The Type of Dietary Fat Modulates Intestinal Tight Junction Integrity, Gut Permeability, and Hepatic Toll‐Like Receptor Expression in a Mouse Model of Alcoholic Liver Disease

Abstract

Background Interactions between the gut, immune system, and the liver, as well as the type of fat in the diet, are critical components of alcoholic liver disease (ALD). The goal of the present study was to determine the effects of saturated and unsaturated fat on ethanol-induced gut-liver interactions in a mouse model of ALD. Methods C57BL/6N mice were fed Lieber-DeCarli liquid diets containing EtOH and enriched in unsaturated (USF, corn oil) or saturated fat (SF, MCT:beef tallow). Control mice were pair-fed on an isocaloric basis. Liver injury and steatosis, blood endotoxin levels, intestinal permeability and tight junction (TJ) integrity, as well as hepatic Toll-like receptor (TLR) gene expression were evaluated. Results After 8 weeks of EtOH feeding liver injury and steatosis were observed in USF+EtOH group compared to control and SF+EtOH. Significantly increased intestinal permeability in conjunction with elevated blood endotoxin levels were observed in the ileal segments of the mice fed USF+EtOH. USF diet alone resulted in down-regulation of intestinal TJ protein mRNA expression compared to SF. Importantly, alcohol further suppressed TJ proteins in USF+EtOH but did not affect intestinal TJ in SF+EtOH group. The type of fat in the diet alone did not affect hepatic TLR expression. Compared to control animals, hepatic TLR (TLR 1, 2, 3, 4, 7, 8, 9) mRNA expression was significantly (p<0.05) increased in USF+EtOH, but not in SF+EtOH group. Notably, TLR5 was the only up-regulated TLR in both SF+EtOH and USF+EtOH groups. Conclusions Dietary fat is an important cofactor in alcohol-associated liver injury. We demonstrate that unsaturated fat (corn oil/linoleic acid) by itself results in dysregulation of intestinal TJ integrity leading to increased gut permeability, and alcohol further exacerbates these alterations. We postulate that elevated blood endotoxin levels in response to unsaturated fat and alcohol in conjunction with up-regulation of hepatic TLRs combine to cause hepatic injury in ALD.

Nonalcoholic Fatty Liver Disease, the Gut Microbiome, and Diet

“…Another mechanism by which the gut microbiota contributes to the development of NAFLD may be through increasing the number of ethanol-producing bacteria (e.g., Escherichia coli) (15). These bacteria produce alcohol, which could participate in the disruption of gut permeability, the generation of ROS, and consequently, liver inflammation (41,42). However, the specific mechanisms of this hypothesis require further investigation.…”

Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats

“…Dietary saturated fat reduced alcoholic hepatotoxicity in rats by altering fatty acid metabolism and membrane composition (38). Recent studies showed that dietary fats differentially modulate the intestinal tight junctions and hepatic inflammatory response, suggesting that dietary fats have an impact on the gut-liver axis (16). Although saturated fats have been shown to attenuate alcohol-induced endotoxemia and hepatic inflammation, the mechanisms have not been fully defined.…”

“…Studies of alcohol exposure with dietary fats enriched with saturated fatty acids have been shown to produce much less liver damage compared with the originally used unsaturated fatty acids. These studies applied saturated fatty acids with different carbon chain lengths, including medium-chain triglycerides (MCT) (17, 22, 24, 30 -32), long-chain saturated fats (cocoa butter, CB) (47,48), or a mixture of long-chain saturated fats and monounsaturated fats (beef tallow) (16,38). However, whether saturated fat sources with different chain lengths make a difference in protection against alcohol-induced liver injury has not been elucidated.…”

Ethane-β-Sultam Modifies the Activation of the Innate Immune System Induced by Intermittent Ethanol Administration in Female Adolescent Rats

“…There is an inability of white cells to migrate to the site of infection or inflammation, as well as functional changes in lymphocytes, [6] natural killer cells, monocytes and macrophages [7] . In addition, alcohol will increase the permeability of the gut; such that gut derived endotoxins will be transported to the liver via the portal vein to stimulate tolllike receptors to induce inflammation and the release of damaging pro-inflammatory cytokines [8]. The release of pro-inflammatory cytokines will activate phagocytic cells, such as macrophages and microglia and induce inflammation in both the liver [9] and specific brain regions [10].…”