Other neurotoxins include methionine derivatives such as thiols, phenols and fatty acids, they may act synergistically with ammonia. Food and gut-derived substances such as pseudoneurotransmitters such as octopamine, benzodiazepine ligands and GABA, are elevated in HE and have been blamed for interfering with neurotransmission.

However, their significance in HE pathogenesis is unclear. The excess ammonia in the intestine is transferred to the brain and causes brain damage.

The urease-producing bacteria which can produce ammonia and endotoxins such as Proteus and Klebsiella are increased in the intestine Milosevic et al. In contrast, genera over-represented in HE Megasphaera , Enterococcus , and Burkholderia were linked to poor cognition and inflammation Bajaj et al.

When compared to cirrhotic patients without HE, a higher proportion of Veillonellaceae was observed in HE, this bacteria was associated with increased inflammatory cytokines IL-6, TNF-α, IL-2, and IL and poor cognition.

The enrichment of the Alcaligenaceae family is related to poor cognitive ability. Proteobacteria is an opportunistic pathogen that can degrade urea to ammonia, and this gives a reasonable explanation for cognitive loss Bajaj, Therefore, it has been assumed that identifying specific fecal microbial characteristics could be used to predict the absence of minimal HE, instead of cognitive testing Bajaj et al.

These findings suggest that the microbiome composition of HE patients is closely related to cognition and inflammation. Hepatocellular carcinoma HCC is the third leading cause of high cancer mortality. Cirrhosis and viral hepatitis may progress to HCC Cabrera and Nelson, Experiments have provided evidence that gut microbiota plays a role in hepatocarcinogenesis Yu and Schwabe, Dipito et al.

found that TLR4 deletion can reduce the number and size of HCC, but cannot prevent the incidence of tumors Dapito et al. Thus, the TLR4-LPS pathway is not required for HCC initiation but HCC promotion.

When the gut barrier was disrupted, LPS from the gut promotes hepatocarcinogenesis through hepatic stellate cells, hepatocyte-tumor compartment, and Kupffer cells Gupta et al.

Another critical mechanism about the LPS—TLR4 axis promotes HCC formation is through NF­κB­mediated pathway. Activated TLR-4 further triggers inflammatory signaling pathways for NF­κB that induce the production and release of inflammatory cytokines IL-1β and IL Yu et al.

Moreover, LPS activates TLR4 in HCC cells can enhance their potential invasive ability and induce the transition of epithelial-mesenchymal Yu and Schwabe, Until now, studies conducted on the gut microbiome and different underlying liver cirrhosis, showing that at least some microbial changes have the same features to different aetiologies.

Secretion of bile reduced and changes in intestinal secretion of anti-microbial peptides and IgA at end-stage of liver disease. The common alteration of gut microbiota composition in patients with liver cirrhosis includes enrichment of Veillonella or Streptococcus and decrease of order Clostridiales Bajaj et al.

In addition, Escherichia coli were significantly increased in fecal samples of HCC patients compared to cirrhosis patients without HCC, indicating that hepatocarcinogenesis may attribute to the overgrowth of E.

coli Grt et al. The most common bacteria isolated from tongue swabs of patients with HCC are Oribacterium and Fusobacterium. On the other hand, decreases of Lactobacillus , Bifidobacterium and Enterococcus were observed in stool samples of HCC patients Zhang et al. It was also reported deoxycholic acid DCA accelerates the HCC development in obese mice by inducing the senescence-related secretory phenotype SASP in HSCs Yoshimoto et al.

In addition to synergy with DCA, lipoteichoic acid enters the liver through TLR2 and up-regulates the expression of SASP and COX-2 in senescent HSCs Loo et al.

Both gut microbiome and their metabolites play a vital role in the process of HCC, microbiome-targeted therapeutic modalities for HCC aroused great interest from scholars, and we will discuss possible approaches in detail in the next paragraph. Gut microbiota-related strategies to manage chronic liver disease were summarized in Table 2.

Table 2 Gut microbiota related strategies to manage chronic liver diseases. Many studies focus on dietary modification to optimize the structure of gut microbiota. Higher intakes of branched-chain amino acids BCAAs, leucine, isoleucine and valine and vegetable proteins have shown benefits in cirrhosis patients Fukushima et al.

BCAA-enriched diet can reduce the progression of liver failure in patients with advanced cirrhosis, which can reduce the severity and frequency of HE, and improve quality of life. Thiamine supplementation should be considered in severely alcoholic patients Satish and Shaik, Fat-soluble vitamin supplementation should be considered in conditions of cholestatic Atarashi et al.

Vitamin K supplementation is only to be considered at high risk of a hemorrhagic situation Atarashi et al. Zinc and magnesium supplementation can indirectly improve nutrient intake and nutritional status Garrett-Laster et al. Calcium and vitamin D supplementation could be considered in patients with cholestasis and osteoporosis Francis, SCFAs regulate liver metabolism and immune function by inhibiting histone deacetylase or activating G-protein coupled receptors, including GPR41, GPR43, GPRa, and OLFR In addition, acetate and propionate have anti-inflammatory properties and inhibit hepatic lipogenesis and lipid accumulation Sahuri-Arisoylu et al.

Butyrate can modulate the GM composition, increase the expression of glucagon-like peptide-1 receptors GLP-1R , reduce inflammatory signals and liver oxide damage, ultimately attenuate steatohepatitis Jin et al.

Recently, Beaumont et al. have proved that after feeding the mice with indole, the expression of tight junction protein was up-regulated, and the mice display resistance to liver inflammation Beaumont et al.

Choline deficiency in diet could lead to reversible hepatic steatosis. Choline has a function in removing fat from hepatocytes Yu et al.

Metagenomic analysis of the microbial communities in the intestinal tracts of 15 women showed that increased Gammaproteobacteria and decreased Erysipelotrichi can prevent steatosis with a choline-depleted diet Spencer et al.

Antibiotics can decrease the total number of gut microbiota, eliminate bacteria with a high ability to translocate and inhibit pro-inflammatory signals arising from the gut ecosystem Zhang et al. Rifaximin could be used to treat HE in clinical trials Kimer et al. It may increase the number of beneficial bacteria while decreasing the number of harmful bacteria, and also improve beneficial bacteria function.

Rifaximin could reduce gut-derived toxins and reduce serum pro-inflammatory cytokines levels Ponziani et al. It may also affect gut microbiota metabolites Bajaj, The research tested the functions of rifaximin on cirrhotic patients with minimal HE.

They analyzed both the structure of gut microbiota and the metabolome of serum and urine. The results showed that after eight weeks of rifaximin treatment, cognition and endotoxemia could be improved. However, the unsaturated and saturated fatty acids in the serum were significantly increased after rifaximin treatment.

The results showed rifaximin does not change the overall composition and diversity of gut microbiota, it modifies the metabolites of the bacteria. Rifaximin can also increase the concentration of linoleic and arachidonic acids, which have brain beneficial functions Tang, Many studies have reported that probiotics have beneficial effects on liver health.

Probiotics have functions in improving nutritional stations, repairing mucosal barrier, providing short-chain acids to prevent apoptosis, improving intestinal epithelial viability Kanauchi et al. These functions prevent the disturbance of pathogens on tight junctions.

Lactobacillus GG can improve intestinal oxidative stress, intestinal leakage, and liver injury in the alcoholic steatohepatitis rat model Forsyth et al. In patients with alcoholic cirrhosis, probiotics Lactobacillus casei Shirota may restore phagocytosis of neutrophils by changing IL secretion and TLR4 expression Stadlbauer et al.

The effectiveness of probiotics on liver cirrhosis can be divided into improving liver function and preventing pathogens infection, hepatic encephalopathy, and other complications.

Intake of VSL 3 daily for six months significantly reduced the risk of hospitalization for HE and improved Child-Turcotte-Pugh CTP and model for end-stage liver disease scores MELD in patients with cirrhosis Dhiman et al.

The ability of probiotics to modulate GM has therapeutic potential. There is some evidence regarding probiotic usage to treat spontaneous bacterial peritonitis SBP and HE. Further research in evaluating gut microbiota and appropriately selected beneficial bacterial strains as treatment modalities should be undertaken Forsyth et al.

Prebiotics are non-digestible but fermentable food substances fermented by bacteria and help the intestine peristaltic and selectively stimulate the growth of gut bacteria.

Some prebiotic foods, like lactulose and pectin, seemed to be promising therapeutic agents to treat liver diseases. Lactulose is an unabsorbable disaccharide, which can acidify the intestinal cavity, inhibit urease-producing bacteria, and limit the diffusion of ammonia into the blood Phongsamran et al.

The main treatment for HE patients is to target the intestine to reduce colonic bacterial generation and reduce blood ammonia.

Pectin can restore the levels of Bacteroides and prevent liver damage in rodent models Ferrere et al. A meta-analysis of NAFLD patients showed significant reductions in BMI, liver enzymes, serum cholesterol, and triglycerides after prebiotic treatment. This suggests that prebiotics may improve NAFLD by regulating intestinal flora homeostasis Loman et al.

Fructooligosaccharide FOS can promote fatty acid oxidation by up-regulating peroxidase expression, inhibiting the expression of SREBP-2 in the liver, and reducing the accumulation of cholesterol Matsumoto et al.

This showed oligosaccharides could reduce bacterial overgrowth and improve alcoholic steatohepatitis by restoring the expression of partial lectin protein reg3g. Lactulose is prebiotic which can promote the growth of Bifidobacterium and Lactobacillus.

Fan et al. used lactulose to treat NASH mice. Symbiotics consist of a combination of probiotics and prebiotics. Symbiotics have the function of regulating the expression of intestinal flora and related functional genes. It can reduce the colitis reaction and liver inflammatory response, reduce the level of SCFA in feces, enhance tight junction of the intestinal barrier, and improve fatty degeneration of the liver as well as insulin resistance.

Meanwhile, symbiotics can reduce the degree of liver fibrosis and LPS in mice. Clinical research indicated that after six months of intervention by Bifidobacterium longum and FOS in 66 NASH patients, serum AST, LPS, and inflammatory response transmitters HOMA-IR , fat denaturation and NASH activity index were significantly reduced Malaguarnera et al.

Symbiotic treatment could be an ideal approach to treat liver diseases since they can protect against inflammation and hepatocyte damage through probiotics and prebiotics. The mechanism of symbiotic protection has not yet been fully clarified. Potential mechanisms of symbiotic effect on liver disease include gut microbiota structure and microbiota metabolite alteration, which have anti-inflammatory and immunomodulatory effects.

There are no adverse effects that have been reported with this approach. Fecal microbiota transplantation FMT means transplanting bacteria from the feces of healthy individuals into the recipient through a series of routes Xu et al. FMT can restore the health of intestinal flora, further reduce the transport of endogenous ethanol, endotoxin, and other metabolites to the liver, reduce the damage of metabolic substances to the liver, and also effectively reduce the inflammatory response and the expansion of liver cells.

Compared with the oral probiotics method, FMT can significantly improve intestinal bacteria disorder, and FMT is the most effective method to restore intestinal microecological balance currently. FMT has been studied more deeply in recent years. The possible mechanism of FMT involves establishing beneficial microbes in the gut and the production of anti-microbial substances.

The number of Bacteroides in alcohol-sensitive mice decreased, and the number of Actinobacteria and Firmicutes increased. Alcohol-sensitive mice had fifty percent fewer Bacteroides than alcohol-resistant mice Ferrere et al. Zhou et al. used fecal bacteria transplantation to treat NAFLD mice caused by a high-fat diet.

The results showed that fecal bacteria transplantation could improve intestinal flora disorder, enhance intestinal barrier function and reduce liver steatosis Zhou et al.

At present, FMT has successfully treated Clostridium difficile infection patients in clinical and promoted the recovery of intestinal ecological balance. Simultaneously, the clinical results showed that the improvement effect was better than that of standard antibiotics.

A clinical trial showed that FMT showed good safety in 10 patients with primary sclerosing cholangitis complicated with IBD, and it could effectively reduce alkaline phosphatase in some patients. Liver enzymes, fecal microflora, and fecal metabonomics were analyzed at 1, 4, 8, 12, and 24 weeks after FMT.

FMT rarely has adverse events. Therefore, FMT can be used as an effective method to treat and prevent chronic liver disease.

The preliminary basic research shows that FMT can restore the probiotics in the intestinal ecosystem Craven et al. Therefore, fecal bacteria transplantation could be a valuable and safe treatment for cirrhosis.

The advantage of FMT is that it can rebulid the whole dysbiotic intestinal environment, but the best optimal route of administration, the duration of treatment and the durability of reaction still need to be determined. There is an urgent need for large-scale and high-quality research in this field in order to evaluate the most effective method to achieve rebiosis.

The gut microbiota plays an important role in the pathogenesis of chronic liver diseases, including NAFLD, ALD, Hepatitis Virus Infection, PCS, cirrhosis, and HE.

The mechanism of connection between liver diseases and the intestine is poorly understood. Intestinal permeability is closely related to chronic liver disease. The increase of intestinal permeability will lead to the release of intestinal inflammation factors and cause flora dysbiosis, which contributes to liver disease development Fukui, The liver can communicate with the gut through bile acids circulation.

The binding of BAs to FXR can induce anti-microbial peptides to produce, which can inhibit gut microbial overgrowth and improve gut barrier function. Choline assists the liver in excreting VLDL particles, preventing the accumulation of triglycerides in hepatic steatosis.

Intestinal bacteria can convert choline into TMA. TMA can be transferred to the liver and converted to TMAO, which is associated with liver injury. Gut microbiota also can produce SCFAs including butyrate, propionate, acetate, etc.

Butyrate can reduce intestinal permeability and subsequent liver injury induced by alcohol. Since the gut microbiota places an important role in the progress of the chronic liver disease, we believe the gut-microbiota-targeted interventions could be used to regulate the intestinal flora community and manage chronic liver diseases.

However, a comprehensive understanding of the interactions between microbes and liver diseases is still not clear. Although animal models help to elucidate many important mechanistic pathways in the etiology of liver diseases. From animal models to human models requires well-designed, large-scale clinical trials spanning multiple disease aetiologies and patient characteristics.

With the increasing recognition of the role of the microbiome in the development, prognosis, and treatment of liver diseases, we emphasize the need for a focus on the microbiome to effectively address the socioeconomic burden of this type of liver disease.

Furthermore, it is critical to use animal models that mimic human disease as closely as possible. JL contributed to manuscript writing.

DY, XW, QZ, and LN critically reviewed the manuscript. PA critically edited the English in the manuscript. LS supervised the whole process and reviewed the manuscript.

All authors contributed to the article and approved the submitted version. This research was financially supported by the Natural Science Foundation of Shanghai 20ZR , the National Natural Science Foundation of China , Shanghai Excellent Technology Leader Program 17XD , Shanghai Municipal Public Health System Construction Three-Year Action Plan GWV The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Cancer Cell 21, — Del Rio, D. The first group are your androgens, like testosterone , and your estrogen; the second are progesterone and cortisol. Cholesterol is necessary in order to manufacture hormones. When people take statins to lower their cholesterol, one of the main side effects is the loss of their sex drive and function due to the reduction in the production of sex hormones.

In addition to making hormones, the liver and gut are also where hormones are broken down and metabolized when they are ready to be removed. The liver has enzymes which help to detox excess hormones and any environmental toxins your body needs to get rid of. These enzymes break hormones down before they are emptied into the intestines, where your microbiome, or the layer of friendly microbes made of bacteria and yeast, further dismantles used and excess hormones.

After they have been broken down, they are eliminated through the natural waste process. I recommend all health regimes begin with cleansing and repairing the gut and the liver. In my practice, I start all my patients on a one-month clean-up campaign to support the healthy functioning of these two organs, which will immediately begin to have a balancing effect on hormones.

This detoxification effort involves removing alcohol, certain foods, and beauty and cleaning products that may be stressing your body due to the presence of endocrine-disrupting chemicals.

When it comes to alcohol, drinking in moderation may be fine for people who are healthy and whose liver and gut are working properly. However, it can be problematic and lead to hormonal disruptions if the liver is working overtime to eliminate other chemicals.

Once the liver and gut are clean and ready, you have a solid foundation on which to build in the next phase of treatment: adding nutrients, food, and supplements to support the balancing and repairing of hormone imbalances or any other specific health problem you are facing.

Not only is this the key to helping your supplements and food work more efficiently, but when you take the time to make sure your digestive system is in top shape, you can focus on having fun in life without worrying that health issues might pop up and derail you. The gut and liver are truly the foundation of good health.

Over the course of the study, researchers compared the gut microbiota of those with NAFLD to those without it. They discovered that 60 percent of the participants who had NAFLD also had a strain of alcohol-producing HiAlc Kpn bacteria at either high or medium levels in their guts.

Because this particular strain of bacteria produces such a higher level of alcohol, it can be difficult for the body to cope.

And even if you never take a sip of alcohol, your gut bacteria might be wreaking unexpected havoc on your liver. The researchers then took their work one step further and tested their hypothesis in mice.

When mice were infected with the HiAlc Kpn bacteria, they began to develop NAFLD within just one month. By the second month, those same mice were starting to show signs of long-term liver damage like liver scarring. But there was a bit of good news discovered: When researchers gave the mice an antibiotic to kill the HiAlc Kpn bacteria, their liver health improved.

While more studies are needed to determine if antibiotics could be helpful for fatty liver disease, these results offer a promising glimpse into potential treatments.