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.

The Gut Microbiome Modifies the Association Between a Mediterranean Diet and Diabetes in USA Hispanic/ Latino Population.

CONTEXT: The interrelationships among the gut microbiome, the Mediterranean diet (MedDiet), and a clinical endpoint of diabetes is unknown. OBJECTIVE: To identify gut microbial features of a MedDiet and examine whether the association between MedDiet and diabetes varies across individuals with different gut microbial profiles. METHODS: This study included 543 diabetic, 805 prediabetic, and 394 normoglycemic participants from a cohort study of USA Hispanic/Latino men and women. Fecal samples were profiled using 16S rRNA gene sequencing. Adherence to MedDiet was evaluated by an index based on 2 24-hour dietary recalls. RESULTS: A greater MedDiet adherence was associated with higher abundances of major dietary fiber metabolizers (e.g., Faecalibacterium prausnitzii, false-discovery-rate-adjusted P [q] = 0.01), and lower abundances of biochemical specialists (e.g., Parabacteroides, q = 0.04). The gut microbiomes of participants with greater MedDiet adherence were enriched for functions involved in dietary fiber degradation but depleted for those related to sulfur reduction and lactose and galactose degradation. The associations between MedDiet adherence and diabetes prevalence were significantly stronger among participants with depleted abundance of Prevotella (pinteraction = 0.03 for diabetes, 0.02 for prediabetes/diabetes, and 0.02 for prediabetes). A 1-SD deviation increment in the MedDiet index was associated with 24% (odds ratio [OR] 0.76; 95% CI, 0.59-0.98) and 7% (OR 0.93; 95% CI, 0.72-1.20) lower odds of diabetes in Prevotella noncarriers and carriers, respectively. CONCLUSION: Adherence to MedDiet is associated with diverse gut microorganisms and microbial functions. The inverse association between the MedDiet and diabetes prevalence varies significantly depending on gut microbial composition.

Fiber mixture-specific effect on distal colonic fermentation and metabolic health in lean but not in prediabetic men.

Infusions of the short-chain fatty acid (SCFA) acetate in the distal colon improved metabolic parameters in men. Here, we hypothesized that combining rapidly and slowly fermentable fibers will enhance distal colonic acetate production and improve metabolic health. In vitro cultivation studies in a validated model of the colon were used to identify fiber mixtures that yielded high distal colonic acetate production. Subsequently, in two randomized crossover studies, lean and prediabetic overweight/obese men were included. In one study, participants received supplements of either long-chain inulin+resistant starch (INU+RS), INU or maltodextrin (PLA) the day prior to a clinical investigation day (CID). The second trial studied beta glucan+RS (BG+RS) versus BG and PLA. During each CID, breath hydrogen, indirect calorimetry, plasma metabolites/hormones were assessed during fasting and postprandial conditions. Additionally, fecal microbiota composition and SCFA were determined. In prediabetic men, INU+RS increased plasma acetate compared to INU or PLA (P < .05), but did not affect metabolic parameters. In lean men, INU+RS increased breath hydrogen and fasting plasma butyrate, which was accompanied by increased energy expenditure, carbohydrate oxidation and PYY and decreased postprandial glucose concentrations (all P < .05) compared to PLA. BG+RS increased plasma butyrate compared to PLA (P < .05) in prediabetic individuals, but did not affect other fermentation/metabolic markers in both phenotypes. Fiber-induced shifts in fecal microbiota were individual-specific and more pronounced with INU+RS versus BG+RS. Administration of INU+RS (not BG+RS) the day prior to investigation improved metabolic parameters in lean but not in prediabetic individuals, demonstrating that effects were phenotype- and fiber-specific. Further research should study whether longer-term supplementation periods are required to elicit beneficial metabolic health in prediabetic individuals. Trial registration numbers: Clinical trial No. NCT03711383 (Inulin study) and Clinical trial No. NCT03714646 (Beta glucan study).

Lactobacillus plantarum HAC01 Supplementation Improves Glycemic Control in Prediabetic Subjects: A Randomized, Double-Blind, Placebo-Controlled Trial.

A recent animal study demonstrated that administration of Lactobacillus plantarum HAC01 isolated from Korean kimchi improved glycemic control in type 2 diabetic mice. In the present study, we evaluated Lactobacillus plantarum HAC01's effects on metabolic parameters of prediabetic human subjects. Forty subjects with isolated impaired glucose tolerance were randomly assigned to receive a daily placebo (n = 20) or a dose of Lactobacillus plantarum HAC01 (n = 20) over eight weeks. The primary endpoint was a change in 2 h postprandial glucose (2h-PPG) levels and the secondary endpoints were assessment of other glucose metabolism parameters, including HbA1c, gut microbiota composition, and fecal short-chain fatty acids (SCFAs). The group with a diet supplemented with Lactobacillus plantarum HAC01 saw a significant reduction in 2h-PPG and HbA1c levels compared to the placebo group. Fasting plasma glucose, insulin, HOMA-IR, QUICKI, microbiota composition, and fecal SCFAs, however, were not significantly altered. No serious adverse effects were reported. This is the first clinical trial to show a beneficial effect of single-strain probiotic supplementation administered over eight weeks on HbA1c levels in prediabetic subjects.

Metformin treatment for 8 days impacts multiple intestinal parameters in high-fat high-sucrose fed mice.

Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, it is well accepted that the gut plays an important role. To gain more insights into the mechanisms occurring in the different regions of the intestine, adult male mice were fed a high-fat-high sucrose (HFS) diet for 8 days and treated with metformin by gavage (300 mg/day/kg body weight) during the HFS diet. Metformin counteracted HFS diet-induced overexpression of a network of genes involved in the transport of glucose and fatty acids in the different regions of the small intestine. It also induced beneficial modification of secondary bile acid profile in the caecum, with a reduction of deoxycholic acid and lithocholic acid levels and increased abundance of ursodeoxycholic acid and tauroursodeoxycholic acid, potentially leading to FRX inhibition. In parallel, metformin treatment was associated with specific changes of the microbiota composition in the lumen of the different regions of the intestine. Metformin induced a marked increase in the abundance of Akkermansia muciniphila in the lumen all along the gut and counteracted the effects of HFS diet on the abundances of some bacterial groups generally associated with metabolic disturbances (f-Lachnospiraceae, f-Petostreptococcaceae, g-Clostidium). Therefore, the present work clearly emphasises the role of all the regions of the intestinal tract in the beneficial action of the antidiabetic drug metformin in a prediabetic mouse model.

The gut microbiome and type 2 diabetes status in the Multiethnic Cohort.

BACKGROUND: The gut microbiome may play a role in inflammation associated with type 2 diabetes (T2D) development. This cross-sectional study examined its relation with glycemic status within a subset of the Multiethnic Cohort (MEC) and estimated the association of circulating bacterial endotoxin (measured as plasma lipopolysaccharide-binding protein (LBP)) with T2D, which may be mediated by C-reactive protein (CRP). METHODS: In 2013-16, cohort members from five ethnic groups completed clinic visits, questionnaires, and stool and blood collections. Participants with self-reported T2D and/or taking medication were considered T2D cases. Those with fasting glucose >125 and 100-125 mg/dL were classified as undiagnosed (UT2D) and pre-diabetes (PT2D) cases, respectively. We characterized the gut microbiome through 16S rRNA gene sequencing and measured plasma LBP and CRP by standard assays. Linear regression was applied to estimate associations of the gut microbiome community structure and LBP with T2D status adjusting for relevant confounders. RESULTS: Among 1,702 participants (59.9-77.4 years), 735 (43%) were normoglycemic (NG), 506 (30%) PT2D, 154 (9%) UT2D, and 307 (18%) T2D. The Shannon diversity index decreased (ptrend = 0.05), while endotoxin, measured as LBP, increased (ptrend = 0.0003) from NG to T2D. Of 10 phyla, Actinobacteria (ptrend = 0.007), Firmicutes (ptrend = 0.003), and Synergistetes (ptrend = 0.02) were inversely associated and Lentisphaerae (ptrend = 0.01) was positively associated with T2D status. Clostridium sensu stricto 1, Lachnospira, and Peptostreptococcaceae were less, while Escherichia-Shigella and Lachnospiraceae were more abundant among T2D patients, but the associations with Actinobacteria, Clostridium sensu stricto 1, and Escherichia-Shigella may be due metformin use. PT2D/UT2D values were closer to NG than T2D. No indication was detected that CRP mediated the association of LBP with T2D. CONCLUSIONS: T2D but not PT2D/UT2D status was associated with lower abundance of SCFA-producing genera and a higher abundance of gram-negative endotoxin-producing bacteria suggesting that the gut microbiome may contribute to chronic systemic inflammation and T2D through bacterial translocation.

Berberine Slows the Progression of Prediabetes to Diabetes in Zucker Diabetic Fatty Rats by Enhancing Intestinal Secretion of Glucagon-Like Peptide-2 and Improving the Gut Microbiota.

Background: Berberine is a plant alkaloid that has multiple beneficial effects against intestine inflammation. In our previous study, we have found that berberine also possesses an antidiabetic effect. However, whether berberine is useful in the prevention of type 2 diabetes mellitus (T2DM) through its effect on intestine endocrine function and gut microbiota is unclear. Aim: To investigate the effects of berberine in the prevention of T2DM, as well as its effects on intestine GLP-2 secretion and gut microbiota in ZDF rats. Methods: Twenty Zucker Diabetic Fatty (ZDF) rats were fed a high-energy diet until they exhibited impaired glucose tolerance (IGT). The rats were then divided into two groups to receive berberine (100 mg/kg/d; berberine group) or vehicle (IGT group) by gavage for 3 weeks. Five Zucker Lean (ZL) rats were used as controls. Fasting blood glucose (FBG) was measured, an oral glucose tolerance test was performed, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. Intestinal expression of TLR-4, NF-κB, TNF-α, mucin, zona occludens-1 (ZO-1) and occludin were assessed (immunohistochemistry). Plasma levels and glutamine-induced intestinal secretion of glucagon-like peptide-1 (GLP-1) and GLP-2 were measured (enzyme-linked immunosorbent assay). The plasma lipopolysaccharide (LPS) level was measured. Fecal DNA extraction, pyrosequencing, and bioinformatics analysis were performed. Results: After 3 weeks of intervention, diabetes developed in all rats in the IGT group, but only 30% of rats in the berberine group. Treatment with berberine was associated with reductions in food intake, FBG level, insulin resistance, and plasma LPS level, as well as increases in fasting plasma GLP-2 level and glutamine-induced intestinal GLP-2 secretion. Berberine could increase the goblet cell number and villi length, and also reverse the suppressed expressions of mucin, occludin, ZO-1 and the upregulated expressions of TLR-4, NF-κB and TNF-α induced in IGT rats (P<0.05). Berberine also improved the structure of the gut microbiota and restored species diversity. Conclusion: Berberine may slow the progression of prediabetes to T2DM in ZDF rats by improving GLP-2 secretion, intestinal permeability, and the structure of the gut microbiota.

Trans-ethnic gut microbial signatures of prediabetic subjects from India and Denmark.

BACKGROUND: Recent studies have indicated an association of gut microbiota and microbial metabolites with type 2 diabetes mellitus (T2D). However, large-scale investigation of the gut microbiota of "prediabetic" (PD) subjects has not been reported. Identifying robust gut microbiome signatures of prediabetes and characterizing early prediabetic stages is important for the understanding of disease development and could be crucial in early diagnosis and prevention. METHODS: The current study performed amplification and sequencing on the variable regions (V1-V5) of the 16S rRNA genes to profile and compare gut microbiota of prediabetic individuals (N = 262) with normoglycemic individuals (N = 275) from two cohorts in India and Denmark. Similarly, fasting serum inflammatory biomarkers were profiled from the study participants. RESULTS: After correcting for strong country-specific cohort effect, 16 operational taxonomic units (OTUs) including members from the genera Prevotella9, Phascolarctobacterium, Barnesiella, Flavonifractor, Tyzzerella_4, Bacteroides, Faecalibacterium, and Agathobacter were identified as enriched in normoglycaemic subjects with respect to the subjects with prediabetes using a negative binomial Wald test. We also identified 144 OTUs enriched in the prediabetic subjects, which included members from the genera Megasphaera, Streptococcus, Prevotella9, Alistipes, Mitsuokella, Escherichia/Shigella, Prevotella2, Vibrio, Lactobacillus, Alloprevotella, Rhodococcus, and Klebsiella. Comparative analyses of relative abundance of bacterial taxa revealed that the Streptococcus, Escherichia/Shigella, Prevotella2, Vibrio, and Alloprevotella OTUs exhibited more than fourfold enrichment in the gut microbiota of prediabetic subjects. When considering subjects from the two geographies separately, we were able to identify additional gut microbiome signatures of prediabetes. The study reports a probable association of Megasphaera OTU(s) with impaired glucose tolerance, which is significantly pronounced in Indian subjects. While the overall results confirm a state of proinflammation as early as in prediabetes, the Indian cohort exhibited a characteristic pattern of abundance of inflammatory markers indicating low-grade intestinal inflammation at an overall population level, irrespective of glycemic status. CONCLUSIONS: The results present trans-ethnic gut microbiome and inflammation signatures associated with prediabetes, in Indian and Danish populations. The identified associations may be explored further as potential early indicators for individuals at risk of dysglycemia.

Alzheimer's Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models.

Alzheimer's disease (AD) is the most common cause of dementia. Epidemiological studies show the association between AD and type 2 diabetes (T2DM), although the mechanisms are not fully understood. Dietary habits and lifestyle, that are risk factors in both diseases, strongly modulate gut microbiota composition. Also, the brain-gut axis plays a relevant role in AD, diabetes and inflammation, through products of bacterial metabolism, like short-chain fatty acids. We provide a comprehensive review of current literature on the relation between dysbiosis, altered inflammatory cytokines profile and microglia in preclinical models of AD, T2DM and models that reproduce both diseases as commonly observed in the clinic. Increased proinflammatory cytokines, such as IL-1ß and TNF-α, are widely detected. Microbiome analysis shows alterations in Actinobacteria, Bacteroidetes or Firmicutes phyla, among others. Altered α- and ß-diversity is observed in mice depending on genotype, gender and age; therefore, alterations in bacteria taxa highly depend on the models and approaches. We also review the use of pre- and probiotic supplements, that by favoring a healthy microbiome ameliorate AD and T2DM pathologies. Whereas extensive studies have been carried out, further research would be necessary to fully understand the relation between diet, microbiome and inflammation in AD and T2DM.

Functional Deficits in Gut Microbiome of Young and Middle-Aged Adults with Prediabetes Apparent in Metabolizing Bioactive (Poly)phenols.

BACKGROUND: Gut microbiota metabolize select dietary (poly)phenols to absorbable metabolites that exert biological effects important in metabolic health. Microbiota composition associated with health/disease status may affect its functional capacity to yield bioactive metabolites from dietary sources. Therefore, this study assessed gut microbiome composition and its related functional capacity to metabolize fruit (poly)phenols in individuals with prediabetes and insulin resistance (PreDM-IR, n = 26) compared to a metabolically healthy Reference group (n = 10). METHODS: Shotgun sequencing was used to characterize gut microbiome composition. Targeted quantitative metabolomic analyses of plasma and urine collected over 24 h were used to assess microbial-derived metabolites in response to a (poly)phenol-rich raspberry test drink. RESULTS: PreDM-IR compared to the Reference group: (1) enriched Blautia obeum and Blautia wexlerae and depleted Bacteroides dorei and Coprococcus eutactus. Akkermansia muciniphila and Bacteroides spp. were depleted in the lean PreDM-IR subset; and (2) impaired microbial catabolism of select (poly)phenols resulting in lower 3,8-dihydroxy-urolithin (urolithin A), phenyl-γ-valerolactones and various phenolic acids concentrations (p < 0.05). Controlling for obesity revealed relationships with microbial species that may serve as metagenomic markers of diabetes development and therapeutic targets. CONCLUSIONS: Data provide insight from multi-omics approaches to advance knowledge at the diet-gut-disease nexus serving as a platform for devising dietary strategies to improve metabolic health.

Alteration of Intestinal Microbiota in 3-Deoxyglucosone-Induced Prediabetic Rats.

Our previous research suggests that 3-deoxyglucosone (3DG), formed in the caramelization course and Maillard reactions in food, is an independent factor for the development of prediabetes. Since the relationship between type 2 diabetes (T2D) and intestinal microbiota is moving from correlation to causality, we investigated the alterations in the composition and function of the intestinal microbiota in 3DG-induced prediabetic rats. Rats were given 50 mg/kg 3DG by intragastric administration for two weeks. Microbial profiling in faeces samples was determined through the 16S rRNA gene sequence. The glucagon-like peptide 2 (GLP-2) and lipopolysaccharide (LPS) levels in plasma and intestinal tissues were measured by ELISA and Limulus test, respectively. 3DG treatment did not significantly change the richness and evenness but affected the composition of intestinal microbiota. At the phylum level, 3DG treatment increased the abundance of nondominant bacteria Proteobacteria but did not cause the change of the dominant bacteria. Meanwhile, the abundance of the Prevotellaceae family and Parasutterela genus and the Alcaligencaeae family and Burkholderiales order and its attachment to the Betaproteobacteria class were overrepresented in the 3DG group. The bacteria of Candidatus Soleaferrea genus, Gelria genus, and Thermoanaerobacteraceae family and its attachment to Thermoanaerobacterales order were apparently more abundant in the control group. In addition, 45 KEGG pathways were altered after two-week intragastric administration of 3DG. Among these KEGG pathways, 13 KEGG pathways were involved in host metabolic function related to amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, and metabolism of terpenoids and polyketides. Moreover, the increased LPS levels and the decreased GLP-2 concentration in plasma and intestinal tissues were observed in 3DG-treated rats, together with the impaired fasting glucose and oral glucose tolerance. The alterations in composition and function of the intestinal microbiota were observed in 3DG-treated rats, which provides a possible mechanism linking exogenous 3DG intake to the development of prediabetes.

The effect of Baduanjin on intestinal flora in patients with prediabetes mellitus: Study protocol for a randomized controlled trial.

BACKGROUND: The incidence rate of prediabetes is increasing year by year. Prediabetes is a continuous ever fount of diabetes. Diabetes is closely related to intestinal flora imbalance and insulin resistance (IR). Previous studies have proved that Baduanjin can effectively improve the blood glucose and blood lipid of patients, but there is no relevant research on intestinal flora and IR. Therefore, this study focuses on the influence of Baduanjin on intestinal flora of patients with prediabetes, so as to improve the effect of IR, and finally delay or prevent the occurrence of to diabetes mellitus 2 type (T2DM). METHODS: This study will recruit 80 patients who meet the diagnostic criteria of prediabetes from Hospital of Chengdu University of traditional Chinese Medicine. Eighty patients will be randomly divided into experimental group and control group, 40 cases in each group. The control group received routine lifestyle intervention, and the experimental group received Baduanjin at least 3 to 5 times a week for a total of 6 months. The researchers monitored the intestinal flora, insulin resistance index, blood glucose, blood lipid, body mass index, and other indicators after 3 months of intervention and 6 months of intervention DISCUSSION:: Based on previous studies, intestinal flora is closely related to the occurrence and development of T2DM-IR. Baduanjin can significantly improve the blood glucose and blood lipid of patients with prediabetes, and has a positive effect on the intestinal flora of the elderly and significantly improve the intestinal microecological balance. This study used randomized controlled trial to explore the control method between Baduanjin and conventional lifestyle, in order to further establish the application of Baduanjin in patients with prediabetes. TRIAL REGISTRATION: This trial protocol has been approved by the research hospital and registered in China clinical trial registration center on July 6, 2020 (ChiCTR2000034490).

Identification of a periodontal pathogen and bihormonal cells in pancreatic islets of humans and a mouse model of periodontitis.

Results from epidemiological and prospective studies indicate a close association between periodontitis and diabetes. However the mechanisms by which periodontal pathogens influence the development of prediabetes/diabetes are not clear. We previously reported that oral administration of a periodontal pathogen, Porphyromonas gingivalis (Pg) to WT mice results in insulin resistance, hyperinsulinemia, and glucose intolerance and that Pg translocates to the pancreas. In the current study, we determined the specific localization of Pg in relation to mouse and human pancreatic α- and ß-cells using 3-D confocal and immunofluorescence microscopy and orthogonal analyses. Pg/gingipain is intra- or peri-nuclearly localized primarily in ß-cells in experimental mice and also in human post-mortem pancreatic samples. We also identified bihormonal cells in experimental mice as well as human pancreatic samples. A low percentage of bihormonal cells has intracellular Pg in both humans and experimental mice. Our data show that the number of Pg translocated to the pancreas correlates with the number of bihormonal cells in both mice and humans. Our findings suggest that Pg/gingipain translocates to pancreas, particularly ß-cells in both humans and mice, and this is strongly associated with emergence of bihormonal cells.

Longitudinal Analysis of Serum Cytokine Levels and Gut Microbial Abundance Links IL-17/IL-22 With Clostridia and Insulin Sensitivity in Humans.

Recent studies using mouse models suggest that interaction between the gut microbiome and IL-17/IL-22-producing cells plays a role in the development of metabolic diseases. We investigated this relationship in humans using data from the prediabetes study of the Integrated Human Microbiome Project (iHMP). Specifically, we addressed the hypothesis that early in the onset of metabolic diseases there is a decline in serum levels of IL-17/IL-22, with concomitant changes in the gut microbiome. Clustering iHMP study participants on the basis of longitudinal IL-17/IL-22 profiles identified discrete groups. Individuals distinguished by low levels of IL-17/IL-22 were linked to established markers of metabolic disease, including insulin sensitivity. These individuals also displayed gut microbiome dysbiosis, characterized by decreased diversity, and IL-17/IL-22-related declines in the phylum Firmicutes, class Clostridia, and order Clostridiales This ancillary analysis of the iHMP data therefore supports a link between the gut microbiome, IL-17/IL-22, and the onset of metabolic diseases. This raises the possibility for novel, microbiome-related therapeutic targets that may effectively alleviate metabolic diseases in humans as they do in animal models.

Progressive Shifts in the Gut Microbiome Reflect Prediabetes and Diabetes Development in a Treatment-Naive Mexican Cohort.

Type 2 diabetes (T2D) is a global epidemic that affects more than 8% of the world's population and is a leading cause of death in Mexico. Diet and lifestyle are known to contribute to the onset of T2D. However, the role of the gut microbiome in T2D progression remains uncertain. Associations between microbiome composition and diabetes are confounded by medication use, diet, and obesity. Here we present data on a treatment-naive cohort of 405 Mexican individuals across varying stages of T2D severity. Associations between gut bacteria and more than 200 clinical variables revealed a defined set of bacterial genera that were consistent biomarkers of T2D prevalence and risk. Specifically, gradual increases in blood glucose levels, beta cell dysfunction, and the accumulation of measured T2D risk factors were correlated with the relative abundances of four bacterial genera. In a cohort of 25 individuals, T2D treatment-predominantly metformin-reliably returned the microbiome to the normoglycemic community state. Deep clinical characterization allowed us to broadly control for confounding variables, indicating that these microbiome patterns were independent of common T2D comorbidities, like obesity or cardiovascular disease. Our work provides the first solid evidence for a direct link between the gut microbiome and T2D in a critically high-risk population. In particular, we show that increased T2D risk is reflected in gradual changes in the gut microbiome. Whether or not these T2D-associated changes in the gut contribute to the etiology of T2D or its comorbidities remains to be seen.

Gut Microbiome Fermentation Determines the Efficacy of Exercise for Diabetes Prevention.

Exercise is an effective strategy for diabetes management but is limited by the phenomenon of exercise resistance (i.e., the lack of or the adverse response to exercise on metabolic health). Here, in 39 medication-naive men with prediabetes, we found that exercise-induced alterations in the gut microbiota correlated closely with improvements in glucose homeostasis and insulin sensitivity (clinicaltrials.gov entry NCT03240978). The microbiome of responders exhibited an enhanced capacity for biosynthesis of short-chain fatty acids and catabolism of branched-chain amino acids, whereas those of non-responders were characterized by increased production of metabolically detrimental compounds. Fecal microbial transplantation from responders, but not non-responders, mimicked the effects of exercise on alleviation of insulin resistance in obese mice. Furthermore, a machine-learning algorithm integrating baseline microbial signatures accurately predicted personalized glycemic response to exercise in an additional 30 subjects. These findings raise the possibility of maximizing the benefits of exercise by targeting the gut microbiota.

Effects of combined D-fagomine and omega-3 PUFAs on gut microbiota subpopulations and diabetes risk factors in rats fed a high-fat diet.

Food contains bioactive compounds that may prevent changes in gut microbiota associated with Westernized diets. The aim of this study is to explore the possible additive effects of D-fagomine and ω-3 PUFAs (EPA/DHA 1:1) on gut microbiota and related risk factors during early stages in the development of fat-induced pre-diabetes. Male Sprague Dawley (SD) rats were fed a standard diet, or a high-fat (HF) diet supplemented with D-fagomine, EPA/DHA 1:1, a combination of both, or neither, for 24 weeks. The variables measured were fasting glucose and glucose tolerance, plasma insulin, liver inflammation, fecal/cecal gut bacterial subgroups and short-chain fatty acids (SCFAs). The animals supplemented with D-fagomine alone and in combination with ω-3 PUFAs accumulated less fat than those in the non-supplemented HF group and those given only ω-3 PUFAs. The combined supplements attenuated the high-fat-induced incipient insulin resistance (IR), and liver inflammation, while increasing the cecal content, the Bacteroidetes:Firmicutes ratio and the populations of Bifidobacteriales. The functional effects of the combination of D-fagomine and EPA/DHA 1:1 against gut dysbiosis and the very early metabolic alterations induced by a high-fat diet are mainly those of D-fagomine complemented by the anti-inflammatory action of ω-3 PUFAs.

Association Between Nitrate-Reducing Oral Bacteria and Cardiometabolic Outcomes: Results From ORIGINS.

Background The enterosalivary nitrate-nitrite-nitric oxide pathway is an alternative pathway of nitric oxide generation, potentially linking the oral microbiome to insulin resistance and blood pressure (BP). We hypothesized that increased abundance of nitrate-reducing oral bacteria would be associated with lower levels of cardiometabolic risk cross-sectionally. Methods and Results ORIGINS (Oral Infections, Glucose Intolerance, and Insulin Resistance Study) enrolled 300 diabetes mellitus-free adults aged 20 to 55 years (mean=34±10 years) (78% women). Microbial DNA was extracted from subgingival dental plaque (n=281) and V3-V4 regions of the 16S rRNA gene were sequenced to measure the relative abundances of 20 a priori-selected taxa with nitrate-reducing capacity. Standardized scores of each taxon's relative abundance were summed, producing a nitrate-reducing taxa summary score (NO3TSS) for each participant. Natural log-transformed homeostatic model assessment of insulin resistance, plasma glucose, systolic BP, and diastolic BP were regressed on NO3TSS in multivariable linear regressions; prediabetes mellitus and hypertension prevalence were regressed on NO3TSS using modified Poisson regression models. Nitrate-reducing bacterial species represented 20±16% of all measured taxa. After multivariable adjustment, a 1-SD increase in NO3TSS, was associated with a -0.09 (95% CI, -0.15 to -0.03) and -1.03 mg/dL (95% CI, -1.903 to -0.16) lower natural log-transformed homeostatic model assessment of insulin resistance and plasma glucose, respectively. NO3TSS was associated with systolic BP only among patients without hypertension; 1-SD increase in NO3TSS was associated with -1.53 (95% CI, -2.82 to -0.24) mm Hg lower mean systolic BP. No associations were observed with prediabetes mellitus and hypertension. Conclusions A higher relative abundance of oral nitrate-reducing bacteria was associated with lower insulin resistance and plasma glucose in the full cohort and with mean systolic BP in participants with normotension.