Western Diet Linked to Microbiome Changes and Chronic Liver Inflammation

(A) Histology of control diet (CD) and Western diet (WD)-fed wild-type (WT) and FXR knockout (KO) mice of both genders. (B) Histology of antibiotic-treated male mice. Abx is a cocktail of antibiotics that provides broad-spectrum coverage. Vancomycin (Vcm) and polymyxin B (PolyB) cover Gram-positive and Gram-negative bacteria, respectively. (C) Relative abundance of cecal microbiota of CD and WD-fed WT as well as FXR KO mice of both genders. (D) Relative abundance of cecal microbiota of antibiotic-treated CD- and WD-fed FXR KO male mice. (Mean values are shown). [The American Journal of Pathology]

The typical western diet, which is high in fat and sugar, has long been suspected to have a negative impact on human health. Now, a team of investigators at UC Davis has just released new findings  showing that a Western diet fed to mice resulted in hepatic inflammation, especially in males. Results from the new study—published today in The American Journal of Pathology in an article entitled “Western Diet–Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment”—also showed that liver inflammation was most obvious in Western diet–fed male mice that also lacked the  bile acid receptor, farnesoid X (FXR). Reduced levels of FXR are often seen in patients with liver cancer and cirrhosis.  

“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,” explained senior study investigator Yu-Jui Yvonne Wan, Ph.D., professor and vice chair of the department of pathology and laboratory medicine at UC Davis Health. “Because the liver receives 70% of its blood supply from the intestine, it is important to understand how the gut contributes to liver disease development. 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.”

The findings from this new study are impactful since they link 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.

The researchers employed the use of an FXR-deficient mouse model (FXR KO), which has become a central tool for better understanding the role of diet and inflammation in the development of liver diseases, including cancer.

The authors wrote that their new study analyzed “the effect of diet through microbiota that affects hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin).”

Contingent on what type of diet was provided, broad-spectrum antibiotics, which eliminated most gut bacteria, affected hepatic inflammation differently in FXR-deficient mice. In control diet–fed mice, the antibiotic cocktail completely blocked hepatic neutrophil and lymphocyte infiltration. However, this cocktail was unable to eliminate hepatic inflammation in Western diet–fed FXR KO mice. Additional analysis showed that many inflammatory genes had higher expression levels in the Western diet than control diet–fed FXR KO mice after Abx treatment.

“These studies show that a Western diet intake and FXR inactivation also increased hepatic inflammatory signaling, with a combined enhanced effect,” Dr. Wan noted.

Interestingly, once the investigators analyzed the composition of the gut microbiota, they found that various microbial species from Proteobacteria and Bacteroidetes phyla persisted after the broad-spectrum antibiotic treatment in the Western diet–fed FXR KO mice. Conversely, 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. The researchers surmised that the adverse effects of Western diet on the liver might be explained in part by the persistence of pro-inflammatory Proteobacteria as well as the reduction of anti-inflammatory Firmicutes in the gut.

Moreover, the research team found that the reduced hepatic inflammation by antibiotics was accompanied by decreased free and conjugated secondary bile acids in a gender-dependent manner. Primary and secondary bile acids are synthesized by liver cells and gut bacteria, respectively, and are considered signaling molecules for lipid and sugar homeostasis as well as inflammatory response.

“Gut and liver health are linked,” remarked Dr. Wan. “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. In addition, gut microbiota and bile acid profiles may explain the gender difference in liver disease, as liver cancer incidence is much higher in men than in women.

Dr. Wan continued, stating that “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.”