Type 2 diabetes mellitus (T2DM) and T2DM-related complications [such as retinopathy, nephropathy, and cardiovascular diseases (CVDs)] are the most prevalent metabolic diseases. Intriguingly, overwhelming findings have shown a strong association of the gut microbiome with the etiology of these diseases, including the role of aberrant gut bacterial metabolites, increased intestinal permeability, and pathogenic immune function affecting host metabolism. Thus, deciphering the specific microbiota, metabolites, and the related mechanisms to T2DM-related complications by combined analyses of metagenomics and metabolomics data can lead to an innovative strategy for the treatment of these diseases. Accordingly, this review highlights the advanced knowledge about the characteristics of the gut microbiota in T2DM-related complications and how it can be associated with the pathogenesis of these diseases. Also, recent studies providing a new perspective on microbiota-targeted therapies are included.

The role and mechanisms of gut microbiota in diabetic nephropathy, diabetic retinopathy and cardiovascular diseases

The gut-brain axis has been shown to play a vital role in the prognosis and recovery of ischemic stroke (IS), which is associated with gut microbiota dysfunction and changes in the gastrointestinal system and epithelial barrier integrity. In turn, gut microbiota and its derived metabolites can influence stroke outcomes. In this review, we first describe the relationship between IS (clinical and experimental IS) and the gut microbiota. Second, we summarize the role and specific mechanisms of microbiota-derived metabolites in IS. Further, we discuss the roles of natural medicines targeting the gut microbiota. Finally, the potential use of the gut microbiota and derived metabolites as a promising therapeutic opportunity for stroke prevention, diagnosis, and treatment is explored. 

New insight into gut microbiota and their metabolites in ischemic stroke: A promising therapeutic target.

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced by the action of gut microbiota and the hepatic enzyme Flavin Mono‑oxygenase 3 (FMO3). TMAO level has a positive correlation with the risk of cardiovascular events, including stroke, and their level is influenced mainly by dietary choice and the action of liver enzyme FMO3. TMAO plays a role in the development of atherosclerosis plaque, which is one of the causative factors of the stroke event. Preclinical and clinical investigations on the TMAO and associated stroke risk, severity, and outcomes are summarised in this review. In addition, mechanisms of TMAO-driven vascular dysfunction are also discussed, such as inflammation, oxidative stress, thrombus and foam cell formation, altered cholesterol and bile acid metabolism, etc. Post-stroke inflammatory cascades involving activation of immune cells, i.e., microglia and astrocytes, result in Blood-brain-barrier (BBB) disruption, allowing TMAO to infiltrate the brain and further aggravate inflammation. This event occurs as a result of the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway through the release of inflammatory cytokines and chemokines that further aggravate the BBB and initiate further recruitment of immune cells in the brain. Thus, it's likely that maintaining TMAO levels and associated gut microbiota could be a promising approach for treating and improving stroke complications. 

Trimethylamine-N-oxide and cerebral stroke risk: A review

Analysis of two intestinal bacterial metabolites (trimethylamine N-oxide and phenylacetylglutamine) in human serum samples of patients with T2DM and AMI using a liquid chromatography tandem mass spectrometry method.

The purposes of this study were to assess the effect of Brazil nut supplementation on trimethylamine N-oxide (TMAO) levels and glutathione peroxidase (GPx) activity in patients with coronary artery disease (CAD). Patients with CAD were randomly assigned to two groups, Brazil nut group (23 patients, 48% male, 62.7 ± 6.8 years, 29.4 ± 5.8 kg/m2 ), which received one Brazil nut per day for 3 months, and the control group (14 patients, 43% male, 63.7 ± 8.7 years, 28.4 ± 4.2 kg/m2 ) who did not receive any supplementation. After 3 months, TMAO levels and their precursors did not change in either group. Although not significant, GPx activity increased by 41% in the Brazil nut group. TMAO levels were negatively associated with total fiber intake (r = -0.385 and p = .02). A 3-month Brazil nut supplementation did not change TMAO levels and GPx activity in CAD patients. PRACTICAL APPLICATIONS: Trimethylamine N-oxide (TMAO) has been associated with oxidative stress and cardiovascular disease risk. Thus, the increase in antioxidants enzymes production could be a promising strategy to reduce TMAO-mediated oxidative stress. In this context, nutritional strategies are well-known as activators of cellular antioxidant responses. As Brazil nuts have a known role in reducing oxidative stress by increasing glutathione peroxidase (GPx) activity (a selenium-dependent antioxidant enzyme), this study hypothesized that Brazil nuts could be a strategy that, via antioxidant capacity, would reduce TMAO plasma levels. Although no changes in TMAO levels and GPx activity can be observed in this study, it is believed that other results can be obtained depending on the dosage used. Thus, this study can open new paths and direct other studies with different doses and treatment times to evaluate the effects of Brazil Nuts on TMAO levels.

Brazil nut supplementation does not affect trimethylamine-n-oxide plasma levels in patients with coronary artery disease.

BACKGROUND
The present study analyzed the relationship between circulating Trimethylamine N-oxide (TMAO) levels and stroke severity in diabetic patients with acute ischemic stroke. A further aim was to investigate whether higher TMAO levels were associated with platelet aggregation and glycemic variability.


METHODS
This was a cross-sectional analysis of 108 patients with type 2 diabetes mellitus (DM) undergoing acute ischemic stroke and 60 healthy controls. Fasting plasma TMAO was measured using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry.


RESULTS
Plasma TMAO levels of patients with acute ischemic stroke were significantly higher than those of healthy controls. Among stroke patients, 50 were defined as undergoing mild stroke, and their plasma TMAO levels were lower compared to those with moderate to severe stroke. Platelet aggregation and mean amplitude of glycemic excursions (MAGE) were both correlated with plasma TMAO levels and these relationships remained significant in multiple linear regression analyses. Moreover, in streptozotocin-induced diabetic rats fed a diet enriched with choline to increase TMAO synthesis, platelet aggregation was significantly increased in the DM+choline and fluctuated DM (FDM)+Choline groups compared to the Control group. This increase was abolished in rats receiving oral ABS, which markedly reduced plasma TMAO levels. Importantly, compared with the DM+choline group, the FDM+Choline group displayed significantly elevated TMAO levels and higher platelet aggregation.


CONCLUSIONS
Our results demonstrated that higher plasma TMAO levels were associated with stroke severity and suggested a novel link between plasma TMAO levels and glycemic variability in diabetic patients with acute ischemic stroke.

Trimethylamine-N-oxide predicts stroke severity in diabetic patients with acute ischemic stroke and is related to glycemic variability.

EEG-ECG correlation in vasovagal syncope triggered by blood-injection-injury phobia.

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Trimethylamine-N-oxide predicts stroke severity in diabetic patients with acute ischemic stroke and is related to glycemic variability.

EEG-ECG correlation in vasovagal syncope triggered by blood-injection-injury phobia.