Hypertension in rats is associated with an increased permeability of the colon to TMA, a gut bacteria metabolite

Jaworska, Kinga; Hutsch, Tomasz; Samborowska, Emilia; Dobrowolski, Leszek; Bielinska, Klaudia; Gawlak, Maciej; Ufnal, Marcin

doi:10.1371/journal.pone.0189310

Cited by 114 publications

(97 citation statements)

References 29 publications

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“…Also, in our previous studies we showed an increased concentration of bacterial metabolites in portal and systemic blood in animal models of portal hypertension and systemic hypertension (Jaworska et al, 2017). However, the concentration of bacterial metabolites in the blood depends strongly on gut bacterial composition and their metabolic activity shaped by diet, drugs, etc.…”

Section: Discussionmentioning

confidence: 85%

“…An increased permeability of the GBB, or a 'leaky gut' , is a pivotal symptom of gut malfunction and is present in numerous intestinal diseases, such as IBD, NEC or acute pancreatitis (Camilleri et al, 2012;Ravisankar et al, 2018;Sonika et al, 2017), and in extra-intestinal diseases, including heart failure (Sandek et al, 2007), hypertension (Jaworska et al, 2017;Santisteban et al, 2017), obesity (Bischoff et al, 2014) and diabetes (Carratu et al, 1999). Therefore, non-invasive evaluation of the GBB might be a promising method for diagnosis and treatment monitoring of diseases associated with GBB malfunction.…”

Section: Discussionmentioning

confidence: 99%

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Inflammatory bowel disease is associated with increased gut‐to‐blood penetration of short‐chain fatty acids: A new, non‐invasive marker of a functional intestinal lesion

Jaworska

Konop

Bielinska

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?‘Leaky gut’ has been found in intestinal and extra‐intestinal diseases. However, functional evaluation of intestinal permeability is not widely used as a diagnostic marker, possibly owing to significant limitations of currently used permeability assays. There is an unmet need for development of a new, non‐invasive test to assess intestinal function. What is the main finding and its importance?We show that an increased blood‐to‐stool ratio of the concentration of gut bacteria‐produced short‐chain fatty acids may be used as a marker of gut permeability. Our findings lay the groundwork for establishing a new, non‐invasive, risk‐free diagnostic tool in diseases associated with intestinal barrier malfunction, such as inflammatory bowel disease. Abstract Intestinal diseases, such as inflammatory bowel disease (IBD), are characterized by an impaired gut–blood barrier commonly referred to as ‘leaky gut’. Therefore, functional evaluation of the gut–blood barrier is a promising diagnostic marker. We hypothesized that short‐chain fatty acids (SCFAs) produced by gut bacteria might serve as a marker in IBD. Animal experiments were performed on male Sprague–Dawley rats with acetic acid‐induced colitis and in sham control animals. The gut–blood barrier permeability was determined by assessing the ratios of the following: (i) portal blood concentration of SCFAs (Cp) to faecal concentration of SCFAs (Cf); (ii) systemic blood concentration of SCFAs (Cs) to faecal concentration of SCFAs (Cf); and (iii) Cp and Cs of fluorescein isothiocyanate (FITC)–dextran administered into the colon. As a clinical study, we evaluated Cs, Cf and the Cs/Cf ratio of SCFAs in six paediatric patients with IBD, assessed as mild/moderate/severe by the Paediatric Ulcerative Colitis Activity Index (PUCAI) and the Paediatric Crohn's Disease Activity Index (PCDAI) at the time of sample collection, and nine age‐matched healthy control subjects. Rats with histologically confirmed IBD had significantly increased ratios of Cp/Cf and Cs/Cf for SCFAs. This was positively correlated with the plasma FITC–dextran concentration. Likewise, IBD patients showed a significantly higher Cs/Cf ratio for SCFAs, including acetic, valeric, isocaproic, caproic and propionic acids, in comparison to control subjects. In conclusion, in the rats and in paediatric patients with IBD we found an increased blood‐to‐stool ratio of SCFAs, suggesting an increased gut‐to‐blood penetration of SCFAs. These findings pave the way for a new, non‐invasive diagnostic tool in IBD and other diseases accompanied by intestinal barrier malfunction.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Inflammatory bowel disease is associated with increased gut‐to‐blood penetration of short‐chain fatty acids: A new, non‐invasive marker of a functional intestinal lesion

Jaworska

Konop

Bielinska

et al. 2019

Experimental Physiology

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“…Although a large body of evidence supports that TMAO is involved in atherosclerosis, the existing body of literature is sparse regarding TMAO and hypertension. Only in HT rats an increased permeability of the colonic gut-blood barrier to TMA, the main TMAO precursor, has been evidenced 47 , but the role of TMAO in HT humans remains unclear.…”

Section: Tmao In Plasma No Significant Differences In Fasting Tmao Cmentioning

confidence: 99%

Gut metagenomic and short chain fatty acids signature in hypertension: a cross-sectional study

Calderón-Pérez

Gosalbes

Yuste

et al. 2020

Sci Rep

149

115

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Hypertension is an independent and preventable risk factor for the development of cardiovascular diseases, however, little is known about the impact of gut microbiota composition in its development. We carried out comprehensive gut microbiota analysis and targeted metabolomics in a cross-sectional study of 29 non-treated hypertensive (HT) and 32 normotensive (NT) subjects. We determined fecal microbiota composition by 16S rRNA gene sequencing and bacterial functions by metagenomic analysis. The microbial metabolites analysed were short chain fatty acids (SCFA) both in plasma and feces, and trimethylamine N-oxide (TMAO) in plasma. The overall bacterial composition and diversity of bacterial community in the two groups were not significantly different. However, Ruminococcaceae NK4A214, Ruminococcaceae_UCG-010, Christensenellaceae_R-7, Faecalibacterium prausnitzii and Roseburia hominis were found to be significantly enriched in NT group, whereas, Bacteroides coprocola, Bacteroides plebeius and genera of Lachnospiraceae were increased in HT patients. We found a positive correlation between the HT-associated species and systolic and diastolic blood pressure after adjusted for measured confounders. SCFA showed antagonistic results in plasma and feces, detecting in HT subjects significant higher levels in feces and lower levels in plasma, which could indicate a less efficient SCFA absorption. Overall, our results present a disease classifier based on microbiota and bacterial metabolites to discriminate HT individuals from NT controls in a first disease grade prior to drug treatment.Hypertension is one of the leading risk factors for the development of cardiovascular diseases (CVD) globally, and lifestyle measures are effective as a preventive strategies 1 . In 2015, hypertension based on office blood pressure (BP) reported the highest rates with a global prevalence of 1.13 billion cases, and 150 million in central and eastern Europe regardless of the income countries status 2-4 .The identification of the determinants of hypertension is still challenging although it is well recognized its multifactorial etiology 5 . It has been elucidated the interplay of genetic and environmental factors related with risk-conferring behaviors, such as, smoking, lack of physical activity, alcohol consumption and unhealthy diet 6,7 .Recently, it has been evidenced the role of gut microbiota dysbiosis on the modulation of high BP, both in animal and human hypertension 8 . Mell et al. (2015) were the first to demonstrate the differential fecal microbial composition of Dahl salt-sensitive and Dahl salt-resistant rats 9 . In the same period, Yang et al. (2015) also found a clear gut dysbiosis in spontaneously hypertensive rats (SHR) mediated by a decrease in microbial richness and open Scientific RepoRtS | (2020) 10:6436 | https://doi.org/10.1038/s41598-020-63475-w www.nature.com/scientificreports www.nature.com/scientificreports/ Scientific RepoRtS | (2020) 10:6436 | https://doi.org/10.1038/s41598-020-63475-w www.nature.com/scientificreports...

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“…It was explained that TMAO exerted an indirect effect on hypertension via prolonging the hypertensive effect of Ang II, an important hormone in hemodynamic regulation (). Furthermore, hypertension impairs gut–blood barrier and increases intestinal permeability of TMAO to blood circulation, making the situation worse (). These findings may strengthen the positive correlation between elevated plasm levels of TMAO and high risk of atherosclerotic events, which provides a potential reason for the development of hypertension ().…”

Section: The Influence Of Tmao On Risk Factors Of Atherosclerosismentioning

confidence: 99%

Gut microbiota in atherosclerosis: focus on trimethylamine N‐oxide

Zhu

Jiang

2020

APMIS

125

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in atherosclerosis: focus on trimethylamine N-oxide. APMIS 2020; 128: 353-366.The increasing prevalence of cardiovascular diseases cannot adequately be explained by traditional risk factors. Recently, accumulating evidence has suggested that gut microbiota-derived numerous metabolites are contributors to atherosclerotic events. Among them, the role of trimethylamine N-oxide (TMAO) in promoting atherosclerosis has gained attention. TMAO is reported to exert the proatherogenic effects by impacting on the traditional risk factors of atherosclerosis and is associated with high risk of cardiovascular events. Besides that, TMAO is involved in the complex pathological processes of atherosclerotic lesion formation, such as endothelial dysfunction, platelet activation and thrombus generation. In light of these promising findings, TMAO may serve as a potential target for atherosclerosis prevention and treatment, which is conceptually novel, when compared with existing traditional treatments. It is likely that regulating TMAO production and associated gut microbiota may become a promising strategy for the anti-atherosclerosis therapy.

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Hypertension in rats is associated with an increased permeability of the colon to TMA, a gut bacteria metabolite

Cited by 114 publications

References 29 publications

Inflammatory bowel disease is associated with increased gut‐to‐blood penetration of short‐chain fatty acids: A new, non‐invasive marker of a functional intestinal lesion

Inflammatory bowel disease is associated with increased gut‐to‐blood penetration of short‐chain fatty acids: A new, non‐invasive marker of a functional intestinal lesion

Gut metagenomic and short chain fatty acids signature in hypertension: a cross-sectional study

Gut microbiota in atherosclerosis: focus on trimethylamine N‐oxide

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