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.

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.

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.

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.

Alterations in the gut virome are associated with type 2 diabetes and diabetic nephropathy.

Although changes in gut microbiome have been associated with the development of T2D and its complications, the role of the gut virome remains largely unknown. Here, we characterized the gut virome alterations in T2D and its complications diabetic nephropathy (DN) by metagenomic sequencing of fecal viral-like particles. Compared with controls, T2D subjects, especially those with DN, had significantly lower viral richness and diversity. 81 viral species were identified to be significantly altered in T2D subjects, including a decrease in some phages (e.g. Flavobacterium phage and Cellulophaga phaga). DN subjects were depleted of 12 viral species, including Bacteroides phage, Anoxybacillus virus and Brevibacillus phage, and enriched in 2 phages (Shigella phage and Xylella phage). Multiple viral functions, particularly those of phage lysing host bacteria, were markedly reduced in T2D and DN. Strong viral-bacterial interactions in healthy controls were disrupted in both T2D and DN. Moreover, the combined use of gut viral and bacterial markers achieved a powerful diagnostic performance for T2D and DN, with AUC of 99.03% and 98.19%, respectively. Our results suggest that T2D and its complication DN are characterized by a significant decrease in gut viral diversity, changes in specific virus species, loss of multiple viral functions, and disruption of viral-bacterial correlations. The combined gut viral and bacterial markers have diagnostic potential for T2D and DN.

[Diabetes mellitus and the intestinal microbiome]. / A diabetes mellitus és a bélmikrobiom.

The intestinal microbiome plays an important role in the body's physiological processes. One of its most decisive roles is the production of short-chain fatty acids, which has crucial importance in the maintenance of an intact intestinal barrier and immune homeostasis. Dysbiosis in the microbiome caused by dietary habits, regular medication use, and other factors can result in damage to the barrier function, which triggers the translocation of lipopolysaccharides into the portal circulation. By maintaining subclinical inflammation, these can lead to the development of obesity, insulin resistance, and fatty liver. The entry of pathogenic bacteria into the portal circulation can cause beta cell destruction through molecular mimicry and consequent autoimmunity. Both mechanisms can lead to diabetes mellitus. The paper reviews the changes in the intestinal microbiome in type 1 and type 2 diabetes mellitus, detailing experimental and clinical data. It points out that even though our knowledge is not yet sufficient to help daily clinical practice, the expansion of data can help the prognostic use of some results. All this, however, requires further investigations and observations. Orv Hetil. 2023; 164(25): 981-987.

Effects of SGLT2 inhibitors on the intestinal bacterial flora in Japanese patients with type 2 diabetes mellitus.

Selective inhibitors of sodium glucose co-transporter-2 (SGLT2) suppress renal glucose reabsorption and promote urinary glucose excretion, thereby lowering blood glucose. SGLT2 inhibitors have been reported to reduce body weight. However, the mechanism underlying the reduction in the body weight induced by SGLT2 inhibitor treatment remains to be elucidated. In this study, we investigated the effects of SGLT2 inhibitors on the intestinal bacterial flora. A total of 36 Japanese patients with type 2 diabetes mellitus received a SGLT2 inhibitor (luseogliflozin or dapagliflozin) for 3 months, and the prevalences of balance-regulating bacteria and balance-disturbing bacteria in the feces of the patients before and after SGLT2 inhibitor treatment were determined. SGLT2 inhibitor treatment was associated with a significant increase of the overall prevalence of the 12 types of balance-regulating bacteria. In addition, significant increases in the prevalences of the short-chain fatty acid (SCFAs)-producing bacteria among the balance-regulating bacteria were also observed. Individual analyses of the balance-regulating bacteria revealed that the SGLT2 inhibitor treatment was associated with a significant increase in the prevalence of Ruminococci, which are balance-regulating bacteria classified as SCFAs-producing bacteria. However, SGLT2 inhibitor had no effect on the balance-disturbing bacteria. These results suggested that SGLT2 inhibitor treatment was associated with an overall increase in the prevalence of balance-regulating bacteria. Among the balance-regulating bacteria, the prevalences of SCFAs-producing bacteria increased. SCFAs have been reported to prevent obesity. The results of the present study suggest that SGLT2 inhibitors might induce body weight reduction via their actions on the intestinal bacterial flora.

Gut Microbiota Contribution to Weight-Independent Glycemic Improvements after Gastric Bypass Surgery.

Roux-en-Y gastric bypass surgery (RYGB) leads to improved glycemic control in individuals with severe obesity beyond the effects of weight loss alone. Here, We addressed the potential contribution of gut microbiota in mediating this favourable surgical outcome by using an established preclinical model of RYGB. 16S rRNA sequencing revealed that RYGB-treated Zucker fatty rats had altered fecal composition of various bacteria at the phylum and species levels, including lower fecal abundance of an unidentified Erysipelotrichaceae species, compared with both sham-operated (Sham) and body weight-matched to RYGB-treated (BWM) rats. Correlation analysis further revealed that fecal abundance of this unidentified Erysipelotrichaceae species linked with multiple indices of glycemic control uniquely in RYGB-treated rats. Sequence alignment of this Erysipelotrichaceae species identified Longibaculum muris to be the most closely related species, and its fecal abundance positively correlated with oral glucose intolerance in RYGB-treated rats. In fecal microbiota transplant experiments, the improved oral glucose tolerance of RYGB-treated compared with BWM rats could partially be transferred to recipient germfree mice, independently of body weight. Unexpectedly, providing L. muris as a supplement to RYGB recipient mice further improved oral glucose tolerance, while administering L. muris alone to chow-fed or Western style diet-challenged conventionally raised mice had minimal metabolic impact. Taken together, our findings provide evidence that the gut microbiota contributes to weight loss-independent improvements in glycemic control after RYGB and demonstrate how correlation of a specific gut microbiota species with a host metabolic trait does not imply causation. IMPORTANCE Metabolic surgery remains the most effective treatment modality for severe obesity and its comorbidities, including type 2 diabetes. Roux-en-Y gastric bypass (RYGB) is a commonly performed type of metabolic surgery that reconfigures gastrointestinal anatomy and profoundly remodels the gut microbiota. While it is clear that RYGB is superior to dieting when it comes to improving glycemic control, the extent to which the gut microbiota contributes to this effect remains untested. In the present study, we uniquely linked fecal Erysipelotrichaceae species, including Longibaculum muris, with indices of glycemic control after RYGB in genetically obese and glucose-intolerant rats. We further show that the weight loss-independent improvements in glycemic control in RYGB-treated rats can be transmitted via their gut microbiota to germfree mice. Our findings provide rare causal evidence that the gut microbiota contributes to the health benefits of metabolic surgery and have implications for the development of gut microbiota-based treatments for type 2 diabetes.

Gut microbiota in patients with COVID-19 and type 2 diabetes: A culture-based method.

Background: The global pandemic of coronavirus disease 2019 (COVID-19) continues to affect people around the world, with one of the most frequent comorbidities being Type 2 Diabetes (T2D). Studies have suggested a link between disbalances in gut microbiota and these diseases, as well as with COVID-19, potentially due to inflammatory dysfunction. This study aims to analyze the changes in gut microbiota in COVID-19 patients with T2D using a culture-based method. Methods: The stool samples were taken from 128 patients with confirmed COVID-19. Changes in the composition of gut microbiota were analyzed by culture-based method. The study used chi-squared and t-test to find significant differences in gut bacteria between samples and non-parametric correlation analysis to examine relationship between gut bacteria abundance, C-reactive protein (CRP) levels and length of stay (LoS) in COVID-19 patients without T2D. Results: The gut microbiota of T2D patients with COVID-19 showed increased Clostridium spp., Candida spp., and decreased Bifidobacterium spp., Lactobacillus spp. Metformin-treated patients with T2D and COVID-19 without antibiotic treatment showed increased Bacteroides spp., Lactobacillus spp., and decreased Enterococcus, Clostridium compared to the same group with antibiotic treatment. The study also found a positive correlation between the abundance of certain gut microbiota genera, such as Klebsiella spp. and Enterococcus spp., and CRP levels and LoS in COVID-19 patients without and with T2D, while the abundance of other genera, such as Bifidobacterium spp. and Lactobacillus spp., was found to have a negative correlation. Conclusion: In conclusion, this study provides important insights into the gut microbiota composition of SARS-CoV-2-infected individuals with T2D and its potential impact on the course of the disease. The findings suggest that certain gut microbiota genera may be associated with increased CRP levels and longer hospital stays. The significance of this study lies in the fact that it highlights the potential role of gut microbiota in the progression of COVID-19 in patients with T2D, and may inform future research and treatment strategies for this patient population. The future impact of this study could include the development of targeted interventions to modulate gut microbiota in order to improve outcomes for COVID-19 patients with T2D.

Association between equol producers and type 2 diabetes mellitus among Japanese older adults.

AIMS/INTRODUCTION: Equol, which is produced by enteric bacteria from soybean isoflavones, has a chemical structure similar to estrogen. Both in vivo and in vitro studies have shown the beneficial metabolic effects of equol. However, its effects on type 2 diabetes remain unclear. We investigated the association between the equol producers/non-producers and type 2 diabetes. MATERIALS AND METHODS: The participants included 147 patients with type diabetes mellitus aged 70-89 years, and 147 age- and sex-matched controls. To ascertain the equol producers or non-producers, we used the comparative logarithm between the urinary equol and daidzein concentrations (cut-off value -1.75). RESULTS: The urinary equol concentration was significantly lower in the diabetes group compared with the non-diabetes group (P = 0.01). A significant difference in the proportion of equol producers was observed among all participants (38.8% in the diabetes group and 53.1% in the non-diabetes group; P = 0.01). The proportion of equol producers among women was significantly lower in the diabetes group (31.4%) than in the non-diabetes group (52.8%; P < 0.01). Additionally, the frequency of dyslipidemia in female equol producers was significantly lower than that in female non-equol producers (P < 0.01). Among men, no such differences were observed. We found a significant positive correlation between the urinary equol and daidzein concentrations among equol producers (r = 0.55, P < 0.01). CONCLUSIONS: Our study findings showed that postmenopausal women had a low proportion of equol producers with diabetes and dyslipidemia.

Alterations in the Gut Microbiota in Pregnant Women with Pregestational Type 2 Diabetes Mellitus.

Human gut dysbiosis is associated with type 2 diabetes mellitus (T2DM); however, the gut microbiome in pregnant women with pregestational type 2 diabetes mellitus (PGDM) remains unexplored. We investigated the alterations in the gut microbiota composition in pregnant women with or without PGDM. The gut microbiota was examined using 16S rRNA sequencing data of 234 maternal fecal samples that were collected during the first (T1), second (T2), and third (T3) trimesters. The PGDM group presented a reduction in the number of gut bacteria taxonomies as the pregnancies progressed. Linear discriminant analyses revealed that Megamonas, Bacteroides, and Roseburia intestinalis were enriched in the PGDM group, whereas Bacteroides vulgatus, Faecalibacterium prausnitzii, Eubacterium rectale, Bacteroides uniformis, Eubacterium eligens, Subdoligranulum, Bacteroides fragilis, Dialister, Lachnospiraceae, Christensenellaceae R-7, Roseburia inulinivorans, Streptococcus oralis, Prevotella melaninogenica, Neisseria perflava, Bacteroides ovatus, Bacteroides caccae, Veillonella dispar, and Haemophilus parainfluenzae were overrepresented in the control group. Correlation analyses showed that the PGDM-enriched taxa were correlated with higher blood glucose levels during pregnancy, whereas the taxonomic biomarkers of normoglycemic pregnancies exhibited negative correlations with glycemic traits. The microbial networks in the PGDM group comprised weaker microbial interactions than those in the control group. Our study reveals the distinct characteristics of the gut microbiota composition based on gestational ages between normoglycemic and PGDM pregnancies. Further longitudinal research involving women with T2DM at preconception stages and investigations using shotgun metagenomic sequencing should be performed to elucidate the relationships between specific bacterial functions and PGDM metabolic statuses during pregnancy and to identify potential therapeutic targets. IMPORTANCE The incidence of pregestational type 2 diabetes mellitus (PGDM) is increasing, with high rates of serious adverse maternal and neonatal outcomes that are strongly correlated with hyperglycemia. Recent studies have shown that type 2 diabetes mellitus is associated with gut microbial dysbiosis; however, the gut microbiome composition and its associations with the metabolic features of patients with PGDM remain largely unknown. In this study, we investigated the changes in the gut microbiota composition in pregnant women with and without PGDM. We identified differential taxa that may be correlated with maternal metabolic statuses during pregnancy. Additionally, we observed that the number of taxonomic and microbial networks of gut bacteria were distinctly reduced in women with hyperglycemia as their pregnancies progressed. These results extend our understanding of the associations between the gut microbial composition, PGDM-related metabolic changes, and pregnancy outcomes.

Abnormal proliferation of gut mycobiota contributes to the aggravation of Type 2 diabetes.

Type 2 diabetes (T2D) constitutes a worldwide health threat, and the underlying mechanism for the development and progression of T2D is complex and multifactorial. During the last decade, gut commensal bacteria have been found to play a crucial role in the regulation of T2D and related metabolic disorders. However, as a considerable component in gut microbiome, the relationship between mycobiota and T2D and related metabolic disorders remains unclear. As a proof-of-concept, we observed that the ablation of the commensal fungi in mice can protect HFD (High fat diet) induced insulin resistance and related metabolic disorders. Both ITS2 (internal transcribed spacer 2) sequencing and culture-dependent analysis show the enrichment of Candida albicans in samples from individuals with T2D (Chinese Clinical Trial Registry, ChiCTR2100042049). Repopulation with C. albicans in HFD mice accelerated insulin resistance and related disorders. Mechanically, we found the ß-glucan from C. albicans mirrored the deteriorating effect of C. albicans through the dectin-1 dependent pathway. Our current findings support that gut mycobiota play an important role in the progress of T2D and indicated the preventing of gut mycobiota is a promising strategy to alleviate insulin resistance and related metabolic dysfunctions.

Metabolic modelling of the human gut microbiome in type 2 diabetes patients in response to metformin treatment.

The human gut microbiome has been associated with several metabolic disorders including type 2 diabetes mellitus. Understanding metabolic changes in the gut microbiome is important to elucidate the role of gut bacteria in regulating host metabolism. Here, we used available metagenomics data from a metformin study, together with genome-scale metabolic modelling of the key bacteria in individual and community-level to investigate the mechanistic role of the gut microbiome in response to metformin. Individual modelling predicted that species that are increased after metformin treatment have higher growth rates in comparison to species that are decreased after metformin treatment. Gut microbial enrichment analysis showed prior to metformin treatment pathways related to the hypoglycemic effect were enriched. Our observations highlight how the key bacterial species after metformin treatment have commensal and competing behavior, and how their cellular metabolism changes due to different nutritional environment. Integrating different diets showed there were specific microbial alterations between different diets. These results show the importance of the nutritional environment and how dietary guidelines may improve drug efficiency through the gut microbiota.

Microbiome Features Differentiating Unsupervised-Stratification-Based Clusters of Patients with Abnormal Glycometabolism.

The alteration of gut microbiota structure plays a pivotal role in the pathogenesis of abnormal glycometabolism. However, the microbiome features identified in patient groups stratified solely based on glucose levels remain controversial among different studies. In this study, we stratified 258 participants (discovery cohort) into three clusters according to an unsupervised method based on 16 clinical parameters involving the levels of blood glucose, insulin, and lipid. We found 67 cluster-specific microbiome features (i.e., amplicon sequence variants [ASVs]) based on 16S rRNA gene V3-V4 region sequencing. Specifically, ASVs belonging to Barnesville and Alistipes were enriched in cluster 1, in which participants had the lowest blood glucose levels, high insulin sensitivity, and a high-fecal short-chain fatty acid concentration. ASVs belonging to Prevotella copri and Ruminococcus gnavus were enriched in cluster 2, which was characterized by a moderate level of blood glucose, serious insulin resistance, and high levels of cholesterol and triglyceride. Cluster 3 was characterized by a high level of blood glucose and insulin deficiency, enriched with ASVs in P. copri and Bacteroides vulgatus. In addition, machine learning classifiers using the 67 cluster-specific ASVs were used to distinguish individuals in one cluster from those in the other two clusters both in discovery and testing cohorts (n = 83). Therefore, microbiome features identified based on the unsupervised stratification of patients with more inclusive clinical parameters may better reflect microbiota alterations associated with the progression of abnormal glycometabolism. IMPORTANCE The gut microbiota is altered in patients with type 2 diabetes (T2D) and prediabetes. The association of particular bacteria with T2D, however, varied among studies, which has made it challenging to develop precision medicine approaches for the prevention and alleviation of T2D. Blood glucose level is the only parameter in clustering patients when identifying the T2D-related bacteria in previous studies. This stratification ignores the fact that patients within the same blood glucose range differ in their insulin resistance and dyslipidemia, which also may be related to disordered gut microbiota. In addition to parameters of blood glucose levels, we also used additional parameters involving insulin and lipid levels to stratify participants into three clusters and further identified cluster-specific microbiome features. We further validated the association between these microbiome features and glycometabolism with an independent cohort. This study highlights the importance of stratification of patients with blood glucose, insulin, and lipid levels when identifying the microbiome features associated with the progression of abnormal glycometabolism.

Dietary regulations for microbiota dysbiosis among post-menopausal women with type 2 diabetes.

Type 2 diabetes (T2D) and T2D-associated comorbidities, such as obesity, are serious universally prevalent health issues among post-menopausal women. Menopause is an unavoidable condition characterized by the depletion of estrogen, a gonadotropic hormone responsible for secondary sexual characteristics in women. In addition to sexual dimorphism, estrogen also participates in glucose-lipid homeostasis, and estrogen depletion is associated with insulin resistance in the female body. Estrogen level in the gut also regulates the microbiota composition, and even conjugated estrogen is actively metabolized by the estrobolome to maintain insulin levels. Moreover, post-menopausal gut microbiota is different from the pre-menopausal gut microbiota, as it is less diverse and lacks the mucolytic Akkermansia and short-chain fatty acid (SCFA) producers such as Faecalibacterium and Roseburia. Through various metabolites (SCFAs, secondary bile acid, and serotonin), the gut microbiota plays a significant role in regulating glucose homeostasis, oxidative stress, and T2D-associated pro-inflammatory cytokines (IL-1, IL-6). While gut dysbiosis is common among post-menopausal women, dietary interventions such as probiotics, prebiotics, and synbiotics can ease post-menopausal gut dysbiosis. The objective of this review is to understand the relationship between post-menopausal gut dysbiosis and T2D-associated factors. Additionally, the study also provided dietary recommendations to avoid T2D progression among post-menopausal women.