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Increasing evidence suggests that the gut microbiota, long considered a \u201cless relevant\u201d to human body health, it plays a crucial role in the pathophysiology of sepsis. Disruption of the host\u2013microbe balance contributes to impaired barrier integrity, microbial translocation, and dysregulated immune responses. This perspective raises the possibility that dysbiosis is not merely a consequence of critical illness, rather an active driver of septic progression. This narrative review explores the relationship between sepsis and gut microbiome. PubMed, Scopus, and EMBASE were searched from inception to September 2025. Recent studies have highlighted the triangular interplay between the intestinal barrier, gut microbiota, and immune system. Altered microbial composition and increased permeability foster systemic inflammation and immune dysfunction. Biomarkers such as diamine oxidase and intestinal fatty acid-binding protein are emerging as promising indicators of gut injury. Experimental therapies (i.e., faecal microbiota transplantation, targeted probiotics, prebiotics, postbiotics, and personalized antibiotic regimens guided by microbial profiling) provide potential to modulate host\u2013microbe interactions. Integration of microbiome analysis with multi-omics and advanced bioinformatics may enable stratification of septic patients by microbial signatures, paving the way for precision medicine approaches. Modulation of gut microbiota represents a novel therapeutic frontier in sepsis. Conceptualizing sepsis as a disease of disrupted host\u2013microbe symbiosis may unravel new diagnostic and therapeutic strategies. Future research should aim at prioritizing high-quality trials, innovative designs, and equitable implementation to target microbiota to improve survival and recovery in patients with sepsis.<\/jats:p>","DOI":"10.1007\/s11739-025-04215-8","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T13:17:20Z","timestamp":1764681440000},"page":"607-619","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Narrative review on microbiota and sepsis: the host\u2019s betrayal?"],"prefix":"10.1007","volume":"21","author":[{"given":"Matteo","family":"Guarino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostino","family":"Di Ciaula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Portincasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0867-5873","authenticated-orcid":false,"given":"Roberto","family":"De Giorgio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"issue":"28","key":"4215_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12093188","volume":"12","author":"M Guarino","year":"2023","unstructured":"Guarino M, Perna B, Cesaro AE, Maritati M, Spampinato MD, Contini C, De Giorgio R (2023) Update on sepsis and septic shock in adult patients: management in the emergency department. 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