Metformin decreases bacterial trimethylamine production and trimethylamine N-oxide levels in db/db mice

Kuka, Janis; Videja, Melita; Makrecka-Kūka, Marina; Liepiņš, Jānis; Grı̄nberga, Solveiga; Sevostjanovs, Eduards; Vilks, Kārlis; Liepinsh, Edgars; Dambrova, Maija

doi:10.1038/s41598-020-71470-4

Cited by 27 publications

(23 citation statements)

References 50 publications

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“…Consistent with the study of Li, JV et al, our results suggested that PAGln was signi cantly correlated with Klebsiella [52]. Klebsiella is widely believed to be a pathogenic bacterium and a strain with the TMA gene [53][54][55]. TMA is an essential precursor of the gut microbiota metabolite TMAO, which has been found to promote thrombosis via increasing platelet reactivity [56].…”

Section: Discussionsupporting

confidence: 89%

Elevated Circulating Levels of Phenylacetylglutamine in Stroke Patients With T2D Are Linked to Specific Gut Microbiota

Xia

Wei

Huang

et al. 2022

Preprint

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Background Type 2 diabetes (T2D) aggravates the injury of ischemic stroke (IS). The gut microbiota-related metabolite phenylacetylglutamine (PAGln) has been shown to elevate in plasma of patients with T2D and promote thrombosis. However, the alterations of gut microbiota and PAGln levels in stroke patients with T2D remain unclear. Therefore, our study aimed to explore the differences in gut microbiota and its metabolite PAGln between IS patients with and without T2D.Methods In our study, 35 IS with T2D (IS-T2D group), 50 IS patients without T2D (IS group), and 29 healthy controls (HC group) were recruited from December 2019 to December 2020. Fecal samples were collected and analyzed using 16S rRNA high throughput sequencing, and plasma samples were subjected to targeted metabolomics to detect metabolite PAGln. Plasma PAGln levels of rats with transplantation of fecal microbes from patients were assessed. Results Our results showed that compared with the IS group, the relative abundances of Proteobacteria, Verrucomicrobiota, Enterobacteriaceae, and Klebsiella were enriched in the IS-T2D group. The plasma PAGln levels in IS-T2D patients were significantly higher than those in IS patients. Correlation analysis showed that plasma PAGln levels were significantly correlated with Enterobacteriaceae, Verrucomicrobiota, and Klebsiella, which were enriched in IS-T2D patients. Further studies demonstrated that plasma PAGln levels were positively correlated with the concentration of NETs, and NETs levels were increased in a dose-dependent manner according to PAGln levels. In addition, the rats transplanted with fecal microbes from IS-T2D patients developed more severe brain injury and higher plasma PAGln levels compared to the rats transplanted with fecal microbes from IS patients. Moreover, a prediction model based on the differential relative abundances of microbiota, plasma PAGln levels, and NETs levels was constructed to discriminate IS-T2D from stroke patients. Conclusions Our results suggest that the gut microbiota is imbalanced and its metabolite PAGln levels are increased in stroke patients with T2D, and T2D potentially aggravates stroke injury via an inflammatory response, which is associated with gut microbiota and its metabolite PAGln modulation.

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Section: Discussionsupporting

confidence: 89%

Elevated Circulating Levels of Phenylacetylglutamine in Stroke Patients With T2D Are Linked to Specific Gut Microbiota

Xia

Wei

Huang

et al. 2022

Preprint

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“…Metformin stimulates the activity of endocrine cells by regulating bile acid conversion, improving intestinal permeability, reducing endotoxin levels, and enhancing the release of GLP-1 and PYY peptides ( 126 ). Metformin also decreases the TMA level and the growth of bacteria that produce it in the gut, and thus the circulating TMAO level in mice ( 127 ). The fact that transferring the microbiota from metformin-treated mice improves metabolic traits in aged mice indicates that the shifts in the gut microbiota by metformin treatment are beneficial ( 111 ).…”

Section: Therapeutic Potential Of Gut Microbiota For T2dmentioning

confidence: 99%

Modulating the Microbiota as a Therapeutic Intervention for Type 2 Diabetes

2021

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Mounting evidence suggested that the gut microbiota has a significant role in the metabolism and disease status of the host. In particular, Type 2 Diabetes (T2D), which has a complex etiology that includes obesity and chronic low-grade inflammation, is modulated by the gut microbiota and microbial metabolites. Current literature supports that unbalanced gut microbial composition (dysbiosis) is a risk factor for T2D. In this review, we critically summarize the recent findings regarding the role of gut microbiota in T2D. Beyond these associative studies, we focus on the causal relationship between microbiota and T2D established using fecal microbiota transplantation (FMT) or probiotic supplementation, and the potential underlying mechanisms such as byproducts of microbial metabolism. These microbial metabolites are small molecules that establish communication between microbiota and host cells. We critically summarize the associations between T2D and microbial metabolites such as short-chain fatty acids (SCFAs) and trimethylamine N-Oxide (TMAO). Additionally, we comment on how host genetic architecture and the epigenome influence the microbial composition and thus how the gut microbiota may explain part of the missing heritability of T2D found by GWAS analysis. We also discuss future directions in this field and how approaches such as FMT, prebiotics, and probiotics supplementation are being considered as potential therapeutics for T2D.

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“…As the production of TMA is strictly microbiota-dependent, another limitation is that we were not able to collect samples to assess the impact of FMD on gut microbiota. Some studies state that alterations in microbiota composition that favour TMA-producing bacteria are a possible mechanism by which plasma TMAO levels increase in T2D patients [ 54 , 55 ]. However, recent research shows that some of the typical deviations observed in gut microbiota composition in patients with T2D [ 56 , 57 ] or atherosclerosis [ 58 ] can be restored by FMD [ 59 , 60 ], thus possibly lowering TMA production and reducing CVD risks.…”

Section: Discussionmentioning

confidence: 99%

Fasting-Mimicking Diet Reduces Trimethylamine N-Oxide Levels and Improves Serum Biochemical Parameters in Healthy Volunteers

et al. 2022

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Elevated plasma levels of trimethylamine N-oxide (TMAO) have been proposed as a diet-derived biomarker of cardiometabolic disease risk. Caloric restriction is the most common dietary intervention used to improve cardiometabolic health; however, novel trends suggest a fasting-mimicking diet (FMD) as a more feasible alternative. FMD is a variation of intermittent fasting, based on caloric restriction and limitation of protein sources of animal origin, applied in daily cycles during a 5-day period. As TMAO is intensively produced by gut microbiota after the consumption of animal-derived products, we aim to investigate whether a 5-day FMD affects plasma TMAO levels and markers of metabolic health. To investigate whether an increase in vegetable intake possesses similar effects on TMAO levels and metabolic parameters, healthy volunteers (n = 24) were subjected to a 5-day FMD and 19 volunteers served as a reference group (VEG). This group of volunteers consumed an additional four servings of vegetables per day, but otherwise stayed on their usual diet. FMD resulted in a twofold decrease in plasma TMAO levels, which was not evident in the volunteers from the VEG group. Moreover, FMD led to a weight loss of 2.8 ± 0.2 kg and a subsequent reduction in BMI compared to baseline. The FMD group exhibited a significant elevation in plasma ketone bodies (14-fold compared to baseline) and a decrease in IGF-1 levels by 37 ± 8 ng/mL. Since fasting glucose and C-peptide levels decreased, all volunteers in the FMD group showed improved insulin sensitivity and a decreased HOMA-IR index. In contrast, in the VEG group, only a slight reduction in plasma levels of fasting glucose and triglycerides was noted. In conclusion, we show that FMD is a viable strategy to reduce plasma levels of TMAO by limiting caloric intake and animal-derived protein consumption. The reduction in the level of TMAO could be an additional benefit of FMD, leading to a reduced risk of cardiometabolic diseases.

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Metformin decreases bacterial trimethylamine production and trimethylamine N-oxide levels in db/db mice

Cited by 27 publications

References 50 publications

Elevated Circulating Levels of Phenylacetylglutamine in Stroke Patients With T2D Are Linked to Specific Gut Microbiota

Elevated Circulating Levels of Phenylacetylglutamine in Stroke Patients With T2D Are Linked to Specific Gut Microbiota

Modulating the Microbiota as a Therapeutic Intervention for Type 2 Diabetes

Fasting-Mimicking Diet Reduces Trimethylamine N-Oxide Levels and Improves Serum Biochemical Parameters in Healthy Volunteers

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