Attenuated portal hypertension in germ‐free mice: Function of bacterial flora on the development of mesenteric lymphatic and blood vessels

Abstract

Intestinal bacterial flora may induce splanchnic hemodynamic and histological alterations that are associated with portal hypertension (PH). We hypothesized that experimental PH would be attenuated in the complete absence of intestinal bacteria. We induced prehepatic PH by partial portal vein ligation (PPVL) in germ‐free (GF) or mice colonized with altered Schaedler's flora (ASF). After 2 or 7 days, we performed hemodynamic measurements, including portal pressure (PP) and portosystemic shunts (PSS), and collected tissues for histomorphology, microbiology, and gene expression studies. Mice colonized with intestinal microbiota presented significantly higher PP levels after PPVL, compared to GF, mice. Presence of bacterial flora was also associated with significantly increased PSS and spleen weight. However, there were no hemodynamic differences between sham‐operated mice in the presence or absence of intestinal flora. Bacterial translocation to the spleen was demonstrated 2 days, but not 7 days, after PPVL. Intestinal lymphatic and blood vessels were more abundant in colonized and in portal hypertensive mice, as compared to GF and sham‐operated mice. Expression of the intestinal antimicrobial peptide, angiogenin‐4, was suppressed in GF mice, but increased significantly after PPVL, whereas other angiogenic factors remained unchanged. Moreover, colonization of GF mice with ASF 2 days after PPVL led to a significant increase in intestinal blood vessels, compared to controls. The relative increase in PP after PPVL in ASF and specific pathogen‐free mice was not significantly different. Conclusion: In the complete absence of gut microbial flora PP is normal, but experimental PH is significantly attenuated. Intestinal mucosal lymphatic and blood vessels induced by bacterial colonization may contribute to development of PH. (Hepatology 2015;61:1685‐1695)

The Gastrointestinal Circulation: Physiology and Pathophysiology

“…These apocynin-induced responses were accompanied by reductions in vessel proliferation, VEGF and VEGFR-2 protein levels, and vascular superoxide formation, suggesting that superoxide (perhaps by inactivating NO) contributes to a proangiogenic mechanism that involves VEGF and its receptor VEGFR-2. Studies of CPH in germ-free mice also implicate a role for intestinal bacteria (and/or their products) in the development of portosystemic collaterals and in the genesis of portal hypertension (337).…”

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

“…Germ-free mice that lack intestinal bacteria have relatively lower blood pressure when compared with conventional mice [91] and fecal transplantation from hypertensive human donors to germ-free mice elevates blood pressure in these animals [90], suggesting that the gut flora influences blood pressure. In addition, rat studies and randomized clinical trials suggest that administration of probiotics can reduce blood pressure [92,93].…”

Microbiota and the liver

“…Modulation of the gut microbiota via the administration of antibiotics and probiotics have shown promising results in hemodynamic changes in clinical studies of portal hypertension . To further delineate the role of the gut microbiota, Moghadamrad et al showed that in an experimental model of portal hypertension induced by partial portal vein ligation, germ‐free mice exhibited attenuated portal pressures compared with colonized mice . The authors observed decreased intestinal vascular and lymphatic vessel formation in germ‐free mice after partial portal vein ligation that may partially explain attenuated portal hypertension from decreased inflow.…”