glucose metabolism.

Alterations in gut microbiota composition are suggested to contribute to cardiometabolic diseases, in part by producing bioactive molecules. Some of the metabolites are produced by very low abundant bacterial taxa, which largely have been neglected due to limits of detection. However, the concentration of microbially produced metabolites from these taxa can still reach high levels and have substantial impact on host physiology. To explore this concept, we focused on the generation of secondary bile acids by 7α-dehydroxylating bacteria and demonstrated that addition of a very low abundant bacteria to a community can change the metabolic output dramatically. We show that Clostridium scindens converts cholic acid into the secondary bile acid deoxycholic acid (DCA) very efficiently even though the abundance of C. scindens is low, but still detectable by digital droplet PCR. We also show that colonization of germ-free female mice with a community containing C. scindens induces DCA production and affects host metabolism. Finally, we show that DCA correlates with impaired glucose metabolism and a worsened lipid profile in individuals with type 2 diabetes, which implies that this metabolic pathway may contribute to the development of cardiometabolic disease.

The effects of gut microbiome manipulation on glycemic indices in patients with non-alcoholic fatty liver disease: a comprehensive umbrella review.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a significant risk factor for non-alcoholic fatty liver disease (NAFLD). Increased fasting blood sugar (FBS), fasting insulin (FI), and insulin resistance (HOMA-IR) are observed in patients with NAFLD. Gut microbial modulation using prebiotics, probiotics, and synbiotics has shown promise in NAFLD treatment. This meta-umbrella study aimed to investigate the effects of gut microbial modulation on glycemic indices in patients with NAFLD and discuss potential mechanisms of action. METHODS: A systematic search was conducted in PubMed, Web of Science, Scopus, and Cochrane Library until March 2023 for meta-analyses evaluating the effects of probiotics, prebiotics, and synbiotics on patients with NAFLD. Random-effect models, sensitivity analysis, and subgroup analysis were employed. RESULTS: Gut microbial therapy significantly decreased HOMA-IR (ES: -0.41; 95%CI: -0.52, -0.31; P < 0.001) and FI (ES: -0.59; 95%CI: -0.77, -0.41; P < 0.001). However, no significant effect was observed on FBS (ES: -0.17; 95%CI: -0.36, 0.02; P = 0.082). Subgroup analysis revealed prebiotics had the most potent effect on HOMA-IR, followed by probiotics and synbiotics. For FI, synbiotics had the most substantial effect, followed by prebiotics and probiotics. CONCLUSION: Probiotics, prebiotics, and synbiotics administration significantly reduced FI and HOMA-IR, but no significant effect was observed on FBS.

Effects of metformin, saxagliptin and repaglinide on gut microbiota in high-fat diet/streptozocin-induced type 2 diabetic mice.

INTRODUCTION: There has been increasing evidence that the gut microbiota is closely related to type 2 diabetes (T2D). Metformin (Met) is often used in combination with saxagliptin (Sax) and repaglinide (Rep) for the treatment of T2D. However, little is known about the effects of these combination agents on gut microbiota in T2D. RESEARCH DESIGN AND METHODS: A T2D mouse model induced by a high-fat diet (HFD) and streptozotocin (STZ) was employed. The T2D mice were randomly divided into six groups, including sham, Met, Sax, Rep, Met+Sax and Met+Rep, for 4 weeks. Fasting blood glucose level, serum biochemical index, H&E staining of liver, Oil red O staining of liver and microbiota analysis by 16s sequencing were used to access the microbiota in the fecal samples. RESULTS: These antidiabetics effectively prevented the development of HFD/STZ-induced high blood glucose, and the combination treatment had a better effect in inhibiting lipid accumulation. All these dosing regimens restored the decreasing ratio of the phylum Bacteroidetes: Firmicutes, and increasing abundance of phylum Desulfobacterota, expect for Met. At the genus level, the antidiabetics restored the decreasing abundance of Muribaculaceae in T2D mice, but when Met was combined with Rep or Sax, the abundance of Muribaculaceae was decreased. The combined treatment could restore the reduced abundance of Prevotellaceae_UCG-001, while Met monotherapy had no such effect. In addition, the reduced Lachnospiraceae_NK4A136_group was well restored in the combination treatment groups, and the effect was much greater than that in the corresponding monotherapy group. Therefore, these dosing regimens exerted different effects on the composition of gut microbiota, which might be associated with the effect on T2D. CONCLUSIONS: Supplementation with specific probiotics may further improve the hypoglycemic effects of antidiabetics and be helpful for the development of new therapeutic drugs for T2D.

Bacteriological analysis and antibiotic resistance in patients with diabetic foot ulcers in Dhaka.

The primary objective of this study was to isolate bacteria from diabetic foot ulcers and subsequently assess their antibiotic resistance capabilities. Seventy-five patients diagnosed with diabetic foot ulcers were investigated. A number of these patients (97.33%) had type 2 diabetes, with a significant proportion of them having been diagnosed for 1-5 years (29.33%). Notably, a substantial number of these individuals were on insulin usage (78.66%). Among the patients under examination, 49.33% reported having no use of tobacco products, alcohol, or betel leaf. The ulcers analyzed in this study were classified into grades 1-5 according to the Wagner scale. Wagner grade 2 diabetic foot ulcers had the highest number of culture-positive patients, at 33.33%. Pus samples collected from patients were cultured on selective media, and bacterial identity was confirmed by biochemical tests and polymerase chain reaction. A total of 141 isolates were isolated. Among the isolates, 82.97% gram-negative bacteria and 17.02% gram-positive bacteria were detected. Klebsiella pneumoniae was the most common isolate. Proteus spp., Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus were also detected. Approximately 61.33% of the ulcers exhibited were polybacterial. In this study, it was observed that all bacterial isolates, except for Proteus spp., were primarily detected in patients classified under Wagner's grade 2. Moreover, antibiotic susceptibility was also tested on these 141 isolates. Among them, Escherichia coli showed the highest multidrug resistance, 81.81%. Most of the gram-negative bacteria were resistant to ampicillin. All of the gram-negative isolates exhibited high levels of susceptibility to piperacillin-tazobactam, and these levels were Klebsiella pneumoniae (97.56%), Pseudomonas aeruginosa (95.24%), Escherichia coli (81.82%), and Proteus spp. (80%). On the other hand, gram-positive Staphylococcus aureus mostly showed sensitivity towards vancomycin and norfloxacin (79.17%).

Causal relationships of Helicobacter pylori and related gastrointestinal diseases on Type 2 diabetes: Univariable and Multivariable Mendelian randomization.

BACKGROUND: Previous observational studies have demonstrated a connection between the risk of Type 2 diabetes mellitus (T2DM) and gastrointestinal problems brought on by Helicobacter pylori (H. pylori) infection. However, little is understood about how these factors impact on T2DM. METHOD: This study used data from the GWAS database on H. pylori antibodies, gastroduodenal ulcers, chronic gastritis, gastric cancer, T2DM and information on potential mediators: obesity, glycosylated hemoglobin (HbA1c) and blood glucose levels. Using univariate Mendelian randomization (MR) and multivariate MR (MVMR) analyses to evaluate the relationship between H. pylori and associated gastrointestinal diseases with the risk of developing of T2DM and explore the presence of mediators to ascertain the probable mechanisms. RESULTS: Genetic evidence suggests that H. pylori IgG antibody (P = 0.006, b = 0.0945, OR = 1.0995, 95% CI = 1.023-1.176), H. pylori GroEL antibody (P = 0.028, OR = 1.033, 95% CI = 1.004-1.064), gastroduodenal ulcers (P = 0.019, OR = 1.036, 95% CI = 1.006-1.068) and chronic gastritis (P = 0.005, OR = 1.042, 95% CI = 1.012-1.074) are all linked to an increased risk of T2DM, additionally, H. pylori IgG antibody is associated with obesity (P = 0.034, OR = 1.03, 95% CI = 1.002-1.055). The results of MVMR showed that the pathogenic relationship between H. pylori GroEL antibody and gastroduodenal ulcer in T2DM is mediated by blood glucose level and obesity, respectively. CONCLUSION: Our study found that H. pylori IgG antibody, H. pylori GroEL antibody, gastroduodenal ulcer and chronic gastritis are all related to t T2DM, and blood glucose level and obesity mediate the development of H. pylori GroEL antibody and gastroduodenal ulcer on T2DM, respectively. These findings may inform new prevention and intervention strategies for T2DM.

Hypoglycemic Effects of Gynura divaricata (L.) DC Polysaccharide and Action Mechanisms via Modulation of Gut Microbiota in Diabetic Mice.

Aiming to provide a basis for the application of Gynura divaricata (L.) DC polysaccharide (GDP) in functional foods, the hypoglycemic effects of GDP, and action mechanisms, were investigated. Results showed that GDP effectively inhibited α-glucosidase and remarkably increased the glucose absorption, glycogen content, and pyruvate kinase and hexokinase activities of insulin-resistant HepG2 cells, indicating its potent in vitro hypoglycemic effect. In streptozotocin-induced type 2 diabetes mice, GDP significantly improved various glycolipid metabolism-related indices in serum and liver, e.g., fasting blood glucose, oral glucose tolerance, glycosylated serum protein content, serum insulin level, antioxidant enzyme activities, TG, TC, LDL-C, and HDL-C levels, and hepatic glycogen content, and recovered the structure of gut microbiota to the normal level. It was also found that GDP significantly affected the expression of related genes in the PI3K/Akt, AMPK, and GS/GSK-3ß signaling pathways. Therefore, GDP regulates blood glucose possibly by directly inhibiting α-glucosidase, exerting antioxidant activity, and regulating intestinal microbiota.

Effect of metformin and metformin/linagliptin on gut microbiota in patients with prediabetes.

Lifestyle modifications, metformin, and linagliptin reduce the incidence of type 2 diabetes (T2D) in people with prediabetes. The gut microbiota (GM) may enhance such interventions' efficacy. We determined the effect of linagliptin/metformin (LM) vs metformin (M) on GM composition and its relationship to insulin sensitivity (IS) and pancreatic ß-cell function (Pßf) in patients with prediabetes. A cross-sectional study was conducted at different times: basal, six, and twelve months in 167 Mexican adults with prediabetes. These treatments increased the abundance of GM SCFA-producing bacteria M (Fusicatenibacter and Blautia) and LM (Roseburia, Bifidobacterium, and [Eubacterium] hallii group). We performed a mediation analysis with structural equation models (SEM). In conclusion, M and LM therapies improve insulin sensitivity and Pßf in prediabetics. GM is partially associated with these improvements since the SEM models suggest a weak association between specific bacterial genera and improvements in IS and Pßf.

Gut Microbiota in Patients with Prediabetes.

Prediabetes is characterized by abnormal glycemic levels below the type 2 diabetes threshold, and effective control of blood glucose may prevent the progression to type 2 diabetes. While the association between the gut microbiota, glucose metabolism, and insulin resistance in diabetic patients has been established in previous studies, there is a lack of research regarding these aspects in prediabetic patients in Asia. We aim to investigate the composition of the gut microbiota in prediabetic patients and their differences compared to healthy individuals. In total, 57 prediabetic patients and 60 healthy adult individuals aged 18 to 65 years old were included in this study. Biochemistry data, fecal samples, and 3 days of food records were collected. Deoxyribonucleic acid extraction and next-generation sequencing via 16S ribosomal ribonucleic acid metagenomic sequencing were conducted to analyze the relationship between the gut microbiota and dietary habits. Prediabetic patients showed a lower microbial diversity than healthy individuals, with 9 bacterial genera being less abundant and 14 others more abundant. Prediabetic patients who consumed a low-carbohydrate (LC) diet exhibited higher diversity in the gut microbiota than those who consumed a high-carbohydrate diet. A higher abundance of Coprococcus was observed in the prediabetic patients on an LC diet. Compared to healthy individuals, the gut microbiota of prediabetic patients was significantly different, and adopting an LC diet with high dietary fiber consumption may positively impact the gut microbiota. Future studies should aim to understand the relationship between the gut microbiota and glycemic control in the Asian population.

Diabetic Rats Induced Using a High-Fat Diet and Low-Dose Streptozotocin Treatment Exhibit Gut Microbiota Dysbiosis and Osteoporotic Bone Pathologies.

Type 2 diabetes mellitus (T2DM) presents a challenge for individuals today, affecting their health and life quality. Besides its known complications, T2DM has been found to contribute to bone/mineral abnormalities, thereby increasing the vulnerability to bone fragility/fractures. However, there is still a need for appropriate diagnostic approaches and targeted medications to address T2DM-associated bone diseases. This study aims to investigate the relationship between changes in gut microbiota, T2DM, and osteoporosis. To explore this, a T2DM rat model was induced by combining a high-fat diet and low-dose streptozotocin treatment. Our findings reveal that T2DM rats have lower bone mass and reduced levels of bone turnover markers compared to control rats. We also observe significant alterations in gut microbiota in T2DM rats, characterized by a higher relative abundance of Firmicutes (F) and Proteobacteria (P), but a lower relative abundance of Bacteroidetes (B) at the phylum level. Further analysis indicates a correlation between the F/B ratio and bone turnover levels, as well as between the B/P ratio and HbA1c levels. Additionally, at the genus level, we observe an inverse correlation in the relative abundance of Lachnospiraceae. These findings show promise for the development of new strategies to diagnose and treat T2DM-associated bone diseases.

Gut Microbiota-Tryptophan Metabolism-GLP-1 Axis Participates in ß-Cell Regeneration Induced by Dapagliflozin.

Sodium-glucose cotransporter 2 inhibitors, efficacious antidiabetic agents that have cardiovascular and renal benefits, can promote pancreatic ß-cell regeneration in type 2 diabetic mice. However, the underlying mechanism remains unclear. In this study, we aimed to use multiomics to identify the mediators involved in ß-cell regeneration induced by dapagliflozin. We showed that dapagliflozin lowered blood glucose level, upregulated plasma insulin level, and increased islet area in db/db mice. Dapagliflozin reshaped gut microbiota and modulated microbiotic and plasmatic metabolites related to tryptophan metabolism, especially l-tryptophan, in the diabetic mice. Notably, l-tryptophan upregulated the mRNA level of glucagon-like peptide 1 (GLP-1) production-related gene (Gcg and Pcsk1) expression and promoted GLP-1 secretion in cultured mouse intestinal L cells, and it increased the supernatant insulin level in primary human islets, which was eliminated by GPR142 antagonist. Transplant of fecal microbiota from dapagliflozin-treated mice, supplementation of l-tryptophan, or treatment with dapagliflozin upregulated l-tryptophan, GLP-1, and insulin or C-peptide levels and promoted ß-cell regeneration in db/db mice. Addition of exendin 9-39, a GLP-1 receptor (GLP-1R) antagonist, or pancreatic Glp1r knockout diminished these beneficial effects. In summary, treatment with dapagliflozin in type 2 diabetic mice promotes ß-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism.

Gut Microbiota and Blood Metabolites Related to Fiber Intake and Type 2 Diabetes.

BACKGROUND: Consistent evidence suggests diabetes-protective effects of dietary fiber intake. However, the underlying mechanisms, particularly the role of gut microbiota and host circulating metabolites, are not fully understood. We aimed to investigate gut microbiota and circulating metabolites associated with dietary fiber intake and their relationships with type 2 diabetes (T2D). METHODS: This study included up to 11 394 participants from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos). Diet was assessed with two 24-hour dietary recalls at baseline. We examined associations of dietary fiber intake with gut microbiome measured by shotgun metagenomics (350 species/85 genera and 1958 enzymes; n=2992 at visit 2), serum metabolome measured by untargeted metabolomics (624 metabolites; n=6198 at baseline), and associations between fiber-related gut bacteria and metabolites (n=804 at visit 2). We examined prospective associations of serum microbial-associated metabolites (n=3579 at baseline) with incident T2D over 6 years. RESULTS: We identified multiple bacterial genera, species, and related enzymes associated with fiber intake. Several bacteria (eg, Butyrivibrio, Faecalibacterium) and enzymes involved in fiber degradation (eg, xylanase EC3.2.1.156) were positively associated with fiber intake, inversely associated with prevalent T2D, and favorably associated with T2D-related metabolic traits. We identified 159 metabolites associated with fiber intake, 47 of which were associated with incident T2D. We identified 18 of these 47 metabolites associated with the identified fiber-related bacteria, including several microbial metabolites (eg, indolepropionate and 3-phenylpropionate) inversely associated with the risk of T2D. Both Butyrivibrio and Faecalibacterium were associated with these favorable metabolites. The associations of fiber-related bacteria, especially Faecalibacterium and Butyrivibrio, with T2D were attenuated after further adjustment for these microbial metabolites. CONCLUSIONS: Among United States Hispanics/Latinos, dietary fiber intake was associated with favorable profiles of gut microbiota and circulating metabolites for T2D. These findings advance our understanding of the role of gut microbiota and microbial metabolites in the relationship between diet and T2D.

Metformin Alters mRNA Expression of FOXP3, RORC, and TBX21 and Modulates Gut Microbiota in COVID-19 Patients with Type 2 Diabetes.

COVID-19 remains a significant global concern, particularly for individuals with type 2 diabetes who face an elevated risk of hospitalization and mortality. Metformin, a primary treatment for type 2 diabetes, demonstrates promising pleiotropic properties that may substantially mitigate disease severity and expedite recovery. Our study of the gut microbiota and the mRNA expression of pro-inflammatory and anti-inflammatory T-lymphocyte subpopulations showed that metformin increases bacterial diversity while modulating gene expression related to T-lymphocytes. This study found that people who did not take metformin had a downregulated expression of FOXP3 by 6.62-fold, upregulated expression of RORC by 29.0-fold, and upregulated TBX21 by 1.78-fold, compared to the control group. On the other hand, metformin patients showed a 1.96-fold upregulation in FOXP3 expression compared to the control group, along with a 1.84-fold downregulation in RORC expression and an 11.4-fold downregulation in TBX21 expression. Additionally, we found a correlation with gut microbiota (F/B ratio and alpha-diversity index) and pro-inflammatory biomarkers. This novel observation of metformin's impact on T-cells and gut microbiota opens new horizons for further exploration through clinical trials to validate and confirm our data. The potential of metformin to modulate immune responses and enhance gut microbiota diversity suggests a promising avenue for therapeutic interventions in individuals with type 2 diabetes facing an increased risk of severe outcomes from COVID-19.

Microbial stars: shedding light on gut microbes' role in insulin resistance and innovative diabetes therapies.

The role of gut microbiota in insulin resistance (IR), Metabolic Syndrome (MetS), and Type 2 Diabetes Mellitus (T2DM) is rapidly gaining recognition. However, the mechanisms and implications of gut bacteria in these conditions remain enigmatic. This commentary not only highlights the findings of a recent multi-omics study by Takeuchi et al. but also offers a unique perspective by integrating personal opinions and insights. The discussion revolves around the intricate connection between gut microbes and IR, suggesting novel therapeutic potential in targeting gut microbial carbohydrate metabolism for improved IR management and metabolic health.

Incorporating metabolic activity, taxonomy and community structure to improve microbiome-based predictive models for host phenotype prediction.

We developed MicroKPNN, a prior-knowledge guided interpretable neural network for microbiome-based human host phenotype prediction. The prior knowledge used in MicroKPNN includes the metabolic activities of different bacterial species, phylogenetic relationships, and bacterial community structure, all in a shallow neural network. Application of MicroKPNN to seven gut microbiome datasets (involving five different human diseases including inflammatory bowel disease, type 2 diabetes, liver cirrhosis, colorectal cancer, and obesity) shows that incorporation of the prior knowledge helped improve the microbiome-based host phenotype prediction. MicroKPNN outperformed fully connected neural network-based approaches in all seven cases, with the most improvement of accuracy in the prediction of type 2 diabetes. MicroKPNN outperformed a recently developed deep-learning based approach DeepMicro, which selects the best combination of autoencoder and machine learning approach to make predictions, in all of the seven cases. Importantly, we showed that MicroKPNN provides a way for interpretation of the predictive models. Using importance scores estimated for the hidden nodes, MicroKPNN could provide explanations for prior research findings by highlighting the roles of specific microbiome components in phenotype predictions. In addition, it may suggest potential future research directions for studying the impacts of microbiome on host health and diseases. MicroKPNN is publicly available at https://github.com/mgtools/MicroKPNN.

Angelica polysaccharides relieve blood glucose levels in diabetic KKAy mice possibly by modulating gut microbiota: an integrated gut microbiota and metabolism analysis.

BACKGROUND: Angelica polysaccharides (AP) have numerous benefits in relieving type 2 diabetes (T2D). However, the underlying mechanisms have yet to be fully understood. Recent many reports have suggested that altering gut microbiota can have adverse effects on the host metabolism and contribute to the development of T2D. Here, we successfully established the T2D model using the male KKAy mice with high-fat and high-sugar feed. Meanwhile, the male C57BL/6 mice were fed with a normal feed. T2D KKAy mice were fed either with or without AP supplementation. In each group, we measured the mice's fasting blood glucose, weight, and fasting serum insulin levels. We collected the cecum content of mice, the gut microbiota was analyzed by targeted full-length 16S rRNA metagenomic sequencing and metabolites were analyzed by untargeted-metabolomics. RESULTS: We found AP effectively alleviated glycemic disorders of T2D KKAy mice, with the changes in gut microbiota composition and function. Many bacteria species and metabolites were markedly changed in T2D KKAy mice and reversed by AP. Additionally, 16 altered metabolic pathways affected by AP were figured out by combining metagenomic pathway enrichment analysis and metabolic pathway enrichment analysis. The key metabolites in 16 metabolic pathways were significantly associated with the gut microbial alteration. Together, our findings showed that AP supplementation could attenuate the diabetic phenotype. Significant gut microbiota and gut metabolite changes were observed in the T2D KKAy mice and AP intervention. CONCLUSIONS: Administration of AP has been shown to improve the composition of intestinal microbiota in T2D KKAy mice, thus providing further evidence for the potential therapeutic application of AP in the treatment of T2D.

Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target.

A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme activity-screening platform to investigate how gut microbiota-derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.

Microbiota dysbiosis caused by dietetic patterns as a promoter of Alzheimer's disease through metabolic syndrome mechanisms.

Microbiota dysbiosis and metabolic syndrome, consequences of a non-adequate diet, generate a feedback pathogenic state implicated in Alzheimer's disease development. The lower production of short chain fatty acids (SCFAs) under dysbiosis status leads to lipid homeostasis deregulation and decreases Angptl4 release and AMPK activation in the adipose tissue, promoting higher lipid storage (adipocyte hypertrophy) and cholesterol levels. Also, low SCFA generation reduces GPR41 and GPR43 receptor activation at the adipose tissue (increasing leptin release and leptin receptor resistance) and intestinal levels, reducing the release of GLP-1 and YPP. Therefore, lower satiety sensation and energy expenditure occur, promoting a weight gaining environment mediated by higher food intake and lipid storage, developing dyslipemia. In this context, higher glucose levels, together with higher free fatty acids in the bloodstream, promote glycolipotoxicity, provoking a reduction in insulin released, insulin receptor resistance, advanced glycation products (AGEs) and type 2 diabetes. Intestinal dysbiosis and low SCFAs reduce bacterial biodiversity, increasing lipopolysaccharide (LPS)-producing bacteria and intestinal barrier permeability. Higher amounts of LPS pass to the bloodstream (endotoxemia), causing a low-grade chronic inflammatory state characterized by higher levels of leptin, IL-1ß, IL-6 and TNF-α, together with a reduced release of adiponectin and IL-10. At the brain and neuronal levels, the generated insulin resistance, low-grade chronic inflammation, leptin resistance, AGE production and LPS increase directly impact the secretase enzymes and tau hyperphosphorylation, creating an enabling environment for ß-amyloid senile plaque and tau tangled formations and, as a consequence, Alzheimer's initiation, development and maintenance.

An Okinawan-Based Nordic Diet Leads to Profound Effects on Gut Microbiota and Plasma Metabolites Linked to Glucose and Lipid Metabolism.

Dietary interventions modify gut microbiota and clinical outcomes. Weight reduction and improved glucose and lipid homeostasis were observed after adopting an Okinawan-based Nordic diet (O-BN) in individuals with type 2 diabetes. The aim of the present study was to explore changes in metabolomics and gut microbiota during O-BN and correlate changes with clinical outcomes. A total of 30 patients (17 women), aged 57.5 ± 8.2 years, diabetes duration 10.4 ± 7.6 years, 90% over-weight, were included. Participants were provided an O-BN for 12 weeks. Before and after intervention, and 16 weeks afterwards, anthropometry and clinical data were estimated and questionnaires were collected, as well as samples of blood and stool. Plasma metabolomics were determined by gas- (GC-MS) or liquid- (LC-MS) chromatography-based mass spectrometry and fecal microbiota determination was based on 16S rRNA amplicons from regions V1-V2. During the intervention, weight (6.8%), waist circumference (6.1%), and levels of glucose, HbA1c, insulin, triglycerides, and cholesterol were decreased. Of 602 metabolites, 323 were changed for any or both periods; 199 (101 lipids) metabolites were decreased while 58 (43 lipids) metabolites were increased during the intervention. Changes in glucose homeostasis were linked to changes in, e.g., 1,5-anhydroglucitol, thyroxine, and chiro-inositol. Changes of microbe beta diversity correlated positively with food components and negatively with IL-18 (p = 0.045). Abundance differences at phylum and genus levels were found. Abundances of Actinobacteria, Bacteroidetes, Firmicutes, and Verrucomicrobia correlated with anthropometry, HbA1c, lipids, inflammation, and food. Changes in metabolites and microbiota were reversed after the intervention. The O-BN-induced changes in metabolomics and gut microbiota correspond to clinical outcomes of reduced weight and inflammation and improved glucose and lipid metabolism.