We sincerely appreciate and offer our immense gratitude to Dr. Soon Kyu Lee and his colleagues for this comprehensive and astute editorial interpretation of our latest article, “Gut microbiome and metabolome signatures in liver cirrhosis-related complications” published in Clinical and Molecular Hepatology [1,2]. As a team, we are extremely grateful for the opportunity to respond and further dissert the significance of our outcomes within the perspective of liver cirrhosis (LC) research. This editorial perceptively emphasizes the intricate connection between the liver and gut, formally acknowledged as the gut-liver axis, and its pivotal pathogenic role in chronic liver diseases. As highlighted, the catastrophe of this axis in LC directs to a cascade of events which involve in gut dysbiosis, intensified intestinal permeability, and amplify the microbial products and metabolites translocation to the liver [3]. Collectively, these processes contribute to the exacerbation of hepatic inflammation and the progression of the disease. We concur with the editorial’s emphasis on the importance of understanding these complex interactions, which formed the foundation of our research [4].

The study aimed to outline the fecal microbiome and metabolic signatures linked to LC and its associated complications, addressing a critical knowledge gap in our understanding of the disease’s pathophysiology. We as a research group appreciate the commentary’s acknowledgement towards our novel findings. Especially, the complicationspecific bacterial species identification and the potential utility of these gut microbial species as differential diagnostic biomarkers between LC and its complications. This editorial precisely summarizes study’s observations regarding the shifts in gut microbiome composition from healthy to LC and LC to cirrhosis-related complications. Importantly, the genera and species increased or decreased in LC patients, align with prior cirrhosis-based studies which reinforce the stability and validate our findings and underlines the reproducibility of these LC-associated microbial shifts across different study populations [5].

Besides, we are vastly motivated by the commentary’s accent on the diagnostic potential of our identified gut mi-crobial bacterial species in fecal sample. These findings are aligned with the growing recognition of the gut microbiome’s role not only in LC pathogenesis but also as a valuable non-invasive diagnostic tool. These gut microbiomebased findings refer to the unmet need for diagnostic and predictive tools in LC management, as highlighted in the editorial. Particularly, the commentary’s supportive argument about the progressive changes in gut microbial ecology in LC advancement, and its potential impact on posttransplantation recovery, is highly insightful. It underscores the extensive implications of gut dysbiosis in LC advancement and stresses the magnitude of our findings in the wider context of LC management and prognosis. This perspective echoes with our research group vision which is, potentially modulating the gut microbiome could have substantially robust therapeutic implications beyond diagnosis.

Likewise, we highly appreciate the editorials thorough analysis of our metabolomic findings which reflect a significance difference between healthy and LC conditions which exhibits potential implications for diagnosis also in understanding the disease mechanisms. These results not only provide potential non-invasive diagnostic markers but also offer insights into the metabolic perturbations linked to LC, opening new avenues for metabolic pathway-targeted therapeutic interventions. We concur with the commentary’s inference regarding the potential direct and indirect effects of these metabolites on liver injury and fibrosis in LC patients. Moreover, discussion on immunological consequences of altered metabolite profiles also provides valuable context for future gut-liver axis research directions. The suggested mechanism in the editorial’s offers a compelling framework for understanding the broader implications of our findings. These interpretations align with our perspective that the LC-linked altered fecal metabolite profile could have farreaching impacts on hepatic and systemic inflammation, contributing to disease expansion [6,7]. We agree that further research required to explore the underlying immunological roles of fecal microbiome and metabolites in LC and its complications which is essential for improving patient outcomes. This study provides a firm base and boost for such investigations by identifying key microbial and metabolic targets for future mechanistic studies in LC. We forecast that this line of research could lead multitudes novel therapeutic strategies aiming to modulate the gut microbiome and/or targeting specific metabolic pathways to confine the LC progression [8].

The editorial aptly noted the correlation between established clinical diagnostic LC markers and our identified gut microbial and metabolic biomarkers. This correlation enhances our results validity and strengthens the potential of these novel LC-associated biomarkers in clinical practice related to liver diseases. This correlation suggests that identified LC-associated fecal microbial and metabolic signatures not only used as diagnostic tool but may also predict the underlying severity of liver dysfunction, potentially offering a crucial prognostic information. We acknowledge the further validation studies suggested by the commentators’ performed in across diverse ethnicities and larger populations to enhance the generalizability of this study findings. Therefore, we concur that multicenter trials by the international collaborations will be an essential next step to solidify the clinical utility of these fecal biomarkers. Such multicenter studies possibly address the potential variations occurs due to genetic factors, geographical, and dietary, ensuring the robustness of this study findings across different populations. Additionally, we understand the importance of evaluating the predictive power of these fecal biomarkers’ markers for LC prognosis, as suggested in the editorial. Therefore, longitudinal studies tracing the evolution of microbial and metabolic profiles alongside LC advancement could offer valuable insights into their predictive abilities. This approach could potentially lead to the produce an array of risk stratification tools that could enabling more personalized management tactics for LC patients.

The editorial’s emphasis on future research investigating the underlying immunological roles of LC-associated fecal microbiome and metabolites strongly resonates with our research group’s vision, mission, and future research directions in the field of the gut-liver axis. We are particularly interested and immensely motivated in narrowing the informational gap between specific gut microbial species, metabolites, and immune-pathophysiological function with the relation to LC. This could involve arrays of in vitro and in vivo experiments to elucidate the defined immunomodulatory effects of the identified specific gut-inhabiting bacterial species and related metabolites which can potentially uncover the new therapeutic targets [9]. Furthermore, as a research group, we are intrigued by the potential of interventional studies aimed at adjusting the gut microbiome or metabolome in LC patients. These interventional studies might involve probiotic, prebiotic, postbiotic, and synbiotic supplementation or even fecal microbiota transplantation (FMT), with the goal of restoring healthy microbial and metabolic profile in LC patients. These approaches could not only establish the causal relationship between LC progression and gut dysbiosis but also pave the way for novel therapeutic approaches [10].

In conclusion, we are deeply grateful for this comprehensive and insightful commentary on our latest work. This editorial not only emphasizes the significance of our study’s outcomes but also places them within the closer context to LC research and potential clinical applications. We are highly motivated by the recognition of this study’s contribution to understanding the changes and roles of the fecal microbiome and metabolites in end-stage liver disease. These findings of distinctive gut microbial species and fecal metabolites profiles in LC and its complications, along with the identification of potential non-invasive biomarkers for LC diagnosis and its complications, epitomize a significant step forward in this gut-liver axis research. Notwithstanding, we consider these results as a beginning rather than an endpoint. The insights stipulated by the editorial commentary have further inspired us to pursue additional avenues of gut-liver axis research, including:

1. To perform further validation studies across diverse populations to validate the generalizability of our findings.

2. To execute longitudinal studies for assessing the prognostic value of identified biomarkers for LC progression and complications in our study.

3. Design the mechanistic studies to elucidate the pathophysiological involvement of gut microbiota and metabolites in immunological and metabolic pathways to influence LC pathogenesis.

4. Design and pursue the interventional studies aiming to modulating the gut microbiome or metabolome to ameliorate the LC patient’s outcomes.

We as a team, firmly believe that the future research in these directions, steered by the thoughtful analysis provided in this editorial, will certainly contribute to advancing the current understanding of LC. Ultimately, lead to improved diagnostic, prognostic, and therapeutic approaches for LC patients with this challenging conditions. Once again, we convey our sincere gratitude to Dr. Soon Kyu Lee and his colleagues for this insightful commentary and the opportunity to further discuss our work. As a research group, we look forward to continuing our research in the gut-liver axis field and contributing to the ongoing efforts to improve patient’s outcomes with liver cirrhosis and its complication.