Novel Insights on Clinical Outcomes Using Integrated Shotgun Metagenomic Profiling of the Gut Microbiome, Resistome, and Host Immune-Inflammatory Response in Hospitalized Patients with Decompensated Cirrhosis

<b>Background and Aims:</b> Sepsis drives mortality in cirrhosis, yet the gut antimicrobial resistance (AMR) landscape remains unmapped in high-burden settings like India. This study aimed to integrate shotgun metagenomics with deep immunophenotyping to define the gut-immune-resistome axis and correlate specific microbial and genetic signatures with clinical outcomes in decompensated cirrhosis. <b>Methods:</b> We analysed 78 hospitalized patients with cirrhosis using stool shotgun metagenomics, multiplex cytokine arrays, and flow cytometry. The microbiome and resistome (AMR genes) were mapped and correlated with disease severity, immune function (monocyte HLA-DR, neutrophil CD64), and clinical endpoints including mortality. <b>Results:</b> Disease severity was characterized by a "Gram-negative bloom" (<i>Klebsiella</i>) alongside pathogenic <i>Enterococcus</i> expansion and novel markers: <i>Clostridium</i> sp. C5-48 (severe decompensation) and <i>Sutterella</i> (ascites). A specific, dense resistome predicted adverse outcomes; the quinolone-resistance gene <i>QnrB4</i> correlated with mortality and immune paralysis, while the carbapenemase <i>OXA-833</i> gene was linked to gastrointestinal bleeding. Notably, the commensal <i>Ligilactobacillus salivarius</i> was associated with systemic inflammatory cytokines. <b>Conclusions:</b> This study reveals a "pathogenic ecosystem" in Indian decompensated cirrhosis where the resistome is intrinsically linked to host immune failure. The identification of specific prognostic markers (<i>QnrB4</i>, <i>OXA-833</i>) and inflammatory associations with <i>L. salivarius</i> challenges generic probiotic use and underscores the urgent need for precision, resistome-targeted therapies.