Indexed In : Science Citation Index Expanded(SCIE), MEDLINE,
Pubmed/Pubmed Central, Elsevier Bibliographic, Google Scholar,
Databases(Scopus & Embase), KCI, KoreaMed, DOAJ
Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.
The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.
Ningning You1 , Lili Zhuo1
, Jingxin Zhou1
, Yu Song2
, Junping Shi1
Correspondence to: Junping Shi
Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou 310015, China
Tel: +86-57188358060, Fax: +86-57188021730, E-mail: 13957121199@126.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver 2020;14(3):291-296. https://doi.org/10.5009/gnl18579
Published online September 30, 2019, Published date May 15, 2020
Copyright © Gut and Liver.
Current studies have confirmed that liver diseases are closely related to intestinal microorganisms; however, those studies have mainly concentrated on bacteria. Although the proportion of intestinal microorganisms accounted for by colonizing fungi is very small, these fungi do have a significant effect on the homeostasis of the intestinal microecosystem. In this paper, the characteristics of intestinal fungi in patients with chronic liver diseases such as alcoholic liver disease, nonalcoholic fatty liver disease and cirrhosis are summarized, and the effects of intestinal fungi and their metabolites are analyzed and discussed. It is important to realize that not only bacteria but also intestinal fungi play important roles in liver diseases.
Keywords: Intestinal fungi, Alcoholic liver disease, Cirrhosis, Non-alcoholic fatty liver disease
The gastrointestinal tracts, as one of the most important and complex micro-ecosystems in human body, harbors large numbers of microorganisms (about 1012 to 1014), including bacteria, archaea, virus, and fungi;1 the enormous quantity and complex structure of intestinal micro-ecology have been a challenge for scientist to have a deep exploration of intestinal microorganism. In recent years, with the advancement of high-throughput sequencing technology, more and more microorganisms have been known and confirmed to be important in maintaining human health, such as immune protection, nutrient absorption, bacterial barrier, anticancer and cancer suppression.2 However, there are also potentially pathogenic microorganisms containing in the intestinal micro-ecology causing disruption of intestinal homeostasis and alterations in the intestinal microorganisms which contributes to the pathogenesis of many disorders, including liver disease. Many studies over the past couple of decades have documented an important role for intestinal bacteria in liver diseases. Growing evidences indicate that like the bacteria, the intestinal fungi are also closely associated with liver disease.
Intestinal fungi, as an important part of intestinal micro-ecology, though the proportion is very low, its role in human health and disease cannot be ignored. Under physiological conditions, a variety of components on fungal cell wall (including β-glucan, zymosan, mannan, chitosan, DNA, and RNA) can be recognized by host cells to activate innate and acquired immunity. The reaction inhibits the overgrowth of the intestinal fungi or the colonization of exogenous pathogens. When the host immune system is deficient3 or a large number of antibiotics are used,4 it will cause changes in the composition of the intestinal microbiota, which will cause a series of liver diseases through the “entero-hepatic axis.” In this review, we will combine the current research on intestinal fungus and chronic liver diseases to analyze the relationship between intestinal fungi and alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) and liver cirrhosis, try to make people realize that not only bacteria but also intestinal fungi play an important role in liver diseases.
Fungi are detectable in all sections of the gastrointestinal tract of about 70% of healthy adults, normally at up to 1,000 fungal cells per milliliter or gram of intestinal contents.5 Culture-independent analyses show that fungi constitute less than 0.1% of the human gut microbiome,6 while accounting for only 0.03% of the fecal microbiota.7 Previous traditional culture-dependent techniques can only detect a small number of fungi, with the maturity of high-throughput sequencing technology, it has gradually replaced traditional culture techniques as the best method for studying fungi. Reports using next generation sequencing have found diverse fungal communities in all sections of the human gut, consisting mainly of the phyla Ascomycota, Basidiomycota, Zygomycota, and Chytridiomycota.8-10 The predominant commensal fungal species in the human intestine are
In 2017, the human microbiome project (HMP) launched the study of the gut mycobiome in human, 317 HMP stool samples were analyzed by sequencing the internal transcribed spacer 2 (ITS2) region as well as the 18S rRNA gene, 701 fungal operational taxonomic units were detected in the sample set, capturing 247 named genera, and the Shannon diversity index varied between 0.004 and 2.94, which was much lower than bacterial communities. The intestinal fungi was dominated by yeast including
Liver acts as a metabolic site for alcohol, when the body excessively consumes alcohol for a long time and exceeds the metabolic load of the liver, it can cause liver damage through multiple routes, and constantly develop into alcoholic fatty liver, alcoholic hepatitis, alcoholic cirrhosis and even liver cancer.14 Since 2015, Szabo15 proposed the role of the entero-hepatic axis in ALD, the importance of an imbalanced intestinal flora in the pathogenesis of ALD has gradually been recognized. In ALD, increased ethanol and its metabolite acetaldehyde in the intestinal lumen mediate weakening of intestinal tight junctions. Consequently, increased translocation of microbial-associated molecular patterns and gut metabolites, such as acetaldehyde, acetate, elicits intestinal and hepatic inflammatory responses, leading to progressive liver damage.16,17
On the basis of a mature mouse model of ALD, Yang
There are few studies on the relationship between intestinal fungi and NAFLD. At present, the most researched is the probiotic
Everard
In addition, the latest research has also found that metabolic syndrome, which is closely related to NAFLD, also shows an imbalance in intestinal fungi. There is a study provides evidence that ingestion of a high-fat diet (HFD) is associated with changes to the fungal, though no difference of richness and diversity was existed between the groups, the abundances of the
Overall, evidence for a causal role of intestinal fungi in NAFLD in humans is limited because the gold-standard method for assessing and diagnosing NAFLD is still a liver biopsy. Improved noninvasive techniques will help enable well-powered studies to be performed to elucidate the role of the gut mycobiota in NAFLD.
Cirrhosis is a result of advanced liver diseases such as alcoholism, viral hepatitis, and fatty liver disease. It is characterized by replacement of live tissue by fibrosis and regenerative nodules; these changes lead to loss of liver function.25
In recent years, more and more studies have found that intestinal fungi have a close correlation with cirrhosis. Patients with cirrhosis are often accompanied by disorders of the intestinal fungi, the main manifestations were the decrease of fungal diversity and species abundance. The abundance of basidiomycetes in the intestinal tract of patients with cirrhosis is significantly reduced, while Ascomycota has an absolute advantage. For Ascomycota, there is a literature report that it is positively correlated with the incidence of end-stage liver disease, and can predict the short-term hospitalization rate of patients with advanced cirrhosis.26 Most of the patients are hospitalized for infection, such as fungal peritonitis, fungemia, fungal esophagitis, etc., most of the pathogens of these infections are Ascomycetes and have been confirmed as intestinal origin.11,27,28 This result tells us that liver cirrhosis patients are accompanied by intestinal fungal flora disorder and mucosal permeability destruction at the same time, intestinal fungi can enter the liver or even the whole body through the damaged intestinal mucosa, however, whether the disturbed fungi can in turn aggravate liver damage through the entero-hepatic axis has not been studied.
In another study by Chen
From the above research, we found that liver cirrhosis caused by different etiology showed different changes in the structure and composition of intestinal fungi, which indicates that it is not the state of cirrhosis which causes the changes of intestinal fungi, but the intestinal fungi under the action of different etiology that lead to the occurrence of liver cirrhosis.
Similar to the intestinal fungi, the study on intestinal fungal metabolites are also at a very early stage. We try to elucidate the mechanism of action of these metabolites, combined with the pathogenesis of chronic liver disease, to explore the relationship between them.
1. PenstyrylpyroneAs one of the metabolites of
Polyamines (spermine, spermidine, putrescine), produced by
Farnesol is a non-sterol isoprenoid that is produced endogenously through the dephosphorylation of farnesyl pyrophosphate, a key branch-point intermediate of the cholesterol biosynthetic pathway. A lot of research has been done on farnesol, in addition to being functional in stimulating mitochondrial generation of ROS and apoptosis41-45 as well as decreases intracellular cyclic adenosine monophosphate levels,46,47 recent study found isoprenoid farnesol can also modulate lipid metabolism and reduces hepatic triglyceride content in steatotic HepaRG cells. This effect involves activation of at least two nuclear receptors, peroxisome proliferator-activated receptor alpha and farnesoid X receptor.48
5. AltenusinAltenusin, a natural nonsteroidal fungal metabolite isolated from the endophytic fungus
The role of intestinal microorganisms in the occurrence and development of various diseases has been paid more attention currently, and the relationship between intestinal fungi and bacterial has gradually deepened. In a variety of liver diseases, the intestinal fungi shows a certain structural and compositional changes, which may provide new directions and targets for the treatment of chronic liver disease, such as apply beneficial fungi for the treatment of some disease by means of fecal microbiota transplantation. Furthermore, with the increasing incidence of NAFLD and the risk of NAFLD transitioning to steatohepatitis, cirrhosis and liver cancer, there is no effective drug for the treatment of NAFLD, we need to further explore the characteristics of intestinal fungi in patients with NAFLD, to verify the causal effect between NAFLD and fungal dysbiosis, providing a new direction for the treatment of NAFLD.
The authors thank all patients who participated in the study, the Science and Technology Planning Project of Hangzhou City (20172016A02), which plays an important role in this article.
No potential conflict of interest relevant to this article was reported.
Gut and Liver 2020; 14(3): 291-296
Published online May 15, 2020 https://doi.org/10.5009/gnl18579
Copyright © Gut and Liver.
Ningning You1 , Lili Zhuo1
, Jingxin Zhou1
, Yu Song2
, Junping Shi1
1Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, and 2Department of Liver Diseases, Zhejiang Chinese Medical University, Hangzhou, China
Correspondence to:Junping Shi
Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou 310015, China
Tel: +86-57188358060, Fax: +86-57188021730, E-mail: 13957121199@126.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Current studies have confirmed that liver diseases are closely related to intestinal microorganisms; however, those studies have mainly concentrated on bacteria. Although the proportion of intestinal microorganisms accounted for by colonizing fungi is very small, these fungi do have a significant effect on the homeostasis of the intestinal microecosystem. In this paper, the characteristics of intestinal fungi in patients with chronic liver diseases such as alcoholic liver disease, nonalcoholic fatty liver disease and cirrhosis are summarized, and the effects of intestinal fungi and their metabolites are analyzed and discussed. It is important to realize that not only bacteria but also intestinal fungi play important roles in liver diseases.
Keywords: Intestinal fungi, Alcoholic liver disease, Cirrhosis, Non-alcoholic fatty liver disease
The gastrointestinal tracts, as one of the most important and complex micro-ecosystems in human body, harbors large numbers of microorganisms (about 1012 to 1014), including bacteria, archaea, virus, and fungi;1 the enormous quantity and complex structure of intestinal micro-ecology have been a challenge for scientist to have a deep exploration of intestinal microorganism. In recent years, with the advancement of high-throughput sequencing technology, more and more microorganisms have been known and confirmed to be important in maintaining human health, such as immune protection, nutrient absorption, bacterial barrier, anticancer and cancer suppression.2 However, there are also potentially pathogenic microorganisms containing in the intestinal micro-ecology causing disruption of intestinal homeostasis and alterations in the intestinal microorganisms which contributes to the pathogenesis of many disorders, including liver disease. Many studies over the past couple of decades have documented an important role for intestinal bacteria in liver diseases. Growing evidences indicate that like the bacteria, the intestinal fungi are also closely associated with liver disease.
Intestinal fungi, as an important part of intestinal micro-ecology, though the proportion is very low, its role in human health and disease cannot be ignored. Under physiological conditions, a variety of components on fungal cell wall (including β-glucan, zymosan, mannan, chitosan, DNA, and RNA) can be recognized by host cells to activate innate and acquired immunity. The reaction inhibits the overgrowth of the intestinal fungi or the colonization of exogenous pathogens. When the host immune system is deficient3 or a large number of antibiotics are used,4 it will cause changes in the composition of the intestinal microbiota, which will cause a series of liver diseases through the “entero-hepatic axis.” In this review, we will combine the current research on intestinal fungus and chronic liver diseases to analyze the relationship between intestinal fungi and alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) and liver cirrhosis, try to make people realize that not only bacteria but also intestinal fungi play an important role in liver diseases.
Fungi are detectable in all sections of the gastrointestinal tract of about 70% of healthy adults, normally at up to 1,000 fungal cells per milliliter or gram of intestinal contents.5 Culture-independent analyses show that fungi constitute less than 0.1% of the human gut microbiome,6 while accounting for only 0.03% of the fecal microbiota.7 Previous traditional culture-dependent techniques can only detect a small number of fungi, with the maturity of high-throughput sequencing technology, it has gradually replaced traditional culture techniques as the best method for studying fungi. Reports using next generation sequencing have found diverse fungal communities in all sections of the human gut, consisting mainly of the phyla Ascomycota, Basidiomycota, Zygomycota, and Chytridiomycota.8-10 The predominant commensal fungal species in the human intestine are
In 2017, the human microbiome project (HMP) launched the study of the gut mycobiome in human, 317 HMP stool samples were analyzed by sequencing the internal transcribed spacer 2 (ITS2) region as well as the 18S rRNA gene, 701 fungal operational taxonomic units were detected in the sample set, capturing 247 named genera, and the Shannon diversity index varied between 0.004 and 2.94, which was much lower than bacterial communities. The intestinal fungi was dominated by yeast including
Liver acts as a metabolic site for alcohol, when the body excessively consumes alcohol for a long time and exceeds the metabolic load of the liver, it can cause liver damage through multiple routes, and constantly develop into alcoholic fatty liver, alcoholic hepatitis, alcoholic cirrhosis and even liver cancer.14 Since 2015, Szabo15 proposed the role of the entero-hepatic axis in ALD, the importance of an imbalanced intestinal flora in the pathogenesis of ALD has gradually been recognized. In ALD, increased ethanol and its metabolite acetaldehyde in the intestinal lumen mediate weakening of intestinal tight junctions. Consequently, increased translocation of microbial-associated molecular patterns and gut metabolites, such as acetaldehyde, acetate, elicits intestinal and hepatic inflammatory responses, leading to progressive liver damage.16,17
On the basis of a mature mouse model of ALD, Yang
There are few studies on the relationship between intestinal fungi and NAFLD. At present, the most researched is the probiotic
Everard
In addition, the latest research has also found that metabolic syndrome, which is closely related to NAFLD, also shows an imbalance in intestinal fungi. There is a study provides evidence that ingestion of a high-fat diet (HFD) is associated with changes to the fungal, though no difference of richness and diversity was existed between the groups, the abundances of the
Overall, evidence for a causal role of intestinal fungi in NAFLD in humans is limited because the gold-standard method for assessing and diagnosing NAFLD is still a liver biopsy. Improved noninvasive techniques will help enable well-powered studies to be performed to elucidate the role of the gut mycobiota in NAFLD.
Cirrhosis is a result of advanced liver diseases such as alcoholism, viral hepatitis, and fatty liver disease. It is characterized by replacement of live tissue by fibrosis and regenerative nodules; these changes lead to loss of liver function.25
In recent years, more and more studies have found that intestinal fungi have a close correlation with cirrhosis. Patients with cirrhosis are often accompanied by disorders of the intestinal fungi, the main manifestations were the decrease of fungal diversity and species abundance. The abundance of basidiomycetes in the intestinal tract of patients with cirrhosis is significantly reduced, while Ascomycota has an absolute advantage. For Ascomycota, there is a literature report that it is positively correlated with the incidence of end-stage liver disease, and can predict the short-term hospitalization rate of patients with advanced cirrhosis.26 Most of the patients are hospitalized for infection, such as fungal peritonitis, fungemia, fungal esophagitis, etc., most of the pathogens of these infections are Ascomycetes and have been confirmed as intestinal origin.11,27,28 This result tells us that liver cirrhosis patients are accompanied by intestinal fungal flora disorder and mucosal permeability destruction at the same time, intestinal fungi can enter the liver or even the whole body through the damaged intestinal mucosa, however, whether the disturbed fungi can in turn aggravate liver damage through the entero-hepatic axis has not been studied.
In another study by Chen
From the above research, we found that liver cirrhosis caused by different etiology showed different changes in the structure and composition of intestinal fungi, which indicates that it is not the state of cirrhosis which causes the changes of intestinal fungi, but the intestinal fungi under the action of different etiology that lead to the occurrence of liver cirrhosis.
Similar to the intestinal fungi, the study on intestinal fungal metabolites are also at a very early stage. We try to elucidate the mechanism of action of these metabolites, combined with the pathogenesis of chronic liver disease, to explore the relationship between them.
1. PenstyrylpyroneAs one of the metabolites of
Polyamines (spermine, spermidine, putrescine), produced by
Farnesol is a non-sterol isoprenoid that is produced endogenously through the dephosphorylation of farnesyl pyrophosphate, a key branch-point intermediate of the cholesterol biosynthetic pathway. A lot of research has been done on farnesol, in addition to being functional in stimulating mitochondrial generation of ROS and apoptosis41-45 as well as decreases intracellular cyclic adenosine monophosphate levels,46,47 recent study found isoprenoid farnesol can also modulate lipid metabolism and reduces hepatic triglyceride content in steatotic HepaRG cells. This effect involves activation of at least two nuclear receptors, peroxisome proliferator-activated receptor alpha and farnesoid X receptor.48
5. AltenusinAltenusin, a natural nonsteroidal fungal metabolite isolated from the endophytic fungus
The role of intestinal microorganisms in the occurrence and development of various diseases has been paid more attention currently, and the relationship between intestinal fungi and bacterial has gradually deepened. In a variety of liver diseases, the intestinal fungi shows a certain structural and compositional changes, which may provide new directions and targets for the treatment of chronic liver disease, such as apply beneficial fungi for the treatment of some disease by means of fecal microbiota transplantation. Furthermore, with the increasing incidence of NAFLD and the risk of NAFLD transitioning to steatohepatitis, cirrhosis and liver cancer, there is no effective drug for the treatment of NAFLD, we need to further explore the characteristics of intestinal fungi in patients with NAFLD, to verify the causal effect between NAFLD and fungal dysbiosis, providing a new direction for the treatment of NAFLD.
The authors thank all patients who participated in the study, the Science and Technology Planning Project of Hangzhou City (20172016A02), which plays an important role in this article.
No potential conflict of interest relevant to this article was reported.