Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome

Abstract

Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.

Consequences of bile salt biotransformations by intestinal bacteria

“…75 It was also found that the baiJ gene was in high abundance, consistent with C. sordellii levels. 73 We reported the baiJKL operon in C. hylemonae and C. scindens which encodes a bile acid CoA transferase (baiK) with similar function and to the baiF gene, a homolog on the baiBCDEAFGHI operon (Fig.…”

Gut microbiome development along the colorectal adenoma–carcinoma sequence

“…B. wadsworthia, in particular, utilizes taurine-conjugated bile acids in sulphite reduction, and promotes colitis in genetically susceptible mice (Il10 À / À ) 44 . Bile acids have also been shown to cause DNA damage and promote hepatocellular carcinoma in mice 45,46 . Future research would help elucidate how the known risk factors like diet, obesity and smoking collectively act on the gut microbiome in the development of colorectal carcinoma.…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Hepatocellular carcinoma (HCC) is one of the deadliest and most common cancers worldwide [69]. In the development of HCC, nutrition and metabolic related factors like alcohol consumption, aflatoxin contamination in food [70], the gut microbiota [71], diabetes [72] and bodyweight [73] influence initiation and progression of HCC. To treat HCC is difficult, because its onset often occurs on top of an underlying liver disease such as hepatitis B or C virus infection, alcoholic liver disease, or non-alcoholic fatty liver disease.…”