Microbiome and complications of liver disease

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Abbreviations

HE

hepatic encephalopathy

MLN

sterile mesenteric lymph node

SBP

spontaneous bacterial peritonitis.

The progression of chronic liver disease occurs through a systemic proinflammatory profile that promotes complications such as hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and ascites.1 Microbiota can influence the development of hepatic fibrosis and can potentiate this inflammatory milieu through dysbiosis, which refers to a microbial imbalance that can negatively impact the host.2 Therefore, most treatments in cirrhosis focus on changing the microbial landscape.3 Gut microbiota studies are evolving in cirrhosis, but important questions remain (Table 1).

Table 1.

Relevant Questions Regarding Studies of Microbiota and Cirrhosis

Are the microbiota changes simply due to advancing liver disease?

Are there specific microbiota changes in the mucosa, stool, or other body surfaces and fluids in patients with cirrhosis?

Is it the relative change in microbial abundance or a change in function that results in overall improvement?

What are the effects of treatments on microbiota?

Bacterial Translocation

Bacterial translocation, a seminal event in the progression of cirrhosis, has been described in animal and human studies.4, 5 Translocation is defined as the presence of viable bacteria in the normally sterile mesenteric lymph nodes (MLNs). Consequently, it is assumed that either the lymphatic drainage or the portal vein transport of bacteria results in infections. In humans, MLN culture positivity has been associated with cirrhosis severity.4 Interestingly, as opposed to the fecal microbiota consisting largely of families belonging to Bacteroides and Firmicutes phyla, the majority of bacteria found in MLNs and ascites belong to Enterobacteriaceae. Although the exact mechanisms are unclear, changes in intestinal barrier, immune surveillance, or specific microbial pathogenicity could potentiate this translocation.

Microbiota Composition

Significant small bowel bacterial overgrowth occurs in cirrhosis, especially with HE.6 On culture‐independent sequencing, patients who have cirrhosis, especially with decompensation, have been noted to have a higher relative abundance of potentially pathogenic families such as Enterobacteriaceae and lower commensal bacteria such as Clostridiales incertae sedis XIV, Ruminococcaceae, and Lachnospiraceae.7 These commensals usually prevent pathogenic bacterial overgrowth and generate beneficial short‐chain fatty acids.7 The imbalance between commensal and pathogenic taxa could potentiate bacterial translocation and has been associated with organ failure and death in inpatients who have cirrhosis.8 Interestingly, it has been shown that despite significant differences in clinical phenotype, stool microbiota changes are not significantly different in cirrhosis patients with or without HE.9 In contrast, it has been reported that colonic mucosal microbiota are different between HE and non‐HE patients with higher dysbiosis in HE.10 This suggests that the location of microbial change may influence the host differently. Dysbiosis in cirrhosis also extends to the ascitic fluid and liver with increasing abundance of Enterobacteriaceae.11, 12 Several studies have shown a significant increase in dysbiosis with worsening cirrhosis severity. Dysbiosis also depends on disease etiology; in mice, it has been shown that bile duct ligation and CCl₄ injury have disparate effects on the microbiota.13 This finding has also been reported in human subjects where, despite cirrhosis, alcoholism and nonalcoholic steatohepatitis had different microbial signatures.8 Interestingly, away from the gut–liver axis, dysbiosis has also been reported in cirrhotic salivary microbiota, which likely reflects a global mucosal‐immune change.14 Table 2 provides an overview of human studies evaluating culture‐independent cirrhotic microbiota composition.

Table 2.

Human Studies Evaluating Culture‐Independent Cirrhotic Microbiota Composition

Study	Population Groups	Tissue Tested	Findings	Relationship With Potential Clinical Endpoints/Outcomes
Chen et al.29	Cirrhosis, controls	Stool	Higher Streptococcaceae, Veillonellaceae, and Enterobacteriaceae and lower Lachnospiraceae in the cirrhosis group	Streptococcaceae were positively linked and Lachnospiraceae were negatively linked with Child‐Pugh score
Bajaj et al.9	Overt HE, no overt HE, controls	Stool	Higher Enterobacteriaceae, Alcaligeneceae, and Fusobacteriaceae and lower Ruminococcaceae and Lachnospiraceae in the cirrhosis group	Higher Veillonellaceae in HE compared with no HE in cirrhosis patients; Alcaligeneceae and Porphyromonadaceae were correlated with cognition
Bajaj et al.10	Overt HE, no overt HE, controls	Sigmoid mucosa and stool	Higher Dorea, Subdoligranulum, Incertae Sedis XIV, Blautia, Roseburia, and Faecalibacterium and lower Enterococcus, Burkholderia, and Proteus in cirrhosis group	Enterococcus, Megasphaera, and Burkholderia were linked to poor cognition and higher inflammation, whereas the opposite was seen for Enterococcus, Megasphaera, and Burkholderia; Alcaligeneceae and Porphyromonadaceae were associated with poor cognition
Zhang et al.30	Minimal HE, no minimal HE, controls	Stool	Higher Streptococceae and Veillonellaceae in the cirrhosis group, higher Streptococcus salivarius in the minimal HE group	Correlation of cognitive function and ammonia with Veillonella parvula and Streptococcus salivarius
Lu et al.31	Hepatitis B from pre‐cirrhosis to decompensated cirrhosis patients	Stool	Lower lactic acid bacteria, Bifidobacteria, and Clostridiales XIV in advancing hepatitis B virus with increase in Enterobacteriaceae in the cirrhosis group	Higher fecal secretory IgA and TNF‐α was seen in hepatitis B virus patients with cirrhosis with worsening gene virulence abundance
Bajaj et al.8	Cross‐sectional and longitudinal study of cirrhosis patients through the spectrum of disease	Stool	Cirrhosis dysbiosis ratio worsened with advancing cirrhosis and remained stable in unchanged disease; was associated with 30‐day mortality, organ failure, and acute‐on‐chronic liver failure in infected patients	In patients who develop their first overt HE episode, there is increase in dysbiosis despite lactulose therapy
Qin et al.19	Cirrhosis, controls, diabetes patients	Stool	Dysbiosis with bacteria normally found in oral microbiota was found in cirrhosis patients, which was different from diabetes	Association with GABA, ammonia, and manganese metabolism in cirrhosis‐associated microbiota
Rogers et al.12	Cirrhosis with ascites	Ascites	Viable bacteria were found in a large proportion of uninfected cirrhosis patients and were mostly Proteobacteria	Bacteria were correlated with ascitic fluid polymorphonuclear cells and Child‐Pugh score
Tuomisto et al.11	Cirrhosis, controls on autopsy	Stool, ascites, and liver	Fluids/organs in cirrhosis patients had significantly higher bacteria compared with controls	Enterobacteriaceae were the most common bacteria in the liver in cirrhosis patients
Bajaj et al.14	Overt HE, no overt HE, controls	Saliva and stool	Increased dysbiosis in both biofluids with Streptococcaceae being predominant in saliva and Bacteroidaceae in stool	Stool microbiota were more correlated with systemic inflammation than salivary microbiota

Abbreviations: GABA, gamma aminobutyric acid; HE, hepatic encephalopathy; IgA, immunoglobulin A; TNF‐α, tumor necrosis factor α.

Microbiota Function

Microbial function, measured using bacterial products, gene activation and metabolite interactions, is a critical component of microbiota change. Products of bacterial metabolism that have been altered in cirrhosis are secondary bile acids and endotoxin, as well as cometabolites such as hippurate and tri‐ and dimethylamines.15, 16, 17, 18 With advancing cirrhosis, there is increased endotoxemia (reflecting increased gram‐negative bacteria) and reduction in total and relative secondary bile acid proportion given that the 7‐α dehydroxylation is restricted to a specific group of autochthonous taxa (bacteria that are indigenous, commensal, and potentially beneficial to the host) that are low in cirrhosis.17 Serum and urine metabolites also change with therapy. Metagenomics of the stool in cirrhosis show activation of different pathways in stool of patients with cirrhosis related to gamma aminobutyric acid, ammonia, and manganese metabolism.19 Therefore, functionality of microbiota is critical when evaluating the effects of disease processes or treatments.

Effect of Therapy

Although treatments that affect gut microbiota (eg, rifaximin, lactulose, prebiotics and probiotics for HE, and antibiotics for SBP prophylaxis) improve outcomes in patients with cirrhosis, their mechanism of action is unclear.20, 21, 22 Preclinical studies with probiotics have not shown reduced bacterial translocation consistently.23 Different treatments have a varying but overall unremarkable impact on stool and mucosal microbial composition.8, 10, 16, 24, 25 A larger impact on function—especially in tri‐ and dimethylamines with lactulose, endotoxin, fatty acids and bile acids with rifaximin, and endotoxin and multiple metabolites with probiotics—has been noted.16, 24, 26 It is also intriguing that proton pump inhibitors, which are ubiquitous in cirrhosis and are associated with infections, dramatically shift stool microbial composition and function within 14 days.15 The role of SBP prophylaxis is evolving, but each antibiotic has its unique effect on microbiota, and the selection of resistant organisms may be an unfortunate result.27, 28 Therefore, each treatment strategy affects the microbiota differently.

Conclusions

Microbiota composition and functional changes in cirrhosis are important determinants of disease severity and complications (Fig. 1). Currently available therapies for cirrhosis that rely on microbial modulation have specific effects on the profile, which should be considered when interpreting cirrhosis‐microbiota studies.

Figure 1.

Schematic for the development of dysbiosis and complications such as hepatic encephalopathy in patients with cirrhosis. Reproduced from Gut Microbes.32 Copyright 2014, Landes Bioscience. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.].