Letter: Reinterpreting the Role of Microbiota‐Driven Nitric Oxide in Cirrhotic Portal Hypertension—A Maladaptive Compensatory Response?

We read with great interest the insightful study by Zhang et al. [1], ‘Alterations of Gut Microbiota and Metabolism in Patients with Cirrhotic Portal Hypertension and Their Impact on Disease Progression,’ published in Alimentary Pharmacology & Therapeutics. The authors demonstrate how a gut dysbiosis rich in Veillonella exacerbates cirrhotic portal hypertension (CPH) by elevating nitric oxide (NO) through the arginine metabolism pathway. This is a landmark contribution that opens new avenues for understanding the gut–liver axis in CPH. While commending this work, we believe the findings on elevated NO can be viewed through the lens of the classic ‘NO paradox’ in cirrhosis [2]. This paradox highlights a critical conflict: the cirrhotic liver suffers from a deficiency of NO that worsens vascular resistance, while the systemic and splanchnic circulation produces an excess of NO. This overproduction drives the hyperdynamic state, and ultimately, both factors synergistically worsen portal hypertension. The animal model data from Zhang et al. revealed significantly increased levels of inducible nitric oxide synthase (iNOS) and NO in both the serum and liver tissues of mice receiving faecal microbiota transplants from CPH patients. We posit that this finding may primarily reflect the systemic/splanchnic component of the NO paradox [3]. Accordingly, we hypothesize that this microbiota-driven systemic surge in NO may not be the primary pathogenic driver of CPH, but rather a maladaptive compensatory response to the severe intrahepatic endothelial dysfunction and profound NO deficit. However, this compensatory response proves counterproductive: while it aims to induce vasodilation, it ends up disproportionately increasing splanchnic blood flow. The resultant rise in portal venous inflow ultimately exacerbates portal pressure. This perspective has critical therapeutic implications. If this hypothesis holds true, therapeutic strategies aimed at globally inhibiting iNOS or scavenging NO (such as non-selective iNOS inhibitors) could be a double-edged sword, potentially worsening the already compromised intrahepatic microcirculation while suppressing splanchnic vasodilation. To validate this hypothesis, future research should first directly confirm the regional disparity in NO signalling within the CPH context. This evidence is pivotal for validating the NO rebalancing strategy. Subsequently, therapeutic approaches such as combining systemic iNOS inhibitors with liver-targeted NO donors could be explored. This combination aims to curb splanchnic hyperemia while simultaneously rescuing intrahepatic endothelial function, thereby synergistically reducing portal pressure. In conclusion, Zhang et al.'s work provides crucial insights into the link between gut dysbiosis and the vascular dysregulation central to CPH. We believe that viewing their data through the lens of the NO paradox and maladaptive compensation does not diminish the importance of their findings, but rather enriches the discussion and may pave the way for a deeper mechanistic understanding and the development of more precise therapeutic strategies for CPH. Meiyu Yang: writing – original draft. Tiantian Zhang: formal analysis, investigation. Susu Zhang: writing – review and editing. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Zhang et al. paper. To view this article, visit https://doi.org/10.1111/apt.70392. The authors have nothing to report.