Gastrointestinal Microbiome in Liver Disease

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1		Nicholas Shalaby	--	2106	2023-09-14 01:20:40	\|
2	format	Jason Zhu	-2 word(s)	2104	2023-09-14 03:34:45	\|

This entry is adapted from the peer-reviewed paper 10.3390/pathogens12091087

Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids.

microbiome liver fibrosis cirrhosis gastrointestinal

1. Introduction

Liver disease causes approximately two million deaths a year, posing a significant global health problem ^[1]. This is the consequence of several aetiologies, including alcohol-related and metabolic-related disease, viral infections, cholestasis and immune disease, leading to fibrosis and, eventually, cirrhosis. While various pharmacological agents are under study, there are currently no specific antifibrotic therapies available to reverse liver fibrosis, so treatment aims at managing the underlying factors to mitigate the development of liver disease ^[2]. Given the bidirectional relationship between the liver and gastrointestinal tract (GIT) mediated through the gastrointestinal microbiota, there is increasing interest in the gastrointestinal microbiome and its capacity to affect liver disease and how this may be manipulated therapeutically.

2. Modifying the Intestinal Environment

Prebiotics, as part of dietary interventions, can ameliorate dysbiosis, potentially mediating the complex interactions between the microbiome and liver disease. Optimising the substrates available to the microbiota alters the intestinal microbiome and may be a safe and low-cost method of resolving dysbiosis. Specifically, high-fibre diets are associated with a healthy microbiome.

Dietary fibre intake is associated with a healthy microbiome but is neglected in the prototypical Western diet. Some fibres are generally poorly fermented by microbiota but boost intestinal transit, while other fibres are highly fermentable into SCFAs. These fermentable fibres act as a nutrient source for the microbiota, therefore, influencing bacterial growth ^[3]^[4]. A systematic review and meta-analysis of 64 studies showed that a high-fibre diet reduces inflammation potentially by increasing the population of Bifidobacterium ^[5]. However, the mechanism for this and the effects of different fibre types on the microbiome remain unclear due to the limitations of these being correlative studies. A double-blind parallel trial conducted on 50 overweight 45–70-year-old men found that a 12-week refined fibre diet increased liver fat and may contribute to MASLD development, while a wholegrain diet was not associated with increased liver fat ^[6].

Prebiotic ingredients, including some types of dietary fibre, are indigestible by human digestive enzymes and serve as substrates to specific bacteria and have shown promise in liver disease. Several prebiotic sources exist, including oats, unrefined wheat, unrefined barely, yacon, pulses as well as indigestible carbohydrates and oligosaccharides. Inulin, a fibre, showed beneficial effects on ALD in a study conducted on mice. Mice were divided into four groups: a control group not fed inulin, another fed inulin and alcohol-fed groups with and without inulin. This demonstrated that alcohol-fed mice supplemented with inulin had a significantly increased content of SCFA, including butyrate, propionate and valerate, increased M2 macrophages, arginase-1 and interleukin 10 compared to the alcohol-fed group that was not treated with inulin. Further, inulin feeding significantly reduced M1 macrophages, inducible nitric oxide synthase and TNF-α ^[7]. As a result, inulin supplementation may provide benefits by increasing SCFA synthesis in liver disease. Further research is required to validate other prebiotic ingredients in the context of liver disease.

While dietary fibre and prebiotics have positive effects on the microbiome, simple sugars can have harmful effects mediated by alterations to the intestinal barrier. Fructose, one of the three simple sugars, is primarily metabolised in the liver by the enzyme fructokinase C ^[8]^[9]. This enzyme is also significantly expressed in the small intestine. Ishimoto et al. found that when fructose is metabolised in the small intestine of mice, there is a disruption to tight junctions that are not observed in fructokinase knockout mice. It is postulated that this is the reason for increased gut permeability secondary to fructose consumption ^[10]. This increased gut permeability leads to endotoxins leaking into the portal vein, which in turn contributes to hepatic inflammation. It is important to note that in that study, the mice were fed a 30–45% fructose diet, whereas the typical Western diet would contain 10–15%. Given these effects, the reduction of simple sugars may be a dietary intervention for individuals with cirrhosis and dysbiosis.

High-fat diets have also been shown to alter the microbiome. David et al. showed that a short-term, high-fat diet compared to a high-fibre plant-based diet, increased the relative abundance of bile-tolerant bacteria ^[11]. While this trial included only nine subjects, a larger study (n = 217) by Wan et al. showed that a higher fat diet increased the relative abundance of Alistipes and Bacteroides and decreased the relative abundance of Faecalibacterium ^[12]. Additionally, a recent meta-analysis concluded that high-fat diets resulted in dysbiosis, promoting inflammation ^[13]. High-fat diets are, by definition, low in fruit, wholegrain and legumes and, therefore, low in dietary fibre, which probably explains the effect on the gut microbiota. In any case, given the minimal data collected (only 29 human faecal samples), the differences between experimental food sources and complex human diets as well as the inter- and intra- individual variation in the microbiome, larger studies should be conducted for these results to be conclusive. It is also important to note that there are different types of fat in the diet, and although high fat intake is associated with negative changes, not all fats are harmful to the microbiome. One study has shown that intake of omega-3 fat correlated with higher microbiota diversity and positive changes to microbiome composition in 876 twins ^[14].

3. Targeting the Microbiome Directly

Antibiotics can be used to target the microbiome. The use of nonabsorbable antibiotics to target the microbiome in liver disease is attractive to reduce broader effects. Rifaximin is one such antibiotic with a wide range of antimicrobial activity and minimal drug interactions and has shown promising results in patients with cirrhosis. A placebo-controlled, double-blind study conducted on 38 patients with cirrhosis and hepatic encephalopathy found that rifaximin-α led to a resolution of overt and covert hepatic encephalopathy, reduced infection likelihood, decreased oralisation of the gut and lower systemic inflammation. Further, this found that rifaximin-α largely mediates its anti-inflammatory effects via gut barrier repair, in turn reducing bacterial translocation and endotoxemia ^[15]. However, despite the promise that antibiotics show as a viable therapy that could be implemented relatively soon, concerns surrounding drug resistance and their lack of specificity remain. As a result, other bactericidal therapies that can be engineered to be more specific may be more desirable in eliminating dysbiosis.

Bacteriophages are viruses that usually target only a single bacterial species which can undergo lytic or lysogenic replication after infecting a host bacterium. In lytic replication, the host cell resources are rapidly utilised to create viral genomes and capsid proteins, causing the cell to die and more copies of the virus to be released ^[16]. This may prove to be a useful method of killing targeted bacterial species that are resistant to antibiotics because the continual evolution of these viruses overcomes bacterial defences via an independent mechanism of action from antibiotics. One study conducted on 26 participants without alcohol use disorder, 44 with alcohol use disorder and 88 with alcoholic hepatitis found that bacteriophages were able to specifically target Enterococcus faecalis, a bacterium that is associated with more severe liver disease ^[17]. As a result, these bacteriophages, if developed to target pathobionts in dysbiosis, may provide a new bactericidal tool that may be deployed to improve microbiome health and hence hepatic fibrosis.

Probiotics are live bacteria or yeasts, which, when consumed, may provide benefits by supporting a healthy microbiome. A study of 58 patients with MASLD administration of a multiprobiotic over 8 weeks was able to improve fatty liver, aminotransferase activity and TNF-α and interleukin-6 levels ^[18]. Further, a phase I trial conducted on patients with cirrhosis demonstrated that the administration of Lactobacillus rhamnosus GG was safe and was able to modulate the microbiome, decreasing Enterobacteriaceae, endotoxemia and TNF-a while increasing Lachnospiraceae ^[19]. Further, in mice with induced liver fibrosis, Lactobacillus rhamnosus GG supplementation was associated with a reduction in liver enzymes. In addition, Saccharomyces cerevisiae and Lactobacillus acidophilus protected mice from inflammation and hepatic oxidative stress by altering signalling pathways, further supporting the efficacy of probiotics to modulate the microbiome and improve health ^[20]. A meta-analysis published in 2016, analysing results from 14 studies including 1152 individuals with cirrhosis, found that probiotics were effective in improving minimal hepatic encephalopathy and preventing its progression ^[21]. However, the same has not been found in primary sclerosing cholangitis, where a small pilot trial found no significant changes to liver markers after three months ^[22]. One method of overcoming this may be to engineer probiotics in order to target or improve specific effects more effectively; this is currently being explored in clinical trials ^[23]. Additionally, it is important to note that dietary supplements of probiotics are often ineffective due to strain and dosing differences between studies and due to personalised responses to probiotics ^[24]. Further, many of these products were developed prior to a well-established understanding of the composition of the microbiome. As such, many of the commercially available probiotic formulations are ineffective at truly altering the microbiome.

FMT is another treatment modality that may become useful in treating liver disease. FMT can be administered via different routes and is mainly used to treat persistent infections with Clostridioides difficile. However, the understanding of the ecological forces that affect the microbiome is still limited, so continued research examining mechanisms, safety, efficacy and methods of collection and transplantation is vital for safer and more effective FMT ^[25]. A randomised control study of 47 MASLD patients who received FMT and 28 MASLD patients who instead received probiotics orally found that FMT was able to decrease liver steatosis and improve dysbiosis, in turn attenuating MASLD ^[26]. Unfortunately, the current body of FMT research in the context of liver disease is limited, often with small sample sizes and without conclusive evidence of long-term efficacy due to the logistical and regulatory difficulties in conducting these trials. If FMT is to become a widespread and accepted practice, high-quality evidence identifying optimal, safe protocols and indications is required. Current research concludes that FMT had no increase in adverse event rates in severe alcoholic hepatitis, MASH and cirrhosis ^[27]^[28]^[29]. Furthermore, in cirrhosis, FMT via oral capsules after antibiotic use has been shown to be safe in the long term ^[30]. These findings, however, need to be confirmed in larger cohorts with blind, randomised control trials that demonstrate a clear benefit before clinical adoption can be achieved.

4. Metabolites and Their Pathways

The interconnection between the microbiome and liver in the bile acid pathway could be leveraged to prevent fibrosis by reducing intestinal permeability or altering the microbiome ^[31]^[32]^[33]. This is possible by treating patients with exogenous FXR agonists. When FXR activation occurs in ileal enterocytes, the expression of fibroblast growth factor 19 (FGF19) is induced. This reaches the liver and, through the portal circulation, activates the fibroblast growth factor receptor 4 (FGFR4)/b-klotho complex on hepatocytes and inhibits the expression of cytochrome P7A1, which reduces bile acid synthesis. This creates a negative feedback loop resulting in reduced FXR activation and is therefore associated with liver fibrosis ^[31]^[32]^[34]. In the ‘Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis’ (FLINT) study, obeticholic acid (OCA), an FXR agonist, was shown to improve primary histological outcomes significantly and reduce liver fibrosis in MASH ^[33]. Some mechanisms of FXR activation that induce these outcomes include the reduction in inflammatory mediator expression in HSCs via the induction of peroxisome proliferator-activated receptor gamma (PPARγ), inhibition of TGF-beta signalling, sensitising HSCs to apoptotic signals, reducing HSC contractility, mitigating collagen expression and increasing matrix metalloprotease activity ^[31]. The FLINT study encouraged the exploration of more efficient and safer FXR agonists of which several are undergoing clinical trials with promising results. One such compound, cilofexor, in a double-blind, placebo-controlled phase 2 trial of 140 patients with MASH, was found to be well tolerated and reduced hepatic steatosis and improved liver markers and serum bile acids over a 24-week period ^[35].

Another means of modulating bacterial byproducts is via carbon nanoparticles such as Yaq-001, a nonabsorbable carbon that can absorb bacterial products such as LPS effectively. As a result, it may be used to counteract gut microbiota alterations and translocation of bacterial-derived products in patients with advanced chronic liver disease. In a study of 12 mice with induced cirrhosis via biliary duct ligation and 12 control mice, increases in Firmicutes and decreases in Bacteroidetes as well as significant reductions in LPS-induced ROS have been demonstrated ^[36]. Before these treatments are available to patients, their safety and efficacy in humans must be tested; this is ongoing through the CARBALIVE study ^[37].

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