BISMUTH SUBSALICYLATE REVERSES HIGH FAT DIET-INDUCED INCREASE IN PORTAL VENOUS FLOW

Abstract

Abstract In animal studies, a high-fat diet (HFD) is associated with fatty liver disease and vascular complications characterized by hyperdynamic circulation. The underlying mechanism for these hemodynamic changes is not known. Hydrogen sulfide (H2S) is a gaseous signaling molecule that plays several roles including that of a vasodilator in the peripheral vascular system. H2S is produced by both mammalian cells and sulfate reducing bacteria (SRB). SRB in the gut are known to convert hydrogen, a by-product of bacterial fermentation, to H2S. Bismuth subsalicylate (BSS) lowers the availability of luminal H2S by binding directly to this gas in the gut lumen. In this study, we tested the hypothesis that a high fat diet may increase portal venous blood flow in a BSS-reversible fashion in rats (n = 8/group) fed one of 4 diets for 8 weeks: HFD, HFD + BSS, standard diet (SDD) and SDD + BSS. Portal venous blood flow was measured in laparotomized animals using a perivascular ultrasonic probe. To directly test the effect of H2S, portal venous blood flow was also compared before (baseline) and after infusing NaHS, a donor of H2S, into the jejunum. We found that baseline rates of portal venous blood flow were significantly greater in the HFD group [23.41 ± 0.4mL/min, p < 0.05] than SDD group [17.48 ± 0.2 mL/min], HFD + BSS [17.95 ± 0.3mL/min] or SDD + BSS [14.49 ± 0.2mL/min]. H2S donor increased portal venous blood flow significantly more in the HFD group [6.1 ± 0.26mL/min, p < 0.05] when compared to SDD group [1.88 ± 0.18mL/min], HFD + BSS [2.00 ± 0.40mL/min] or SDD + BSS [3.45 ± 0.34mL/min). qPCR using primers targeting the dissimilatory sulfite reductase beta-subunit (dsrB) of SRB ([NiFe] hydrogenase gene fragment), the phyla Firmicutes and Bacteroidetes showed no difference between groups in the distal small intestine. The liver enzymes AST and ALT were significantly elevated in the HFD group than HFD + BSS, SDD and SDD + BSS (p = 0.044, 0.011, respectively). In conclusion, an increase in portal venous blood flow consistent with a hyperdynamic circulation was observed in HFD-fed animals with a further increase induced by infusion of NaHS. In HFD-fed animals, the increase in portal venous blood flow at baseline and the further increase following NaHS infusion were both reversed by H2S-binding BSS administered to the gut supporting the conclusion that increased portal venous blood flow in HFD-fed animals was driven by gut bacteria-derived H2S.