Faecal Microbiota transplantation affects liver DNA methylation in Non-alcoholic fatty liver disease: a multi-omics approach

Abstract

Individuals with nonalcoholic fatty liver disease (NAFLD) have an altered gut microbiota composition. Moreover, hepatic DNA methylation may be altered in the state of NAFLD. Using a fecal microbiota transplantation (FMT) intervention, we aimed to investigate whether a change in gut microbiota composition relates to altered liver DNA methylation in NAFLD. Moreover, we assessed whether plasma metabolite profiles altered by FMT relate to changes in liver DNA methylation. Twenty-one individuals with NAFLD underwent three 8-weekly vegan allogenic donor ( n = 10) or autologous ( n = 11) FMTs. We obtained hepatic DNA methylation profiles from paired liver biopsies of study participants before and after FMTs. We applied a multi-omics machine learning approach to identify changes in the gut microbiome, peripheral blood metabolome and liver DNA methylome, and analyzed cross-omics correlations. Vegan allogenic donor FMT compared to autologous FMT induced distinct differential changes in I) gut microbiota profiles, including increased abundance of Eubacterium siraeum and potential probiotic Blautia wexlerae ; II) plasma metabolites, including altered levels of phenylacetylcarnitine (PAC) and phenylacetylglutamine (PAG) both from gut-derived phenylacetic acid, and of several choline-derived long-chain acylcholines; and III) hepatic DNA methylation profiles, most importantly in Threonyl-TRNA Synthetase 1 ( TARS) and Zinc finger protein 57 ( ZFP57) . Multi-omics analysis showed that Gemmiger formicillis and Firmicutes bacterium _ CAG _170 positively correlated with both PAC and PAG. E siraeum negatively correlated with DNA methylation of cg16885113 in ZFP57 . Alterations in gut microbiota composition by FMT caused widespread changes in plasma metabolites (e.g. PAC, PAG, and choline-derived metabolites) and liver DNA methylation profiles in individuals with NAFLD. These results indicate that FMTs might induce metaorganismal pathway changes, from the gut bacteria to the liver.

Multidimensional Interactive Cascading Nanochips for Detection of Multiple Liver Diseases via Precise Metabolite Profiling

“…[31] N-phenylacetylglutamic acid (m/z 304.06, [M + K] + ) (Figure 6k), also known as glutamic acid and its derivatives, it has been reported to be related to liver metabolism. [32] The violin plot revealed that HBV-infected patients exhibited a significant decrease in N-phenylacetylglutamic acid compared to HC, which could be ascribed to impaired liver function; However, as HBV progressed to HCC, a pronounced increase was seen in the N-phenylacetylglutamic acid level, which may be attributed to the breakdown of proteins into glutamic acid and its derivatives by cancer cells.…”

Understanding the role of ursodeoxycholic acid and gut microbiome in non-alcoholic fatty liver disease: current evidence and perspectives

“…Another clinical trial demonstrated that FMT affected hepatic DNA methylation and levels of phenylacetate- and choline-derived metabolites in individuals with NAFLD. As for gut microbial composition changes, Blautia wexlerae , a potential anti-obesogenic probiotic, was increased upon allogenic FMT compared with autologous FMT ( Stols-Gonçalves et al, 2023 ). The proportions of beneficial bacteria Bacteroidetes , Christensenellaceae , and Lactobacillus were also increased by FMT intervention.…”

“…These results showed that NAFLD-associated gut microbiome disturbance was, at least partially, corrected after FMT. While changes in the microbial metabolites, such as butyrate concentrations of the cecal content ( Zhou et al, 2017 ), plasma phenylacetylcarnitine, and phenylacetylglutamine ( Stols-Gonçalves et al, 2023 ), as well as gut microbiome structure were indicated, it would be highly interesting to explore the correlation between another microbial metabolite, bile acids, especially UDCA, and FMT intervention in NAFLD.…”

Updated Insights into Probiotics and Hepatobiliary Diseases

“…The findings demonstrate that the abundance of Eubacterium siraeum and potential probiotic Blautia wexlerae were increased in the gut microbiota profiles after fecal microbiota transplantation (FMT), and the hepatic DNA methylation profiles, especially threonyl-TRNA synthetase 1 (TARS) and zinc finger protein 57 (ZFP57), were altered. The probiotics isolated from FMTs might be developed into probiotic therapy for NAFLD via the modulation of hepatic DNA methylation [ 44 ].…”