A new study published today in The American Journal of Pathology found that mice fed a high-fat, high-sugar Western diet developed hepatic inflammation, which was more common in males than females and most pronounced in mice that also lacked a bile acid receptor known as farnesoid x receptor, or FXR.
The study is important because it links diet to changes in the gut microbiota as well as bile acid profile, opening the possibility that probiotics and bile acid receptor agonists may be useful for the prevention and treatment of hepatic inflammation and progression into advanced liver diseases such as cancer.
“We know the transition from steatosis, or fatty liver, to steatohepatitis (inflammation in the fatty liver) plays a crucial role in liver injury and carcinogenesis. Because the liver receives 70 percdent of its blood supply from the intestine, it is important to understand how the gut contributes to liver disease development,” explained lead investigator Yu-Jui Yvonne Wan, professor and vice chair of the Department of Pathology and Laboratory Medicine at UC Davis Health.
“Our data show that diet, gender, and different antibiotic treatments alter the gut microbiota as well as bile acid profile and have different effects on liver inflammation," she said.
Wan and her team used an FXR-deficient mouse model (FXR KO), which has become an important tool to better understand the role of diet and inflammation in the development of liver diseases including cancer because patients with cirrhosis or liver cancer also have low FXR levels.
Other published data have already shown that FXR-deficient mice spontaneously develop steatohepatitis and liver tumors even when they are fed a normal rodent diet. In this study, wild-type and FXR-deficient mice were fed either a Western diet or a matching control diet for 10 months. They found similarities between Western diet intake and FXR deficiency. For instance, both Western diet–fed wild-type mice and control diet–fed FXR KO mice developed steatosis, which also was more severe in males than females. Interestingly, however, only the FXR-deficient male mice had massive lymphocyte and neutrophil infiltration in the liver, and only Western diet–fed male FXR KO mice had fatty adenomas.
“These studies show that a Western diet intake and FXR inactivation also increased hepatic inflammatory signaling, with a combined enhanced effect,” Wan said. “Introducing antibiotics to reduce inflammation also had different effects based on the diets the mice received.”
Depending on the type of diet mice received, broad-spectrum antibiotics, which eliminated most gut bacteria, affected hepatic inflammation in FXR-deficient mice differently. In control diet–fed mice, a cocktail of ampicillin, neomycin, metronidazole and vancomycin completely blocked hepatic neutrophil and lymphocyte infiltration. However, this cocktail of antibiotics (Abx) was not able to eliminate hepatic inflammation in Western diet–fed FXR KO mice. Additional analysis showed that many inflammatory genes had higher expression levels in Western diet than control diet–fed FXR KO mice after Abx treatment.
Analyzing the composition of the gut microbiota, investigators found that Proteobacteria and Bacteroidetes persisted after broad-spectrum antibiotic treatment in Western diet–fed FXR KO mice. In contrast, Gram-negative coverage antibiotic (i.e., polymyxin B) increased Firmicutes and decreased Proteobacteria as well as hepatic inflammation in Western diet–fed FXR KO male mice. They suggest that the adverse effects of Western diet on the liver may be explained in part by the persistence of pro-inflammatory Proteobacteria as well as the reduction of anti-inflammatory Firmicutesin the gut.
Primary and secondary bile acids are synthesized by liver cells and gut bacteria, respectively. Bile acids are signaling molecules for lipid and sugar homeostasis as well as inflammatory response. The data generated from this group revealed that the reduced hepatic inflammation by antibiotics was accompanied by decreased free and conjugated secondary bile acids in a gender-dependent manner.
“Gut and liver health are linked,' Wan said. "It is clear that microbial imbalance and dysregulated bile acid synthesis are inseparable, and they jointly contribute to hepatic inflammation via the gut-liver axis. Gut microbiota and bile acid profiles also may explain gender differences in liver disease, as liver cancer incidence is much higher in men than women. Moreover, in antibiotic-treated mice, the change in the profile of bile acids can also be primary as well as secondary to the alterations in gut microbiota because antibiotics can directly eliminate bile acid–generating bacteria, which in turn causes additional changes in the bile acid composition. Our results suggest that probiotics and FXR agonists hold promise for the prevention and treatment of hepatic inflammation and progression into advanced liver diseases such as cancer.”
The article is “Western Diet–Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment,” by Prasant K. Jena, Lili Sheng, Hui-Xin Liu, Karen M. Kalanetra, Annie Mirsoian, William J. Murphy, Samuel W. French, Viswanathan V. Krishnan, David A. Mills, and Yu-Jui Yvonne Wan (http://dx.doi.org/10.1016/j.ajpath.2017.04.019). It will appear in The American Journal of Pathology, volume 187, issue 8 (August 2017) published by Elsevier.
This research was supported by National Institutes of Health grant U01CA179582.