The Gut Microbiome and Liver Disease

The Microbial Influence on Cirrhosis Development and Progression

World Liver Day is celebrated annually around the world, promoting the study of the liver and liver diseases. The theme for 2025 is ‘Food is Medicine’, focusing on raising awareness of how a balanced diet can help prevent illness and support healthy liver function. We have therefore chosen to honour this day by shining a light on the relationship between the gut and the liver, and how the gut microbiome has a link with liver diseases, such as cirrhosis.

Cirrhosis is a serious chronic liver condition in which normal functioning tissue (parenchyma) is replaced with scar tissue.  Early symptoms include tiredness, weakness and loss of appetite, later progressing to itchiness, swollen lower legs, ascites and jaundice _[1]. Approximately 45% of cases are caused by alcohol abuse and 41% by hepatitis C infection.  Incidence is higher in men and the mean age at diagnosis is 59.5 - 62.4 years, but rates are increasing in younger people _[1]. The pathophysiology is focal in the liver, but the gut does play a key role in terms of blood and toxin supply _[1]. During severe liver injury, hepatic myofibroblasts and macrophages are activated, and fibrosis occurs in the extracellular matrix, which subsequently disrupts the blood flow between hepatocytes and sinusoids _[1]. There is also a loss in hepatocytes, limiting the metabolic function of the liver in protein synthesis, nutrient storage, bilirubin clearance and detoxification _[1]. One grave result of cirrhosis progression is hepatic encephalopathy.  In healthy subjects, nitrogen-containing compounds from the intestine, generated by gut bacteria from food, are transported to the liver, where 80% – 90% are metabolised and/or excreted immediately. This process is impaired in cirrhosis, allowing these compounds to reach the brain _[1]. Gut-derived toxins such as ammonia are amongst the causes of hepatic encephalopathy _[1]. Pivotal in this process is the gut-liver axis: the bidirectional communication between the gut, its microbiome, and the liver. This communication is facilitated by the portal vein, which carries nutrients and gut-derived products to the liver, and the liver's feedback through bile and antibodies to the intestine. F

When the intestinal barrier has increased permeability, toxins and pathogen-associated molecular patterns travel across the barrier and act on hepatocytes as well as the Kupffer cells and stellate cells of the hepatic innate immune system; gut dysbiosis may further exacerbate these issues _[2]. The liver also has a key role in regulating microbial populations by influencing intestinal microbes via bile acids and immunoglobulin A _[2].

Much research has focussed on the influence of the gut microbiome and the liver, more specifically the microbial communities in advanced cirrhosis.  Metagenomic sequencing of faecal and saliva samples in patients with cirrhosis _[3] has revealed changes in the gut and oral microbiome.  As cirrhosis progresses, there is a reduction in alpha-diversity _[3] and an increased prevalence of pathobionts, such as Enterococcaceae.  Bacterial families such as Veillonellaceae and Streptococcaceae were found in significant numbers as cirrhosis severity increased _[3]. Escherichia and Campylobacter were among the pathobionts present in one of the salivatypes, SAL2, which is arguably unexpected as these commensals originate in the lower intestine and are not usually found in the oral cavity _[3]. There are also a substantial number of antimicrobial resistance genes in the oral and gut microbiomes in those with cirrhosis; this is a significant clinical concern, as subsequent infections in those with cirrhosis may be more difficult to treat, leading to poorer medical outcomes _[3].

The relationship between oral/gut microbial composition and liver disease severity suggests that the gut-liver axis link could be a possible therapeutic target for cirrhosis.  Targeting gut microbes with treatments such as faecal microbiota transplantation, or probiotics could be viable avenues to explore. Since the oral-gut-liver axis has a vital role in systemic complications in cirrhosis, targeting the oral/gut microbiome could be a way of improving clinical outcomes including survival and quality of life.

References

1. Tapper E, Parikh N. Diagnosis and Management of Cirrhosis and Its Complications A Review. HHS Public Access. 2023 May 9;329(18):1589–602.
2. Konturek P, Harsch I, Konturek K, Schink M, Konturek T, Neurath M, et al. ut–Liver Axis: How Do Gut Bacteria Influence the Liver? ut–Liver Axis: How Do Gut Bacteria Influence the Liver? 2018 Sep 17;17(6).
3. Lee S, Arefaine B, Neelu N, Stamouli M, Witherden E, Mohamad M, et al. Oral-gut microbiome interactions in advanced cirrhosis: characterisation of pathogenic enterotypes and salivatypes, virulence factors and antimicrobial resistance. Journal of Hepatology. 2025 Apr 1;82(4):622–33.