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.

KEYWORDS:

• DNA methylation
• faecal microbiota transplantation (FMT)
• non-alcoholic fatty liver disease (NAFLD)
• multi-omics analysis

Data availability statement

The raw DNA methylation data and metagenomic sequencing data generated for this study have been published under controlled access for research purposes at the European Genome-phenome Archive at EGAS00001006893, https://ega-archive.org.

Disclosure statement

AGH had acted as lecturer and consultant for Novo Nordisk, Inventiva, Julius Clinical, Echosens and Gilead. M.N. is founder and a member of the Scientific Advisory Board of Caelus Pharmaceuticals, The Netherlands; E.L. is founder of Horaizon BV; M.S.M. is employed by Gubra; E.B. is member of the Scientific Advisory Board of Madrigal. However, none of these possible conflicts of interest bear direct relations to the outcomes of this specific paper.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2223330

Additional information

Funding

E. vd V. is supported by a CVON INCONTROL-2 grant. M.N. is supported by a personal ZONMW VICI grant 2020 (09150182010020). M.S.M. is supported by a grant from Innovation Fund Denmark [7038-00008B]. A.G.H. is supported by the Amsterdam UMC Fellowship grant, the Amsterdam UMC Innovation grant, two grants from the Dutch Gastroenterology Foundation MLDS and two grants from Holland~Health TKI‐PPP.