Unveiling the distinctive gut microbiota and metabolites in liver cirrhosis and its complications: Novel diagnostic biomarkers: Editorial on “Gut microbiome and metabolome signatures in liver cirrhosis-related complications”
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There is a close relationship between the gut and liver through the portal vein and bile acids, commonly referred to as the gut-liver axis. Under healthy conditions, three barriers in the gut—comprising the mucus layer with eubiotic microbiota, epithelial cells with tight junctions, and the gut vascular barrier with various immune cells—effectively control the transfer of microbes and their metabolites to the liver [1]. However, in chronic liver disease, along with altered gut microbiota, increased intestinal permeability, and disruption of the gut vascular barrier, there is a rise in the infiltration of microbiota, metabolites, and pathogen-associated molecular patterns (PAMPs) to the liver via the portal flow. This influx exacerbates liver injury by triggering the activation of inflammatory cytokines and chemokines [2,3]. In patients with liver cirrhosis (LC), gut dysbiosis worsens alongside reduced bile acid flow and decreased intestinal motility. These factors further increase intestinal inflammation, bacterial translocation, and the leakage of metabolites and PAMPs, such as lipopolysaccharide (LPS), leading to worsening hepatic inflammation [1,4]. This close interplay between the gut and liver underscores the need for a deeper understanding of gut microbial changes in patients with LC and its complications.
Under these circumstances, Sharma et al. [5] investigated the gut microbiome and metabolic signatures associated with liver cirrhosis and its complications. Through detailed analyses, they observed significant shifts in gut microbiome composition, transitioning from healthy individuals to cirrhosis patients, and further to patients with cirrhosis-re-lated complications using V3-V4 16S rRNA sequencing. Specifically, in cirrhosis patients, increases were noted in genera such as Veillonella, Lactobacillus, Enterococcus, and Streptococcus, while Bacteroidetes (phylum), Prevotella, and Faecalibacterium (genus) were decreased compared to healthy individuals. These distinctive microbial shifts were consistent with findings from previous studies [6,7]. Furthermore, Sharma et al. [5] identified complicationspecific bacterial species in cirrhosis patients, including Bacteroides ovatus, Clostridium symbiosum, Emergencia timonensis, Fusobacterium varium, and Hungatella_uc. By combining the most distinct bacterial species, the authors demonstrated robust diagnostic performance, with areas under the receiver operating characteristic curve (AUROC) for diagnosing liver cirrhosis, encephalopathy, hepatorenal syndrome, and mortality at 0.863, 0.733, 0.71, and 0.69, respectively.
One of the novel findings of this study is the potential utility of the gut microbiome as a diagnostic biomarker for cirrhosis and its complications, with high performance. Previous studies have reported that an altered gut microbiome is associated with cirrhosis-related complications and survival, with a further reduction in microbial diversity as liver cirrhosis progresses [6,8]. These worsening changes in gut microbial composition can even affect microbial recovery after liver transplantation [9], suggesting the persistent impact of gut dysbiosis on the prognosis of cirrhosis patients. Along with these findings, there has been an unmet need for diagnostic and predictive tools for cirrhosis and its complications using microbiota. The authors of this study have now highlighted the potential of the microbiome as a biomarker for the diagnosis of cirrhosis and its complications.
Another important finding of the study was the comparative analysis of fecal metabolites between healthy controls and LC patients. Metabolites, such as short-chain fatty acids (SCFA; butyrate, propionate, and acetate), indoles, and complex polysaccharides, predominantly originate from the microbiome and contribute to hepatic and systemic inflammation [6,10]. These metabolites have also been shown to differ significantly in patients with cirrhosis and acute-onchronic liver failure (ACLF) [8], suggesting their potential as biomarkers for the diagnosis and prognosis of LC patients. Sharma et al. identified the most significantly increased and decreased metabolites in LC patients and demonstrated a high AUROC (0.894) for the diagnosis of LC using metabolites such as indole-3-lactic acid, palmitoylcarnitine, N6,N6,N6-trimethyl-L-lysine, 8-hydroxyquinoline, and Lthreonic acid. These novel findings suggest that metabolites could serve as effective diagnostic markers for LC.
Considering the inflammatory and immunologic role of metabolites [11], we can infer that these increased and decreased metabolites may directly and indirectly affect liver injury and fibrosis in patients with LC. A reduction in SCFAs in LC patients can lead to decreased stimulation of peroxisome proliferator-activated receptor gamma, reduced inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, and subsequently impaired differentiation of regulatory T (Treg) cells [12,13]. Indole-3-lactic acid, an intermediate indole metabolite, is also known to regulate T-cell-mediated immunomodulation [14]. Moreover, another study demonstrated that isoallolithocholic acid, a bile acid metabolite, contributes to the differentiation of Treg cells and T helper 17 cells [15]. Therefore, based on the novel findings of this study, further research investigating the underlying immunological roles of the microbiome and metabolites in LC patients and its complications is needed to improve patient prognosis.
Lastly, the authors not only highlight the high AUROC of the microbiome and metabolites for diagnosing LC and its complications but also emphasize their significant correlation with clinical markers used to assess the severity of liver function in LC patients, such as MELD and CTP scores. These findings enhance the reliability of the study results and underscore the potential of the microbiome and metabolites as diagnostic biomarkers in LC patients. Further validation studies conducted in multicenter trials and across different countries and ethnicities are warranted to strengthen the findings of this study. Moreover, these results suggest the need to evaluate the predictive power of these markers for the prognosis of LC patients.
In conclusion, this study identified distinctive gut microbiome profiles and fecal metabolites in patients with LC and its complications. Moreover, the authors propose several microbial species and metabolites as potential biomarkers for diagnosing cirrhosis and its complications. This research provides valuable insights into the changes and roles of the microbiome and metabolites in end-stage liver disease. Further studies are needed to validate these findings in other countries and populations to enhance the robustness and generalizability of the results.
Notes
Authors’ contribution
S.K.L designed and wrote the manuscript. J.Y.C. revised the manuscript and supervised the study.
Conflicts of Interest
The authors have no conflicts to disclose.
Acknowledgements
This study received financial support of the he Catholic Medical Center Research Foundation made in the program year of 2024 (S.K.L). This work was also supported by the Technology Innovation Program (or Industrial Strategic Technology Development Program) (20024163, Development of microbiome-based treatment technology to improve the treatment and prognosis of liver transplant patients) funded By the Ministry of Trade, Industry & Energy (MOTIE, Korea) (S.K.L).
Abbreviations
ACLF
acute-on-chronic liver failure
AUROC
areas under the receiver operating characteristic curve
isoalloLCA
isoallolithocholic acid
LC
liver cirrhosis
LPS
lipopolysaccharide
NF-κB
the nuclear factor kappa-light-chain-enhancer of activated B cells
PAMPs
pathogen-associated molecular patterns
PPAR-γ
peroxisome proliferator-activated receptor gamma
SCFA
short-chain fatty acids
Th17
T helper 17
Treg
regulatory T