International Journal of Molecular Sciences

Research

20 pages, 3643 KiB

Open AccessArticle

Microbiota Dysbiosis and Gut Barrier Dysfunction Associated with Non-Alcoholic Fatty Liver Disease Are Modulated by a Specific Metabolic Cofactors’ Combination

by Sergio Quesada-Vázquez, Caitlin Bone, Shikha Saha, Iris Triguero, Marina Colom-Pellicer, Gerard Aragonès, Falk Hildebrand, Josep M. del Bas, Antoni Caimari, Naiara Beraza and Xavier Escoté

Int. J. Mol. Sci. 2022, 23(22), 13675; https://doi.org/10.3390/ijms232213675 - 8 Nov 2022

Cited by 14 | Viewed by 3212

Abstract

The gut is a selective barrier that not only allows the translocation of nutrients from food, but also microbe-derived metabolites to the systemic circulation that flows through the liver. Microbiota dysbiosis occurs when energy imbalances appear due to an unhealthy diet and a [...] Read more.

The gut is a selective barrier that not only allows the translocation of nutrients from food, but also microbe-derived metabolites to the systemic circulation that flows through the liver. Microbiota dysbiosis occurs when energy imbalances appear due to an unhealthy diet and a sedentary lifestyle. Dysbiosis has a critical impact on increasing intestinal permeability and epithelial barrier deterioration, contributing to bacterial and antigen translocation to the liver, triggering non-alcoholic fatty liver disease (NAFLD) progression. In this study, the potential therapeutic/beneficial effects of a combination of metabolic cofactors (a multi-ingredient; MI) (betaine, N-acetylcysteine, L-carnitine, and nicotinamide riboside) against NAFLD were evaluated. In addition, we investigated the effects of this metabolic cofactors’ combination as a modulator of other players of the gut-liver axis during the disease, including gut barrier dysfunction and microbiota dysbiosis. Diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (NAFLD group) or with a combination of metabolic cofactors (NAFLD-MI group), and small intestines were harvested from all animals for histological, molecular, and omics analysis. The MI treatment ameliorated gut morphological changes, decreased gut barrier permeability, and reduced gene expression of some proinflammatory cytokines. Moreover, epithelial cell proliferation and the number of goblet cells were increased after MI supplementation. In addition, supplementation with the MI combination promoted changes in the intestinal microbiota composition and diversity, as well as modulating short-chain fatty acids (SCFAs) concentrations in feces. Taken together, this specific combination of metabolic cofactors can reverse gut barrier disruption and microbiota dysbiosis contributing to the amelioration of NAFLD progression by modulating key players of the gut-liver axis. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

24 pages, 5947 KiB

Open AccessArticle

Investigation of Intestinal Absorption and Excretion of Paracetamol in Streptozotocin-Induced Hyperglycemia

by Petra Mészáros, Sára Kovács, Győző Kulcsár, Melinda Páskuj and Attila Almási

Int. J. Mol. Sci. 2022, 23(19), 11913; https://doi.org/10.3390/ijms231911913 - 7 Oct 2022

Cited by 5 | Viewed by 4238

Abstract

The phenolic drug molecules can be metabolized, among others, by the small intestine’s enterocytes. The conjugation reactions (glucuronidation and sulfation) show great importance in these transformations, although the oxidation reactions can be significant. These processes are dependent on the substituents of the phenolic [...] Read more.

The phenolic drug molecules can be metabolized, among others, by the small intestine’s enterocytes. The conjugation reactions (glucuronidation and sulfation) show great importance in these transformations, although the oxidation reactions can be significant. These processes are dependent on the substituents of the phenolic compounds or the reacting functional groups (hydroxyl or carboxyl). Pathologic conditions, e.g., permanent hyperglycemia and diabetes, can alter the activities of the conjugative and possibly the oxidative enzymes, thus forming a change in the metabolic pattern and eventually provoking oxidative stress. A rat intestinal perfusion model was used to investigate the way in which experimental hyperglycemia affects the paracetamol’s intestinal elimination and metabolism. Hyperglycemia was induced by the administration of streptozotocin. Two hundred and fifty µM paracetamol was used in the intestinal perfusion solution. For the quantitation of the paracetamol and its major metabolites in the intestinal perfusate, an isocratic high-performance liquid chromatography method with UV-Vis detection was developed. The results revealed that quantities of all of the measured metabolites (glucuronide, sulfate, cysteine, and mercapturic acid conjugates) increased as the effect of the streptozotocin-induced hyperglycemia also did. In the small intestine’s homogenate, the glutathione levels showed that there was a decrease in the hyperglycemia levels after the paracetamol administration. In contrast, the tissue levels of the cysteine were lower in the streptozotocin-induced hyperglycemia and increased after the administration of the paracetamol. The changes in the activity of the intestinal CYP 3A4, CYP 2E1, and cyclooxygenase (COX) enzymes were determined in the control and the hyperglycemic cases. Still, there was a significant observable enzyme activity elevation in the intestinal COX enzymes, but there was a decrease in the amount of activity of the intestinal CYP3A4 enzymes, and the CYP2E1 enzyme activity was practically changeless. The results on the cysteine levels in the intestinal homogenate, at least partly, can be explained by the regulation function of the cysteine during the occurrence of oxidative stress. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

14 pages, 6625 KiB

Open AccessArticle

Effect of Calcium-Sulphate-Bicarbonate Water in a Murine Model of Non-Alcoholic Fatty Liver Disease: A Histopathology Study

by Guido Carpino, Diletta Overi, Paolo Onori, Antonio Franchitto, Vincenzo Cardinale, Domenico Alvaro and Eugenio Gaudio

Int. J. Mol. Sci. 2022, 23(17), 10065; https://doi.org/10.3390/ijms231710065 - 2 Sep 2022

Cited by 2 | Viewed by 3307

Abstract

The progression of nonalcoholic fatty liver disease (NAFLD) is associated with alterations of the gut–liver axis. The activation of toll-like receptor 4 (TLR4) pathways by endotoxins, such as lipopolysaccharide (LPS), contributes to liver injury. The aim of the present study was to evaluate [...] Read more.

The progression of nonalcoholic fatty liver disease (NAFLD) is associated with alterations of the gut–liver axis. The activation of toll-like receptor 4 (TLR4) pathways by endotoxins, such as lipopolysaccharide (LPS), contributes to liver injury. The aim of the present study was to evaluate the possible beneficial effects of a calcium-sulphate-bicarbonate natural mineral water on the gut–liver axis by evaluating liver and terminal ileum histopathology in a murine model of NAFLD. NAFLD was induced in mice by administrating a methionine-choline-deficient (MCD) diet. The following experimental groups were evaluated: controls (N = 10); MCD+Tap water (MCD; N = 10); MCD+Calcium-sulphate-bicarbonate water (MCD/W_csb; N = 10). Mice were euthanised after 4 and 8 weeks. Liver and terminal ileum samples were collected. Samples were studied by histomorphology, immunohistochemistry, and immunofluorescence. In mice subjected to the MCD diet, treatment with mineral water improved inflammation and fibrosis, and was associated with a reduced number of activated hepatic stellate cells when compared to MCD mice not treated with mineral water. Moreover, MCD/W_csb mice showed lower liver LPS localization and less activation of TLR4 pathways compared to the MCD. Finally, W_csb treatment was associated with improved histopathology and higher occludin positivity in intestinal mucosa. In conclusion, calcium-sulphate-bicarbonate water may exert modulatory activity on the gut–liver axis in MCD mice, suggesting potential beneficial effects on NAFLD. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

15 pages, 4073 KiB

Open AccessArticle

Hemp-Derived Nanovesicles Protect Leaky Gut and Liver Injury in Dextran Sodium Sulfate-Induced Colitis

by Jung-Young Eom, Sang-Hun Choi, Hyun-Jin Kim, Dong-ha Kim, Ju-Hyun Bae, Gi-Seok Kwon, Dong-hee Lee, Jin-Hyeon Hwang, Do-Kyun Kim, Moon-Chang Baek and Young-Eun Cho

Int. J. Mol. Sci. 2022, 23(17), 9955; https://doi.org/10.3390/ijms23179955 - 1 Sep 2022

Cited by 13 | Viewed by 3298

Abstract

Hemp (Cannabis sativa L.) is used for medicinal purposes owing to its anti-inflammatory and antioxidant activities. We evaluated the protective effect of nanovesicles isolated from hemp plant parts (root, seed, hemp sprout, and leaf) in dextran sulfate sodium (DSS)-induced colitis in mice. [...] Read more.

Hemp (Cannabis sativa L.) is used for medicinal purposes owing to its anti-inflammatory and antioxidant activities. We evaluated the protective effect of nanovesicles isolated from hemp plant parts (root, seed, hemp sprout, and leaf) in dextran sulfate sodium (DSS)-induced colitis in mice. The particle sizes of root-derived nanovesicles (RNVs), seed-derived nanovesicles (SNVs), hemp sprout-derived nanovesicles (HSNVs), and leaf-derived nanovesicles (LNVs) were within the range of 100–200 nm as measured by nanoparticle tracking analysis. Acute colitis was induced in C57BL/N mice by 5% DSS in water provided for 7 days. RNVs were administered orally once a day, leading to the recovery of both the small intestine and colon lengths. RNVs, SNVs, and HSNVs restored the tight (ZO-1, claudin-4, occludin) and adherent junctions (E-cadherin and α-tubulin) in DSS-induced small intestine and colon injury. Additionally, RNVs markedly reduced NF-κB activation and oxidative stress proteins in DSS-induced small intestine and colon injury. Tight junction protein expression and epithelial cell permeability were elevated in RNV-, SNV-, and HSNV-treated T84 colon cells exposed to 2% DSS. Interestedly, RNVs, SNVs, HSNVs, and LNVs reduced ALT activity and liver regeneration marker proteins in DSS-induced liver injury. These results showed for the first time that hemp-derived nanovesicles (HNVs) exhibited a protective effect on DSS-induced gut leaky and liver injury through the gut–liver axis by inhibiting oxidative stress marker proteins. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

17 pages, 2113 KiB

Open AccessArticle

Heat-Inactivated Akkermansia muciniphila Improves Gut Permeability but Does Not Prevent Development of Non-Alcoholic Steatohepatitis in Diet-Induced Obese Ldlr−/−.Leiden Mice

by Martine C. Morrison, Eveline Gart, Wim van Duyvenvoorde, Jessica Snabel, Mette Juul Nielsen, Diana Julie Leeming, Aswin Menke and Robert Kleemann

Int. J. Mol. Sci. 2022, 23(4), 2325; https://doi.org/10.3390/ijms23042325 - 19 Feb 2022

Cited by 16 | Viewed by 4099

Abstract

The development of non-alcoholic steatohepatitis (NASH) has been associated with alterations in gut microbiota composition and reduced gut barrier function. Akkermansia muciniphila is a gut microbe that is thought to have health-promoting properties, including the ability to improve gut barrier function and host [...] Read more.

The development of non-alcoholic steatohepatitis (NASH) has been associated with alterations in gut microbiota composition and reduced gut barrier function. Akkermansia muciniphila is a gut microbe that is thought to have health-promoting properties, including the ability to improve gut barrier function and host metabolism, both when administered live and after heat-inactivation. We questioned whether heat-inactivated A. muciniphila may reduce NASH development. Ldlr−/−.Leiden mice, a translational, diet-induced model for NASH, were fed a NASH-inducing high-fat diet (HFD) supplemented with heat-inactivated A. muciniphila. After 28 weeks, effects of the treatment on obesity and associated metabolic dysfunction in the gut (microbiota composition and permeability), adipose tissue, and liver were studied relative to an untreated HFD control. Treatment with heat-inactivated A. muciniphila did not affect body weight or adiposity and had no effect on plasma lipids, blood glucose, or plasma insulin. Heat-inactivated A. muciniphila had some minor effects on mucosal microbiota composition in ileum and colon and improved gut barrier function, as assessed by an in vivo functional gut permeability test. Epidydimal white adipose tissue (WAT) hypertrophy and inflammation were not affected, but heat-inactivated A. muciniphila did reduce hypertrophy in the mesenteric WAT which is in close proximity to the intestine. Heat-inactivated A. muciniphila did not affect the development of NASH or associated fibrosis in the liver and did not affect circulating bile acids or markers of liver fibrosis, but did reduce PRO-C4, a type IV collagen synthesis marker, which may be associated with gut integrity. In conclusion, despite beneficial effects in the gut and mesenteric adipose tissue, heat-inactivated A. muciniphila did not affect the development of NASH and fibrosis in a chronic disease setting that mimics clinically relevant disease stages. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

12 pages, 1256 KiB

Open AccessArticle

Association between Equol Production Status and Nonalcoholic Steatohepatitis

by Takemi Akahane, Daisuke Kaya, Ryuichi Noguchi, Kosuke Kaji, Haruna Miyakawa, Yukihisa Fujinaga, Yuki Tsuji, Hiroaki Takaya, Yasuhiko Sawada, Masanori Furukawa, Koh Kitagawa, Takahiro Ozutsumi, Hideto Kawaratani, Kei Moriya, Tadashi Namisaki and Hitoshi Yoshiji

Int. J. Mol. Sci. 2021, 22(21), 11904; https://doi.org/10.3390/ijms222111904 - 2 Nov 2021

Cited by 9 | Viewed by 2519

Abstract

Equol is a metabolite of daidzein, a major soybean isoflavone with estrogenic and antioxidant activities. As the production of equol depends on the presence of certain members of the intestinal microflora, not all individuals can produce equol. We examined the relationship between NASH [...] Read more.

Equol is a metabolite of daidzein, a major soybean isoflavone with estrogenic and antioxidant activities. As the production of equol depends on the presence of certain members of the intestinal microflora, not all individuals can produce equol. We examined the relationship between NASH histological features and equol production. In an animal model, obese OLETF rats were intraperitoneally injected with a porcine serum to augment liver fibrogenesis. Equol-rich soy product, SE5-OH was orally administered during the experimental period. Treatment with SE5-OH markedly attenuated the development of liver fibrosis and expression of alpha-smooth muscle actin. In clinical research, 38 NAFLD patients (13 men and 25 women) were included. The degree of fibrosis and ballooning in equol-nonproducers was significantly higher than in equol-producers in women. The percentage of nonproducers with NAFLD activity score (NAS) ≥ 5 was significantly higher than that of producers. None of the histological features were significantly different between nonproducers and producers in men. Decision tree analysis identified predictors for NAS ≥ 5 in women. The status of equol production was the strongest predictor, followed by fasting glucose. Since equol can be noninvasively detected in urine, it can be applied as a screening tool for the progression of NASH in women. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

16 pages, 4081 KiB

Open AccessArticle

Astaxanthin Prevents Diet-Induced NASH Progression by Shaping Intrahepatic Immunity

by Ming Yang, Eric T. Kimchi, Kevin F. Staveley-O’Carroll and Guangfu Li

Int. J. Mol. Sci. 2021, 22(20), 11037; https://doi.org/10.3390/ijms222011037 - 13 Oct 2021

Cited by 20 | Viewed by 4988

Abstract

Dietary change leads to a precipitous increase in non-alcoholic fatty liver disease (NAFLD) from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH), affecting approximately 25% of the global population. Although significant efforts greatly advance progress in clarifying the pathogenesis of NAFLD [...] Read more.

Dietary change leads to a precipitous increase in non-alcoholic fatty liver disease (NAFLD) from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH), affecting approximately 25% of the global population. Although significant efforts greatly advance progress in clarifying the pathogenesis of NAFLD and identifying therapeutic targets, no therapeutic agent has been approved. Astaxanthin (ASTN), a natural antioxidant product, exerts an anti-inflammation and anti-fibrotic effect in mice induced with carbon tetrachloride (CCl₄) and bile duct ligation (BDL); thus, we proposed to further investigate the potential effect of ASTN on a diet-induced mouse NASH and liver fibrosis, as well as the underlying cellular and molecular mechanisms. By treating pre-development of NASH in mice induced with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), we have demonstrated that oral administration ASTN preventively ameliorated NASH development and liver fibrosis by modulating the hepatic immune response, liver inflammation, and oxidative stress. Specifically, ASTN treatment led to the reduction in liver infiltration of monocyte-derived macrophages, hepatic stellate cell (HSC) activation, oxidative stress response, and hepatocyte death, accompanied by the decreased hepatic gene expression of proinflammatory cytokines such as TNF-α, TGF-β1, and IL-1β. In vitro studies also demonstrated that ASTN significantly inhibited the expression of proinflammatory cytokines and chemokine CCL2 in macrophages in response to lipopolysaccharide (LPS) stimulation. Overall, in vivo and in vitro studies suggest that ASTN functions as a promising therapeutic agent to suppress NASH and liver fibrosis via modulating intrahepatic immunity. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

Review

Jump to: Research, Other

26 pages, 1531 KiB

Open AccessReview

Research Progress on the Therapeutic Effect of Polysaccharides on Non-Alcoholic Fatty Liver Disease through the Regulation of the Gut–Liver Axis

by Xiang Chen, Menghan Liu, Jun Tang, Ning Wang, Yibin Feng and Haotian Ma

Int. J. Mol. Sci. 2022, 23(19), 11710; https://doi.org/10.3390/ijms231911710 - 3 Oct 2022

Cited by 15 | Viewed by 3762

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting global public health at present, which can induce cirrhosis and liver cancer in serious cases. However, NAFLD is a multifactorial disease, and there is still a lack of research on [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting global public health at present, which can induce cirrhosis and liver cancer in serious cases. However, NAFLD is a multifactorial disease, and there is still a lack of research on its mechanism and therapeutic strategy. With the development of the gut–liver axis theory, the association between the gut–liver axis and the pathogenesis of NAFLD has been gradually disclosed. Polysaccharides, as a kind of natural product, have the advantages of low toxicity, multi-target and multi-pathway action. It has been reported that polysaccharides can affect the gut–liver axis at multiple interrelated levels, such as maintaining the ecological balance of gut microbiota (GM), regulating the metabolites of GM and improving the intestinal barrier function, which thereby plays a protective role in NAFLD. These studies have great scientific significance in understanding NAFLD based on the gut–liver axis and developing safe and effective medical treatments. Herein, we reviewed the recent progress of polysaccharides in improving nonalcoholic fatty liver disease (NAFLD) through the gut–liver axis. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

11 pages, 744 KiB

Open AccessReview

Current Research on the Pathogenesis of NAFLD/NASH and the Gut–Liver Axis: Gut Microbiota, Dysbiosis, and Leaky-Gut Syndrome

by Takashi Kobayashi, Michihiro Iwaki, Atsushi Nakajima, Asako Nogami and Masato Yoneda

Int. J. Mol. Sci. 2022, 23(19), 11689; https://doi.org/10.3390/ijms231911689 - 2 Oct 2022

Cited by 37 | Viewed by 5702

Abstract

Global lifestyle changes have led to an increased incidence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), requiring further in-depth research to understand the mechanisms and develop new therapeutic strategies. In particular, high-fat and high-fructose diets have been shown to increase [...] Read more.

Global lifestyle changes have led to an increased incidence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), requiring further in-depth research to understand the mechanisms and develop new therapeutic strategies. In particular, high-fat and high-fructose diets have been shown to increase intestinal permeability, which can expose the liver to endotoxins. Indeed, accumulating evidence points to a link between these liver diseases and the intestinal axis, including dysbiosis of the gut microbiome and leaky-gut syndrome. Here, we review the mechanisms contributing to these links between the liver and small intestine in the pathogenesis of NAFLD/NASH, focusing on the roles of intestinal microbiota and their metabolites to influence enzymes essential for proper liver metabolism and function. Advances in next-generation sequencing technology have facilitated analyses of the metagenome, providing new insights into the roles of the intestinal microbiota and their functions in physiological and pathological mechanisms. This review summarizes recent research linking the gut microbiome to liver diseases, offering new research directions to elucidate the detailed mechanisms and novel targets for treatment and prevention. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

20 pages, 808 KiB

Open AccessReview

The Link between Gut Microbiota and Hepatic Encephalopathy

by Sung-Min Won, Ki Kwang Oh, Haripriya Gupta, Raja Ganesan, Satya Priya Sharma, Jin-Ju Jeong, Sang Jun Yoon, Min Kyo Jeong, Byeong Hyun Min, Ji Ye Hyun, Hee Jin Park, Jung A. Eom, Su Been Lee, Min Gi Cha, Goo Hyun Kwon, Mi Ran Choi, Dong Joon Kim and Ki Tae Suk

Int. J. Mol. Sci. 2022, 23(16), 8999; https://doi.org/10.3390/ijms23168999 - 12 Aug 2022

Cited by 23 | Viewed by 7412

Abstract

Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome [...] Read more.

Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome and disease can be positively utilized not only in the diagnosis area of HE but also in the treatment area. Probiotics and prebiotics aim to resolve gut dysbiosis and increase beneficial microbial taxa, while fecal microbiota transplantation aims to address gut dysbiosis through transplantation (FMT) of the gut microbiome from healthy donors. Antibiotics, such as rifaximin, aim to improve cognitive function and hyperammonemia by targeting harmful taxa. Current treatment regimens for HE have achieved some success in treatment by targeting the gut microbiota, however, are still accompanied by limitations and problems. A focused approach should be placed on the establishment of personalized trial designs and therapies for the improvement of future care. This narrative review identifies factors negatively influencing the gut–hepatic–brain axis leading to HE in cirrhosis and explores their relationship with the gut microbiome. We also focused on the evaluation of reported clinical studies on the management and improvement of HE patients with a particular focus on microbiome-targeted therapy. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

21 pages, 1696 KiB

Open AccessReview

Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease

by Ji Ye Hyun, Seul Ki Kim, Sang Jun Yoon, Su Been Lee, Jin-Ju Jeong, Haripriya Gupta, Satya Priya Sharma, Ki Kwong Oh, Sung-Min Won, Goo Hyun Kwon, Min Gi Cha, Dong Joon Kim, Raja Ganesan and Ki Tae Suk

Int. J. Mol. Sci. 2022, 23(15), 8749; https://doi.org/10.3390/ijms23158749 - 6 Aug 2022

Cited by 15 | Viewed by 4044

Abstract

Alcohol consumption is a global healthcare problem. Chronic alcohol consumption generates a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, fibrosis, and cirrhosis. Alcoholic liver diseases (ALD) refer to liver damage and metabolomic changes caused by excessive alcohol [...] Read more.

Alcohol consumption is a global healthcare problem. Chronic alcohol consumption generates a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, fibrosis, and cirrhosis. Alcoholic liver diseases (ALD) refer to liver damage and metabolomic changes caused by excessive alcohol intake. ALD present several clinical stages of severity found in liver metabolisms. With increased alcohol consumption, the gut microbiome promotes a leaky gut, metabolic dysfunction, oxidative stress, liver inflammation, and hepatocellular injury. Much attention has focused on ALD, such as alcoholic fatty liver (AFL), alcoholic steatohepatitis (ASH), alcoholic cirrhosis (AC), hepatocellular carcinoma (HCC), a partnership that reflects the metabolomic significance. Here, we report on the global function of inflammation, inhibition, oxidative stress, and reactive oxygen species (ROS) mechanisms in the liver biology framework. In this tutorial review, we hypothetically revisit therapeutic gut microbiota-derived alcoholic oxidative stress, liver inflammation, inflammatory cytokines, and metabolic regulation. We summarize the perspective of microbial therapy of genes, gut microbes, and metabolic role in ALD. The end stage is liver transplantation or death. This review may inspire a summary of the gut microbial genes, critical inflammatory molecules, oxidative stress, and metabolic routes, which will offer future promising therapeutic compounds in ALD. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

14 pages, 1064 KiB

Open AccessReview

Host Factors in Dysregulation of the Gut Barrier Function during Alcohol-Associated Liver Disease

by Luca Maccioni, Isabelle A. Leclercq, Bernd Schnabl and Peter Stärkel

Int. J. Mol. Sci. 2021, 22(23), 12687; https://doi.org/10.3390/ijms222312687 - 24 Nov 2021

Cited by 12 | Viewed by 2690

Abstract

Chronic alcohol consumption and alcohol-associated liver disease (ALD) represent a major public health problem worldwide. Only a minority of patients with an alcohol-use disorder (AUD) develop severe forms of liver disease (e.g., steatohepatitis and fibrosis) and finally progress to the more advanced stages [...] Read more.

Chronic alcohol consumption and alcohol-associated liver disease (ALD) represent a major public health problem worldwide. Only a minority of patients with an alcohol-use disorder (AUD) develop severe forms of liver disease (e.g., steatohepatitis and fibrosis) and finally progress to the more advanced stages of ALD, such as severe alcohol-associated hepatitis and decompensated cirrhosis. Emerging evidence suggests that gut barrier dysfunction is multifactorial, implicating microbiota changes, alterations in the intestinal epithelium, and immune dysfunction. This failing gut barrier ultimately allows microbial antigens, microbes, and metabolites to translocate to the liver and into systemic circulation. Subsequent activation of immune and inflammatory responses contributes to liver disease progression. Here we review the literature about the disturbance of the different host defense mechanisms linked to gut barrier dysfunction, increased microbial translocation, and impairment of liver and systemic inflammatory responses in the different stages of ALD. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Figure 1

Other

Jump to: Research, Review

11 pages, 1126 KiB

Open AccessBrief Report

Effect of DSS-Induced Ulcerative Colitis and Butyrate on the Cytochrome P450 2A5: Contribution of the Microbiome

by Stefan Satka, Veronika Frybortova, Iveta Zapletalova, Pavel Anzenbacher, Eva Anzenbacherova, Hana Kozakova, Dagmar Srutkova, Tomas Hudcovic and Lenka Jourova

Int. J. Mol. Sci. 2022, 23(19), 11627; https://doi.org/10.3390/ijms231911627 - 1 Oct 2022

Cited by 4 | Viewed by 3013

Abstract

Several studies have indicated the beneficial anti-inflammatory effect of butyrate in inflammatory bowel disease (IBD) therapy implying attempts to increase butyrate production in the gut through orally administered dietary supplementation. Through the gut–liver axis, however, butyrate may reach directly the liver and influence [...] Read more.

Several studies have indicated the beneficial anti-inflammatory effect of butyrate in inflammatory bowel disease (IBD) therapy implying attempts to increase butyrate production in the gut through orally administered dietary supplementation. Through the gut–liver axis, however, butyrate may reach directly the liver and influence the drug-metabolizing ability of hepatic enzymes, and, indirectly, also the outcome of applied pharmacotherapy. The focus of our study was on the liver microsomal cytochrome P450 (CYP) 2A5, which is a mouse orthologue of human CYP2A6 responsible for metabolism of metronidazole, an antibiotic used to treat IBD. Our findings revealed that specific pathogen-free (SPF) and germ-free (GF) mice with dextran sulfate sodium (DSS)-induced colitis varied markedly in enzyme activity of CYP2A and responded differently to butyrate pre-treatment. A significant decrease (to 50%) of the CYP2A activity was observed in SPF mice with colitis; however, an administration of butyrate prior to DSS reversed this inhibition effect. This phenomenon was not observed in GF mice. The results highlight an important role of gut microbiota in the regulation of CYP2A under inflammatory conditions. Due to the role of CYP2A in metronidazole metabolism, this phenomenon may have an impact on the IBD therapy. Butyrate administration, hence, brings promising therapeutic potential for improving symptoms of gut inflammation; however, possible interactions with drug metabolism need to be further studied. Full article

(This article belongs to the Special Issue Liver–Gut Axis 2.0)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Liver–Gut Axis 2.0

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (13 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI