We thank Haedge et al. for their interest in our study identifying serum villin-1 (VIL1) as a gut barrier damage marker in acutely decompensated (AD) cirrhosis 1. Independent validation is essential, and we acknowledge our study's limitations, including the limited number of ACLF cases in the validation cohort and varying cut-offs. However, valid comparison requires alignment with the original design, and methodological discrepancies complicate interpretation. A major challenge is phenotype definition. Haedge et al. describe patients as “decompensated with ascites” without stratifying by established AD severity groups 2, such as stable/unstable AD, pre-ACLF 3, or CLIF-C AD score-based 4 categories. Their cohort may therefore pool a heterogeneous spectrum of patients including non-acute decompensation 5, 6. In contrast, our study strictly enrolled hospitalized patients fulfilling EASL-CLIF AD criteria, encompassing all six acute phenotypes. Furthermore, Haedge et al. do not specify how sampling was temporally anchored to AD onset, precipitating events, or ACLF evolution. These details are paramount because, in our study, the prognostic value of VIL1 was concentrated in severe AD (CLIF-C AD score ≥ 50 or ACLF). In non-severe AD, short-term mortality was virtually absent, making further stratification uninformative. Crucially, VIL1 exhibits a bimodal dynamic across disease stages (Figure 1); thus, inadequate phenotype definition can obscure prognostic signal. They further report highest VIL1 levels in compensated cirrhosis; however, their data demonstrate only a flat, non-significant statistical trend 2. This is compatible with broad cohort definition and absent severity stratification rather than contradictory to our findings. Moreover, the numerical trend aligns perfectly with the bimodal pattern we proposed. Regarding the potential confounding effect of acute kidney injury, Haedge et al. suggest that elevated serum VIL1 in ACLF-1a (isolated kidney failure; creatinine ≥ 2 mg/dL) indicates a tubular origin. While we previously acknowledged the kidneys as potential secondary contributors 1, Haedge et al.'s own data argue against tubular injury as a primary driver: they detected no significant correlation between VIL1 and creatinine 2. Furthermore, VIL1 did not increase with higher ACLF grades, which inherently also include patients with renal failure 7 becoming progressively severe with advancing disease 8. If tubular injury were a primary mechanism, progressively elevated VIL1 levels would be expected. On the other hand, hemodynamic disturbances in advanced AD may simultaneously cause renal ischemia and intestinal hypoxia 9, reflecting concurrent, rather than strictly causal associations. Haedge et al. also note the highest VIL1 concentrations in alcoholic hepatitis patients. While we did not detect VIL1 level differences across alcohol-use subgroups in our cohorts—warranting further confirmation—these results bear high mechanistic importance. Severe alcohol abuse is a potent driver of mucosal inflammation, structural gut-barrier disruption and permeability 10. Consequently, elevated VIL1 in these patients reinforces, rather than confounds, VIL1's role as a direct marker of acute gut barrier damage. Finally, the substantially higher absolute VIL1 values reported by Haedge et al., despite using the same ELISA, underscore the need to standardize pre-analytical handling, sample dilution, assay-related variations, phenotype definitions and sampling before clinical implementation. Overall, biomarker-based evaluation of “acute-on-chronic” gut-barrier failure demands AD-only cohorts, severity-based stratification, and integration of structural-damage, functional and systemic inflammatory markers. David Tornai: conceptualization, writing – original draft, visualization. Maria Papp: conceptualization, writing – review and editing. The study was supported by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, No. 138041. The MICROB-PREDICT project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 825694. This reflects only the authors' view, and the European Commission is not responsible for any use that may be made of the information it contains. D.T. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences and the ÚNKP-22-5 and ÚNKP-23-5 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Tornai et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70481 and https://doi.org/10.1111/apt.70649. The authors have nothing to report.
Tornai et al. (Wed,) studied this question.