Editorial: The Gut-Liver Axis: the Main Role of Microbiome in Liver Diseases

Giovanni Tarantino ^1* Tiziana Di Renzo ² Mauro Cataldi ¹

• ¹ Clinical and Experimental Medicine, University of Naples Federico II, Naples, Italy
• ² CNR Avellino, Avellino, Italy

It is clear that alteraBons in the composiBon of gut microbiota may contribute to the pathogenesis of liver diseases in mulBple ways by affecBng, among the others, gut permeability, immune response, and biliary salt metabolism [1]. Therefore, this special issue was launched to provide a broad spectrum perspecBve on new acquisiBons on microbiota involvement in the mulBfaceted field of liver diseases covering different condiBons from liver cirrhosis to autoimmune cholangiBs to NAFLD.Several arBcles of this special issue invesBgated the relevance of alteraBons in microbiota in the pathogenesis of NAFLD by using completely different experimental strategies. Lin et al. [2] used an animal model of the disease. They compared the intesBnal microbiome of 9 mice with NAFLD induced by a high fat diet with that of control mice and found that specific bacteria including Ileibacterium, Ruminococcaceae, Olsenella, Duncaniella, Paramuribaculum, Bifidobacterium and Coriobacteriaceae_UCG_002 were specifically associated with NAFLD. Different metabolic profiles also corresponded to the different composiBon of gut microbiome. UlBmately, the autors idenBfied a set of 8 bacterial strains, 14 genes and 83 metabolites, which strongly discriminate normal from NAFLD mice. By contrast, Pan et al. [3] used mendelian randomizaBon with published data obtained in humans to assess the causal relaBonship between the presence of specific bacterial strains in the gut with the development of NAFLD. The results of this analysis showed that 8 bacterial strains are strongly associated with this disease (the AcBnomycetales, NB1n, the family AcBnomycetaceae, Oxalobacteraceae and the genus Ruminococcaceae UCG005 were posiBvely correlated, whereas Lactobacillaceae, the Christensenellaceae R7 group, and Intes*nibacter were negaBvely correlated). Also in the analysis performed by Pan et al, differences in the microbiome corresponded to metabolic differences. The results were also validated in a mice model of NAFLD. A completely different approach was used by Shera et al. [4] who transplanted the feces from paBents who underwent bariatric surgery and, therefore, improved their NAFLD, into mice receiving high fat diet. This treatment significantly reduced the development of NAFLD in these mice and aZenuated the changes in the paZern of cytokine and T-lymphocytes characterisBcally associated with this disease.NAFLD may progress to NASH (nonalcoholic steatohepaBBs), which is characterized by significant liver inflammaBon and may progress to cirrhosis. The reason why this progression takes place in some paBents but not in others is largely unknown, but the data reported by Huang et al. [5] in this special issue point to microbiota composiBon as a key factor. They found, in fact, that Megamonas and Fusobacterium were significantly enriched in the fecal microbiome of NASH paBents in comparison with control subjects and NAFLD paBents. KEGG pathway analysis unveiled major metabolic differences in gut microbiota from NAFLD and NASH paBents.The relevance of changes in microbiota in the pathogenesis of liver cirrhosis was invesBgated in the arBcle by Li et al. [6] who compared the composiBon of microbiota and mycobiota in 45 cirrhoBc paBents and in 30 healthy controls. DisBncBve alteraBons were idenBfied since, in cirrhoBc paBents, Streptococcus, Akkermansia, Ligilactobacillus, Pseudescherichia were increased whereas Blau*a, Anaerobutyricum, Gemmiger, Ruminococcus, and Dorea were decreased. The major changes in mycobiota were an increase in Saccharomyces with a parallel decrease in Aspergillus, Penicillium, Auricularia, and Cladosporium. By combining, metagenomic data with the results of metabolomic analyses the authors developed a diagnosBc tesBng system which was able to idenBfy cirrhoBc paBents with a high accuracy (AUC of 0.938 at the ROC analysis).In the two arBcles by Cui et al. [7] and Zhang et al. [8] the associaBon between changes in gut microbiome and autoimmune liver diseases (was assessed by using mendelian randomizaBon (primary biliary cholangiBs and primary sclerosing cholangiBs).Natural products have been claimed to exert beneficial effect in liver diseases which can depend at least in part on changes in gut microbiota composiBon. Data in support of this hypothesis has been reported in two arBcles of this special issue. Sun et al. [9] reviewed the evidence that some tradiBonal Chinese medicine remedies, claimed to be effecBve in liver cirrhosis, could be acBng not only as anBoxidant, anBinflammatory and anB-fibroBc agents but also through modificaBons in gut microbiota. This has been shown for purified natural products used in tradiBonal Chinese medicine including polyphenols such as Resveratrol, Alkaloids such as Berberine, Terpenoids such as Ginko Biloba, Carbohydrates such as alginate, Glycosides such as FTA, a glycoside extracted from the dried fruit of Forsythia suspensa. Some evidence of beneficial changes in microbiota composiBon is also available for herbal prescripBons which contain mulBple compounds from different sources. Liang et al. [10] invesBgated the effect of licorice on the hepatoxicity of the Evodiae Fructus, a medicinal herb with analgesic, anB-tumor, and anB-inflammatory properBes. They showed that, in mice, the Evodiae Fructus, especially in the small-flowered forms, induces oxidaBve damage and inflammaBon in the liver and that these effects are aZenuated if the extract is given in combinaBon with licorice extracts. Changes in microbiota composiBon may contribute to licorice protecBve acBon. In fact, licorice prevented Evodiae Fructus-induced decrease in the abundance of Corynebacterium at the same Bme causing an increase in Candidatus Arthromitus. Importantly, the abundance of these two bacterial genera correlated respecBvely in a posiBve and negaBve way with biochemical markers of oxidaBve damage and inflammaBon. These results not only emphasize that natural products may protect the liver by modifying gut microbiota but also highlight that toxic substances may damage the liver in a microbiota-dependent manner. This concept was also addressed in the arBcle by TaranBno et al. [11] that explores the role of gut microbiota in the hepatotoxicity induced by drugs of abuse. The authors reviewed literature evidence showing that opioids alter the composiBon of intesBnal microbiota by inducing an increase in Gram-posiBve bacterial species such as Staphylococcus sciuri, Staphylococcus cohnii, and Staphylococcus aureus, as well as Enterococcus durans, Enterococcus casseliflavus, Enterococcus faecium, and Enterococcus faecalis. This opioid-induced dysbiosis causes the permeabilizaBon of the intesBnal barrier and, consequently, the translocaBon of bacterial species in the liver, which, in turn, is a strong inducer of inflammaBon and cell damage. Importantly, data are available to suggest that similar mechanisms also parBcipate in alcohol-induced hepatotoxicity. If the hypothesis that gut dysbiosis has an important role in the pathogenesis of alcohol-induced liver damage is correct, then it could be suggested that intervenBons aiming to modify the composiBon of intesBnal microbiota could be beneficial for this condiBon. This has been explored by Wei et al [12] who showed that alcohol feeding causes gut dysbiosis in mice by increasing the abundance of Oscillibacter, Escherichia/Shigella, and Alis*pes and a parallel increase in liver T-helper (Th) 1 and Th17 lymphocytes which is accompanied by a decrease in Treg. These changes were all reverted by the combined administraBon of Akkermansia muciniphila and of inosine, a compound which acts as an energy source and is also provided with anBnflammatory and immunomodulatory effects. Remarkably, this combined treatment promoted the growth of butyrateproducing bacteria including not only Akkermansia, but also Lactobacillus, and Clostridium IV.The molecular mechanisms by which intesBnal microorganisms may exert beneficial or detrimental effect on the liver have been extensively invesBgated and crucial factors have been idenBfied including bacterial translocaBon and endotoxin release, the release of indole and trimethylamine, bacterial metabolism o biliary acids and changes in the level of short chain faZy acids (Fig. 1). The arBcle by Sun et al. [13] describes a new potenBal mechanism for liver protecBon by gut microbiome. By using quadrupole Bme-of-flight mass spectrometry (Q-TOF-MS)-based metabolomics they showed that, in mice, steroid hormone biosynthesis liver regeneraBon ajer parBal hepatectomy is accompanied by a substanBal increase in liver steroid hormone biosynthesis possibly related to the observed increase in Escherichia, Shigella, Lactobacillus, Akkermansia, and Muribaculaceae in gut microbiome. In conclusion, with this research topic we aimed at improving our understanding of the potenBal mechanisms explaining the connecBon between gut flora dysbiosis and liver damage. The 16 publicaBons gathered in this Research Topic have expanded our knowledge about the role of the microbiome and its involvement in liver diseases. It remains to further explore the hypothesis that modifying the composiBon of gut microbiota with probioBcs/prebioBcs/symbioBcs such liver diseases could be ameliorated or prevented.