Modulating phenylalanine metabolism by L. acidophilus alleviates alcohol-related liver disease through enhancing intestinal barrier function

BackgroundImpaired metabolic functions of gut microbiota have been demonstrated in alcohol-related liver disease (ALD), but little is known about changes in phenylalanine metabolism.MethodsBacterial genomics and fecal metabolomics analysis were used to recognize the changes of phenylalanine metabolism and its relationship with intestinal flora. Intestinal barrier function was detected by intestinal alkaline phosphatase (IAP) activity, levels of tight junction protein expression, colonic inflammation and levels of serum LPS. Lactobacillus acidophilus was chosen to correct phenylalanine metabolism of ALD mice by redundancy analysis and Pearson correlation analysis.ResultsUsing 16S rRNA sequencing and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods, we identified elevated levels of phenylalanine and its' metabolites in the gut of alcohol-fed mice compared to control mice and were negatively correlated with the abundance of Lactobacillus, which mainly metabolized phenylalanine. The intestinal phenylalanine level was positively correlated with the colon inflammatory factors TNF-alpha and IL-6, and negatively correlated with ZO-1 and Occludin. While intestinal alkaline phosphatase (IAP) activity was negatively correlated with the colon inflammatory factors TNF-alpha, IL-6 and MCP-1, and positively correlated with ZO-1 and Occludin. Increased phenylalanine inhibited IAP activity, blocked LPS dephosphorylation, increased colonic inflammation and bacterial translocation. Phenylalanine supplementation aggravated alcohol-induced liver injury and intestinal barrier dysfunction. Among the 37 Lactobacillus species, the abundance of Lactobacillus acidophilus was most significantly decreased in ALD mice. Supplementation with L. acidophilus recovered phenylalanine metabolism and protected mice from alcohol-induced steatohepatitis.ConclusionsRecovery of phenylalanine metabolism through the oral supplementation of L. acidophilus boosted intestinal barrier integrity and ameliorated experimental ALD.

Automated summary

Impaired phenylalanine metabolism and its relationship with gut microbiota in alcohol-related liver disease (ALD) were investigated. Elevated levels of phenylalanine and its metabolites were found in the intestines of alcohol-fed mice, negatively correlated with the abundance of Lactobacillus. Phenylalanine levels were correlated with colon inflammation and intestinal barrier dysfunction, while oral supplementation of L. acidophilus improved phenylalanine metabolism and protected mice from ALD.