Mastiha (Pistacia lentiscus) Improves Gut Microbiota Diversity, Hepatic Steatosis, and Disease Activity in a Biopsy‐Confirmed Mouse Model of Advanced Non‐Alcoholic Steatohepatitis and Fibrosis

Abstract

ScopeAs a result of the obesity epidemic, the prevalence of non‐alcoholic steatohepatitis (NASH) is increasing. No drug is approved for the treatment of NASH. In this study, the effect of a nutritional supplement, Mastiha or Chios mastic gum, on metabolic and histological parameters and on the gut microbiome in mice with NASH and fibrosis was investigated.Methods and resultsAdvanced NASH was induced by feeding C57BL/6J mice a diet rich in fat, sucrose, and cholesterol for 41 weeks. After randomization, animals received the NASH‐inducing diet with or without 0.2% (w/w) Mastiha for a further 8 weeks. Disease activity was assessed by liver histology and determination of plasma transaminase activities. Fecal microbiota DNA extraction and 16S rRNA amplicon sequencing were used to determine the composition of the gut microbiome.Mastiha supplementation led to a significant reduction in circulating alanine aminotransferase (ALT) activity, improvement in hepatic steatosis and collagen content, and a reduction in NAFLD activity score. Furthermore, it resulted in a partial but significant recovery of gut microbiota diversity and changes in identity and abundance of specific taxa.ConclusionThis is the first study demonstrating an improvement in disease activity in mice with advanced NASH with fibrosis by a diet containing Mastiha.

The Gut Microbiota and Its Metabolites, Novel Targets for Treating and Preventing Non‐Alcoholic Fatty Liver Disease

“…Mastiha or Chios mastic gum, a kind of natural food obtained from Pistacia lentiscus, was found to be beneficial in the treatment of advanced NASH in mice by decreasing alanine transaminase (ALT) level and NAS score. [100] It is noteworthy that Mastiha treated mice exhibit a recovery of microbiome diversity and a slight change in gut microbiota composition. [100] In a rat model of NAFLD, the Chinese medicine Qushi Huayu decoction and its key bioactive compounds (geniposide and chlorogenic acid) significantly improved the gut barrier and decreased liver lipid synthesis by enhancing the enrichment of Treg-inducing bacteria and beneficial intestinal bacteria, suggesting a gut microbiota-modulated mechanism of herbal medicines in the treatment of NAFLD.…”

“…[100] It is noteworthy that Mastiha treated mice exhibit a recovery of microbiome diversity and a slight change in gut microbiota composition. [100] In a rat model of NAFLD, the Chinese medicine Qushi Huayu decoction and its key bioactive compounds (geniposide and chlorogenic acid) significantly improved the gut barrier and decreased liver lipid synthesis by enhancing the enrichment of Treg-inducing bacteria and beneficial intestinal bacteria, suggesting a gut microbiota-modulated mechanism of herbal medicines in the treatment of NAFLD. [101] Yang et al demonstrated that the major ingredients of the Dachaihu decoction, including Chinese thorowax, scutellaria, and white peony roots, reduce pro-inflammatory cytokine expression in the liver and maintain the intestinal barrier to protect against liver injury in www.advancedsciencenews.com www.mnf-journal.com Table 2.…”

“…Mice with advanced NASH ↓ ALT levels ↓ Hepatic steatosis ↓ Total hepatic cholesterol [ 100] QHD and GC Rats and mice fed with HFD ↓ Hepatic lipid synthesis ↓ Serum LPS level ↑ Gut barrier function [ 101] DCHD NASH rats fed a high-fat, high-fructose diet ↓ ALT and AST levels ↓ Liver coefficient ↓ Plasma endotoxin [ 102] Baicalin Mice fed with HFD ↓ Weight gain ↓ Hepatic steatosis ↓ Liver fat accumulation ↓ Hepatic TAG and cholesterol [ 103] Celastrol DIO and db/db mice ↓ Hepatic steatosis ↑ Insulin sensitivity ↓ ALT and AST levels [ 108] Ganoderma lucidum and its water extract HFD-fed mice ↓ Fat accumulation ↓ Liver inflammation ↓ Endotoxemia and IR [ 106] Micronutrient antioxidants -cryptoxanthin CL diet-fed mice ↓ Fat accumulation ↓ TBARS level ↓ Hepatic steatosis ↓ Liver inflammation ↓ IR and lipid peroxidation [ 109,110] Astaxanthin CL diet-fed mice ↓ Hepatic steatosis ↑ M2-dominat macrophages ↓ IR and liver inflammation ↓ Liver fibrosis [ 111] Liver samples from NAFLD patients ↓ Hepatic steatosis ↓ Total NAS score Lycopene HFD/CL diet-fed mice ↓ Lipid accumulation in liver ↓ Liver inflammation and IR ↑ M2-macrophage polarization [ 113,114] Vitamin D WD/VDD +/+ diet-fed rats ↑ Hepatic steatosis ↑ TLR4 activity ↑ NAS score [ 116] Vitamin E NASH patients ↓ ALT level ↓ NAS and fibrosis score [ 117] Polyphenols HepG2 cells ↓ ROS, TAG, and ALT ↓ Lipid peroxidation ↑ CAT, GPx, and SOD activities [ 118,165] MCD-fed NASH mice ↓ Hepatic steatosis ↓ ALT and AST level ↓ TBARS level [ 119] Probiotics…”

Triantennary GalNAc Molecular Imaging Probes for Monitoring Hepatocyte Function in a Rat Model of Nonalcoholic Steatohepatitis

“…Our structural studies of GN probe binding to ASGPR and HSA provide a basis for probe optimization not only for imaging studies but also potentially for liver-specific drug delivery via ASGPR. [46][47][48] Overall, we describe a complete toolkit including "first-inclass" chemical imaging probes to launch new lines of preclinical investigation into the molecular pathways of NASH onset and progression as well as to more effectively explore and understand the impact of treatment intervention in a more relevant in vivo model which will significantly aid the translation of preclinical research into the clinical setting.…”

Natural Compounds in the Modulation of the Intestinal Microbiota: Implications in Human Physiology and Pathology

“…The effect of P. lentiscus was investigated in mice with obesity, nonalcoholic steatohepatitis (NASH), and liver fibrosis induced by HFD. Treatment with P. lentiscus promoted a partial but significant recovery of microbiota diversity associated with a decrease in Bacteroidia and an increase in Proteobacteria relative abundance [154].…”