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 high-performance 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.

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.

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.

BACKGROUND: Electronic medical records (EMRs) offer the promise of computationally identifying sarcoidosis cases. However, the accuracy of identifying these cases in the EMR is unknown. OBJECTIVE: The 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: ICD 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.

Genetically determined hypertensive phenotype affects gut microbiota composition, but not vice versa.

OBJECTIVES: Research suggests reciprocal crosstalk between the host and gut bacteria. This study evaluated the interaction between gut microbiota and arterial blood pressure (BP) in rats. METHODS: Continuous telemetry recordings of BP were started in 7-week-old normotensive Wistar--Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Two weeks later, half of the WKY and SHR were subjected to cross-transplantation of fecal matter, with stools harvested from either WKY or SHR and BP measurements until the age of 14 weeks. The composition of gut bacteria was assessed through analysis of the bacterial 16S ribosomal RNA gene sequence. The concentration of microbiota-derived metabolites was evaluated using HPLC-MS. RESULTS: There was a significant difference between WKY and SHR in the composition of gut bacteria at the start and end of the study. This was accompanied by significant histological differences in the colon. SHR, but not WKY, showed a gradual increase in BP throughout the experiment. For both WKY and SHR, there was no significant difference in BP or metabolic parameters between animals receiving fecal transplantation from either SHR or WKY. CONCLUSION: Genetically induced hypertension in SHR is associated with alterations in the composition of gut bacteria and histological morphology of the colon. An inter-strain fecal transplant does not affect BP and does not produce long-term changes in gut bacteria composition. We propose that the impact of the host genotype and/or phenotype on the gut bacteria may be greater than the impact of the gut bacteria on the host BP.

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.

TMAO, a seafood-derived molecule, produces diuresis and reduces mortality in heart failure rats.

Trimethylamine-oxide (TMAO) is present in seafood which is considered to be beneficial for health. Deep-water animals accumulate TMAO to protect proteins, such as lactate dehydrogenase (LDH), against hydrostatic pressure stress (HPS). We hypothesized that TMAO exerts beneficial effects on the circulatory system and protects cardiac LDH exposed to HPS produced by the contracting heart. Male, Sprague-Dawley and Spontaneously-Hypertensive-Heart-Failure (SHHF) rats were treated orally with either water (control) or TMAO. In vitro, LDH with or without TMAO was exposed to HPS and was evaluated using fluorescence correlation spectroscopy. TMAO-treated rats showed higher diuresis and natriuresis, lower arterial pressure and plasma NT-proBNP. Survival in SHHF-control was 66% vs 100% in SHHF-TMAO. In vitro, exposure of LDH to HPS with or without TMAO did not affect protein structure. In conclusion, TMAO reduced mortality in SHHF, which was associated with diuretic, natriuretic and hypotensive effects. HPS and TMAO did not affect LDH protein structure.

Heart failure is a common cause of death in industrialized countries with aging populations. Japan, however, has lower rates of heart failure and fewer deaths linked to this disease than the United States or Europe, despite having the highest proportion of elderly people in the world. Dietary differences between these regions may explain the lower rate of heart failure in Japan. The Japanese diet is rich in seafood, which contains nutrients that promote heart health, such as omega-3 fatty acids. Seafood also contains other compounds, including trimethylamine oxide (TMAO). Fish that live in deep waters undergo high pressures, which can damage their proteins, but TMAO seems to protect the proteins from harm. In humans, eating seafood increases TMAO levels in the blood and urine, but it is unclear what effects this has on heart health. Increased levels of TMAO in the blood are associated with cardiovascular diseases, but scientists are not sure whether TMAO itself harms the heart. A toxic byproduct of gut bacteria called TMA is converted in TMAO in the body, so it is possible that TMA rather than TMAO is to blame. To assess the effects of dietary TMAO on heart failure, Gawrys-Kopczynska et al. fed the compound to healthy rats and rats with heart failure for one year. TMAO had no effects on the healthy rats. Of the rats with heart failure that were fed TMAO, all of them survived the year, while one third of rats with heart failure that were not fed TMAO died. TMAO-treated rats with heart failure had lower blood pressure and urinated more than untreated rats with the condition. The experiments suggest that dietary TMAO may mimic the effects of heart failure treatments, which remove excess water and salt and lower pressure on the heart. More studies are needed to confirm whether TMAO has this same effect on humans.

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.

Gut Mycobiota and Fungal Metabolites in Human Homeostasis.

BACKGROUND: Accumulating evidence suggests that microbiota play an important role in host's homeostasis. Thus far, researchers have mostly focused on the role of bacterial microbiota. However, human gut is a habitat for several fungal species, which produce numerous metabolites. Furthermore, various types of food and beverages are rich in a wide spectrum of fungi and their metabolites. METHODS: We searched PUBMED and Google Scholar databases to identify clinical and pre-clinical studies on fungal metabolites, composition of human mycobiota and fungal dysbiosis. RESULTS: Fungal metabolites may serve as signaling molecules and exert significant biological effects including trophic, anti-inflammatory or antibacterial actions. Finally, research suggests an association between shifts in gut fungi composition and human health. Changes in mycobiota composition have been found in obesity, hepatitis and inflammatory bowel diseases. CONCLUSION: The influence of mycobiota and dietary fungi on homeostasis in mammals suggests a pharmacotherapeutic potential of modulating the mycobiota which may include treatment with probiotics and fecal transplantation. Furthermore, antibacterial action of fungi-derived molecules may be considered as a substitution for currently used antibacterial agents and preservatives in food industry.