an-vivo-method-for-evaluating-gut-blood-barrier-liver-metabolism

An <em>In Vivo</em> Method for Evaluating the Gut-Blood Barrier and Liver Metabolism of Microbiota Products

The gut-blood barrier (GBB) controls the passage of nutrients, bacterial metabolites and drugs from intestinal lumen to the bloodstream. The GBB integrity ...

Medical University of Warsaw

Hydrogen sulfide, a toxic gas, at low concentrations is also a biological mediator in animals. In the colon, hydrogen sulfide is produced by intestinal tissues and gut sulfur bacteria. Gut-derived molecules undergo liver metabolism. Portal hypertension is one of the most common complications contributing to the high mortality in liver cirrhosis. We hypothesized that the colon-derived hydrogen sulfide may affect portal blood pressure. Sprague-Dawley rats were maintained either on tap water (controls) or on water solution of thioacetamide to produce liver cirrhosis (CRH-R). Hemodynamics were measured after administration of either saline or NaS, a hydrogen sulfide donor, into (1) the colon, (2) the portal vein, or (3) the femoral vein. Expression of enzymes involved in hydrogen sulfide metabolism was measured by RT-PCR. CRH-R showed a significantly higher portal blood pressure but a lower arterial blood pressure than controls. Saline did not affect hemodynamic parameters. In controls, intracolonic hydrogen sulfide decreased arterial blood pressure and portal blood flow but increased portal blood pressure. Similarly, hydrogen sulfide administered into the portal vein decreased arterial blood pressure but increased portal blood pressure. In contrast, hydrogen sulfide administered into the systemic vein decreased both arterial and portal blood pressures. CRH-R showed significantly greater responses to hydrogen sulfide than controls. CRH-R had a significantly higher liver concentration of hydrogen sulfide but lower expression of rhodanese, an enzyme converting hydrogen sulfide to sulfate. In conclusion, colon-administered hydrogen sulfide increases portal blood pressure while decreasing the systemic arterial blood pressure. The response to hydrogen sulfide is more pronounced in cirrhotic rats which show reduced hydrogen sulfide liver metabolism. Therefore, colon-derived hydrogen sulfide may be involved in the regulation of portal blood pressure, and may contribute to portal hypertension. Impact statement Accumulating evidence suggests that gut-derived molecules affect the control of the circulatory system. Mechanisms controlling liver circulation have been profoundly studied; however, the effects of gut bacteria-derived molecules on portal blood pressure have not been established. In the colon, hydrogen sulfide is produced by intestinal tissues and gut sulfur bacteria. We found that colon-administered hydrogen sulfide increases portal blood pressure while decreasing the systemic arterial blood pressure. The hemodynamic response to hydrogen sulfide was more pronounced in cirrhotic rats which showed reduced hydrogen sulfide liver metabolism, i.e. lower expression of rhodanese, an enzyme converting hydrogen sulfide to sulfate. We propose that colon-derived hydrogen sulfide may affect the regulation of portal and arterial blood pressures and may be involved in portal hypertension.

Colonic hydrogen sulfide produces portal hypertension and systemic hypotension in rats.

An increased blood trimethylamine N-oxide (TMAO) has emerged as a marker of cardiovascular mortality, however, the mechanisms of the increase are not clear. We evaluated if hypertension was associated with changes in the colon permeability to trimethylamine (TMA), a TMAO precursor. We did experiments on male, 24-26-week-old normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and SHR treated with enalapril, an antihypertensive drug (SHR-E). To check the colon permeability and liver TMA clearance, blood was collected from the portal vein and hepatic veins confluence, at baseline and after the intracolonic administration of TMA. Arterial blood pressure (BP) and intestinal blood flow (IBF) recordings and histological assessment of the colon were performed. SHR showed an increased gut-blood barrier permeability to TMA. Namely, at baseline SHR had a higher BP and portal blood TMA, but a lower IBF than WKY. After the intracolonic administration of TMA, SHR had a significantly higher portal blood TMA and higher TMA liver clearance than WKY. In SHR the arteriolar walls of the colon mucosa were significantly thicker than in WKY. Furthermore, SHR showed a significant decrease in the height of the mucosa. In contrast, SHR-E had lower portal blood TMA, lower BP and smaller thickness of arteriolar walls, but higher IBF than SHR, which indicates improved function of the gut-blood barrier in SHR-E. All groups had similar immunostaining of occludin and zonula occludens-1, markers of tight junctions. In conclusion, hypertensive rats show an increased permeability of the colon to TMA, which is accompanied by morphological and hemodynamic alterations in the colon. Therefore, cardiovascular diseases may be characterized by an increased permeability of the gut-blood barrier to bacterial metabolites such as TMA.

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

A high-salt diet is considered a cardiovascular risk factor; however, the mechanisms are not clear. Research suggests that gut bacteria-derived metabolites such as trimethylamine N-oxide (TMAO) are markers of cardiovascular diseases. We evaluated the effect of high salt intake on gut bacteria and their metabolites plasma level.

Article	Year
Colonic hydrogen sulfide produces portal hypertension and systemic hypotension in rats. Experimental biology and medicine (Maywood, N.J.)\| PubMed ID: 29130338	2018
Hypertension in rats is associated with an increased permeability of the colon to TMA, a gut bacteria metabolite. PloS one\| PubMed ID: 29236735	2017
High salt intake increases plasma trimethylamine N-oxide (TMAO) concentration and produces gut dysbiosis in rats. Nutrition (Burbank, Los Angeles County, Calif.)\| PubMed ID: 29705499	2018

Kinga Jaworska

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