Daily Dose of Bovine Lactoferrin Prevents Ethanol‐Induced Liver Injury and Death in Male Mice by Regulating Hepatic Alcohol Metabolism and Modulating Gut Microbiota

Abstract

Scope Lactoferrin (Lf) possess a protective potential to liver, but whether it can prevent alcoholic liver injury (ALI) remains unclear. Methods and Results Four groups of male C57BL/6J mice are fed with different diets, namely, AIN‐93G diet for control (CON) and ethanol (EtOH) groups, and AIN‐93G diet with 0.4% and 4% casein replaced by Lf for low‐dose Lf (LLf) and high‐dose Lf (HLf) groups, respectively. ALI is induced by giving 20% ethanol ad libitum combined with four “binges”. Lf can remarkably decrease EtOH‐induced mortality. Lf promotes aldehyde dehydrogenase‐2 (ALDH2) expression and suppressing cytochrome P450 2E1 (CYP2E1) overexpression, resulting in the reduced hepatic superoxide and inflammation levels, which ultimately leads to the hepatic injury alleviation. However, HLf increases acetyl‐CoA carboxylase and fatty acid synthase protein levels, which suggests that excessive intake may weaken the beneficial effects of Lf. Moreover, LLf increases the relative abundances of Akkermansia and Lactobacillus. Additionally, the study shows that Lf likely exerts action in its digestive product forms rather than intact Lf molecular in normal condition. Conclusion LLf can ameliorate ALI, which is associated with the regulation of hepatic alcohol metabolism and the modulation of gut microbiota. However, excessive Lf intake may result in a diminished benefit.

Lactoferrin Alleviates Acute Alcoholic Liver Injury by Improving Redox-Stress Response Capacity in Female C57BL/6J Mice

“…Although superoxide is not a strong oxidant, it may be one of the most abundant ROS in the body, and it is a precursor of most other ROS . Thus, superoxide can reflect the total ROS level, at least to a certain extent . In our study, no hydroxyl radical and hydrogen peroxide ESR signals were captured, likely due to their relative low content.…”

“…These results indicated that our animal model of acute ALI is convincing. Unlike LLf, which has more obvious preventive effects in male mice, Lf pretreatment reduced the liver weights and serum transaminase levels in a dose-dependent manner and the differences were significant only in the HLf group. The ameliorating effects of HLf were more obvious on hepatic morphology than LLf, which illustrated that HLf pretreatment had more potent preventive effects of acute ALI for the female mice.…”

“…Therefore, we did not conduct the reductive stress-relevant experiments. Our previous study reported that gut microbiota modulation by Lf also plays a role in ALI in male mice, although it is weak . In the present study, we did not investigate gut microbiota based on the following three considerations.…”

“…Our previous study found that Lf prevents ALI in male mice mainly by regulating hepatic alcohol metabolism . Thus, we first investigated whether similar regulatory mechanisms were involved in the acute ALI prevention in female mice.…”

“…Some studies have reported that Lf exhibits fair application potentials in NAFLD. − Since AALD has an overlapping pathophysiology with NAFLD, it is likely that Lf has protective effects on AALD. Moreover, our previous study also demonstrated the preventive effects of Lf on ethanol-induced liver injury in male mice . However, this experimental model simultaneously mimicked acute and chronic alcoholic liver injury (ALI).…”