Heart Failure Disturbs Gut–Blood Barrier and Increases Plasma Trimethylamine, a Toxic Bacterial Metabolite

Trimethylamine (TMA) is a gut bacteria product oxidized by the liver to trimethylamine-N-oxide (TMAO). Clinical evidence suggests that cardiovascular disease is associated with increased plasma TMAO. However, little headway has been made in understanding this relationship on a mechanistic and molecular level. We investigated the mechanisms affecting plasma levels of TMAO in Spontaneously Hypertensive Heart Failure (SHHF) rats. Healthy Wistar Kyoto (WKY) and SHHF rats underwent metabolic, hemodynamic, histopathological and biochemical measurements, including tight junction proteins analysis. Stool, plasma and urine samples were evaluated for TMA and TMAO using ultra performance liquid chromatography-mass spectrometry. SHHF presented disturbances of the gut–blood barrier including reduced intestinal blood flow, decreased thickness of the colonic mucosa and alterations in tight junctions, such as claudin 1 and 3, and zonula occludens-1. This was associated with significantly higher plasma levels of TMA and TMAO and increased gut-to-blood penetration of TMA in SHHF compared to WKY. There was no difference in kidney function or liver oxidation of TMA to TMAO between WKY and SHHF. In conclusion, increased plasma TMAO in heart failure rats results from a perturbed gut–blood barrier and increased gut-to-blood passage of TMAO precursor, i.e., TMA. Increased gut-to-blood penetration of bacterial metabolites may be a marker and a mediator of cardiovascular pathology

Trimethylamine, a gut bacteria metabolite and air pollutant, increases blood pressure and markers of kidney damage including proteinuria and KIM-1 in rats

BACKGROUND: Trimethylamine oxide (TMAO) is a biomarker in cardiovascular and renal diseases. TMAO originates from the oxidation of trimethylamine (TMA), a product of gut microbiota and manufacturing industries-derived pollutant, by flavin monooxygenases (FMOs). The effect of chronic exposure to TMA on cardiovascular and renal systems is undetermined. METHODS: Metabolic, hemodynamic, echocardiographic, biochemical and histopathological evaluations were performed in 12-week-old male SPRD rats receiving water (controls) or TMA (200 or 500 µM/day) in water for 18 weeks. TMA and TMAO levels, the expression of FMOs and renin-angiotensin system (RAS) genes were evaluated in various tissues. RESULTS: In comparison to controls, rats receiving high dose of TMA had significantly increased arterial systolic blood pressure (126.3 ± 11.4 vs 151.2 ± 19.9 mmHg; P = 0.01), urine protein to creatinine ratio (1.6 (1.5; 2.8) vs 3.4 (3.3; 4.2); P = 0.01), urine KIM-1 levels (2338.3 ± 732.0 vs. 3519.0 ± 953.0 pg/mL; P = 0.01), and hypertrophy of the tunica media of arteries and arterioles (36.61 ± 0.15 vs 45.05 ± 2.90 µm, P = 0.001 and 18.44 ± 0.62 vs 23.79 ± 2.60 µm, P = 0.006; respectively). Mild degeneration of renal bodies with glomerulosclerosis was also observed. There was no significant difference between the three groups in body weight, water-electrolyte balance, echocardiographic parameters and RAS expression. TMA groups had marginally increased 24 h TMA urine excretion, whereas serum levels and 24 h TMAO urine excretion were increased up to 24-fold, and significantly increased TMAO levels in the liver, kidneys and heart. TMA groups had lower FMOs expression in the kidneys. CONCLUSIONS: Chronic exposure to TMA increases blood pressure and increases markers of kidney damage, including proteinuria and KIM-1. TMA is rapidly oxidized to TMAO in rats, which may limit the toxic effects of TMA on other organs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03687-y

Hypertensive rats show increased renal excretion and decreased tissue concentrations of glycine betaine, a protective osmolyte with diuretic properties

Hypertension leads to water-electrolyte disturbances and end-organ damage. Betaine is an osmolyte protecting cells against electrolyte imbalance and osmotic stress, particularly in the kidneys. This study aimed to evaluate tissue levels and hemodynamic and renal effects of betaine in normotensive and hypertensive rats. Betaine levels were assessed using highperformance liquid chromatography-mass spectrometry (HPLC-MS) in normotensive rats (Wistar-Kyoto, WKYs) and Spontaneously Hypertensive rats (SHRs), a model of genetic hypertension. Acute effects of IV betaine on blood pressure, heart rate, and minute diuresis were evaluated. Gene and protein expression of chosen kidney betaine transporters (SLC6a12 and SLC6a20) were assessed using real-time PCR and Western blot. Compared to normotensive rats, SHRs showed significantly lower concentration of betaine in blood serum, the lungs, liver, and renal medulla. These changes were associated with higher urinary excretion of betaine in SHRs (0.20 ± 0.04 vs. 0.09 ± 0.02 mg/ 24h/ 100g b.w., p = 0.036). In acute experiments, betaine increased diuresis without significantly affecting arterial blood pressure. The diuretic response was greater in SHRs than in WKYs. There were no significant differences in renal expression of betaine transporters between WKYs and SHRs. Increased renal excretion of betaine contributes to decreased concentration of the protective osmolyte in tissues of hypertensive rats. These findings pave the way for studies evaluating a causal relation between depleted betaine and hypertensive organ damage, including kidney injury

Microbiota and Malodor—Etiology and Management

Accumulating evidence indicates that microbiota plays a critical role in physiological processes in humans. However, it might also contribute to body malodor by producing numerous odorous molecules such as ammonia, volatile sulfur compounds or trimethylamine. Although malodor is commonly overlooked by physicians, it constitutes a major problem for many otherwise healthy people. Thus, this review aims to investigate most common causes of malodor and describe potential therapeutic options. We searched PUBMED and Google Scholar databases to identify the clinical and pre-clinical studies on bad body smell, malodor, halitosis and microbiota. Unpleasant smell might originate from the mouth, skin, urine or reproductive fluids and is usually caused by odorants that are produced by resident bacterial flora. The accumulation of odorous compounds might result from diet, specific composition of microbiota, as well as compromised function of the liver, intestines and kidneys. Evidence-based guidelines for management of body malodor are lacking and no universal treatment exists. However, the alleviation of the symptoms may be achieved by controlling the diet and physical elimination of bacteria and/or accumulated odorants

Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease

Actions of symbiotic gut microbiota are in dynamic balance with the host’s organism to maintain homeostasis. Many different factors have an impact on this relationship, including bacterial metabolites. Several substrates for their synthesis have been established, including tryptophan, an exogenous amino acid. Many biological processes are influenced by the action of tryptophan and its endogenous metabolites, serotonin, and melatonin. Recent research findings also provide evidence that gut bacteria-derived metabolites of tryptophan share the biological effects of their precursor. Thus, this review aims to investigate the biological actions of indole-3-propionic acid (IPA), a gut microbiota-derived metabolite of tryptophan. We searched PUBMED and Google Scholar databases to identify pre-clinical and clinical studies evaluating the impact of IPA on the health and pathophysiology of the immune, nervous, gastrointestinal and cardiovascular system in mammals. IPA exhibits a similar impact on the energetic balance and cardiovascular system to its precursor, tryptophan. Additionally, IPA has a positive impact on a cellular level, by preventing oxidative stress injury, lipoperoxidation and inhibiting synthesis of proinflammatory cytokines. Its synthesis can be diminished in the presence of different risk factors of atherosclerosis. On the other hand, protective factors, such as the introduction of a Mediterranean diet, tend to increase its plasma concentration. IPA seems to be a promising new target, linking gut health with the cardiovascular system

Performance of a Computational Phenotyping Algorithm for Sarcoidosis Using Diagnostic Codes in Electronic Medical Records: Case Validation Study From 2 Veterans Affairs Medical Centers.

BackgroundElectronic medical records (EMRs) offer the promise of computationally identifying sarcoidosis cases. However, the accuracy of identifying these cases in the EMR is unknown.ObjectiveThe aim of this study is to determine the statistical performance of using the International Classification of Diseases (ICD) diagnostic codes to identify patients with sarcoidosis in the EMR.MethodsWe used the ICD diagnostic codes to identify sarcoidosis cases by searching the EMRs of the San Francisco and Palo Alto Veterans Affairs medical centers and randomly selecting 200 patients. To improve the diagnostic accuracy of the computational algorithm in cases where histopathological data are unavailable, we developed an index of suspicion to identify cases with a high index of suspicion for sarcoidosis (confirmed and probable) based on clinical and radiographic features alone using the American Thoracic Society practice guideline. Through medical record review, we determined the positive predictive value (PPV) of diagnosing sarcoidosis by two computational methods: using ICD codes alone and using ICD codes plus the high index of suspicion.ResultsAmong the 200 patients, 158 (79%) had a high index of suspicion for sarcoidosis. Of these 158 patients, 142 (89.9%) had documentation of nonnecrotizing granuloma, confirming biopsy-proven sarcoidosis. The PPV of using ICD codes alone was 79% (95% CI 78.6%-80.5%) for identifying sarcoidosis cases and 71% (95% CI 64.7%-77.3%) for identifying histopathologically confirmed sarcoidosis in the EMRs. The inclusion of the generated high index of suspicion to identify confirmed sarcoidosis cases increased the PPV significantly to 100% (95% CI 96.5%-100%). Histopathology documentation alone was 90% sensitive compared with high index of suspicion.ConclusionsICD codes are reasonable classifiers for identifying sarcoidosis cases within EMRs with a PPV of 79%. Using a computational algorithm to capture index of suspicion data elements could significantly improve the case-identification accuracy