Modulation of intestinal microbiota by glycyrrhizic acid prevents high-fat diet-enhanced pre-metastatic niche formation and metastasis

Abstract

High-fat diet (HFD) promotes lung pre-metastatic niche formation and metastasis. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. Here we demonstrate that glycyrrhizic acid (GA) prevents HFDenhanced pre-metastatic niche formation and metastasis through gut microbiota. GA reduced HFD-enhanced myeloid-derived suppressor cell recruitment, pro-metastatic protein S100A8/A9 expression and metastasis burden of 4T1 breast cancer and B16F10 melanoma, accompanied by gut microbiota alteration and colonic macrophage polarization far away the M1-like phenotype. These parameters were greatly decreased by treatment with antibiotics, recolonization of Desulfovibrio vulgaris and Clostridium sordellii, and administration of lipopolysaccharide or deoxycholic acid. Macrophage depletion attenuated HFD-enhanced pre-metastatic niche formation and metastasis, but failed to further affect the effects of GA. Mechanistically, counteraction of HFD-enhanced gut microbiota dysbiosis by GA inhibited Gr-1 + myeloid cell migration and S100A8/A9 expression through decreasing the proportion of M1-like macrophages and their production of CCL2 and TNF-α in the colons via LPS/HMGB1/NF-κB signaling inactivation. Together, targeting the gut microbiota by GA to modulate colonic macrophages could be a novel strategy for the prevention of HFDenhanced pre-metastatic niche formation and metastasis.

Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

“…Several studies have described the ability of immunomodulatory drugs to modulate the gut microbiota, inducing dysbiosis [44] or improving the dysbiotic condition found in several pathologies [45]. Last year, the way in which gut dysbiosis is displayed in DOCA-salt hypertension was reported [8,9].…”

Regulation of Gut Microbiota and Metabolic Endotoxemia with Dietary Factors

“…In addition, Xie et al reported in mice that the increase of Desulfovibrio in feces was positively correlated with the increase of LPS levels in feces, liver, and blood [45]. Qui et al reported that ingestion of a high-fat diet in mice increased fecal Clostridium and Desulfovibrio , and oral administration of these bacteria to the normal chow-fed mice increased fecal and blood LPS levels [158]. These reports suggest that Desulfovibrio plays an important role as a source of LPS in the intestine.…”

Host–microbe cross-talk in the lung microenvironment: implications for understanding and treating chronic lung disease

“…High-fibre diets induce the production of short-chain fatty acids by gut bacteria, which are transported systemically to the lung, where they exert anti-inflammatory actions and ameliorate AAD in mice [47]. In contrast, a lipid-rich diet alters the microbiota and promotes metabolic inflammation [50], and has been associated with premetastatic niche development in lung cancer [51]. However, the detailed mechanisms of action remain unclear.…”