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This review explores the intricate cross-talk between the gut microbiota and the host immune system, emphasizing how microbial communities shape immune cell differentiation, modulate inflammatory responses, and contribute to immune homeostasis. Interactions among innate and adaptive immune cells, microbial metabolites including short-chain fatty acids, and roles in early-life immune development and barrier integrity are discussed. 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This review explores the intricate cross-talk between the gut microbiota and the host immune system, emphasizing how microbial communities shape immune cell differentiation, modulate inflammatory responses, and contribute to immune homeostasis. Key interactions between innate and adaptive immune cells – including macrophages, dendritic cells, natural killer cells, innate Lymphoid cells, T cells, and B cells – and gut microbiota-derived metabolites such as short-chain fatty acids are discussed. The role of commensal bacteria in neonatal immune system development, mucosal barrier integrity, and systemic immunity is highlighted, along with implications for autoimmune diseases, inflammatory conditions, and cancer immunotherapy. Recent advances in metagenomics, metabolomics, and single-cell sequencing have provided deeper insights into the microbiota-immune axis, opening new avenues for microbiome-based therapeutic strategies. Understanding these interactions paves the way for novel interventions targeting immune-mediated diseases and optimizing health through microbiome modulation.  \nKey Words: Gut microbiome; Immune system; Microbiota-immune axis; Dysbiosis; Inflammation  \n©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.  \n WJGP  [https://www.wjgnet.com](https://www.wjgnet.com) 1 December 22, 2025  Volume 16  Issue 4   \nGhosh N et al. Gut microbiota-immune axis  \nCore Tip: This review highlights the critical interplay between the gut microbiome and the host immune system, focusing on how gut microbes and their metabolites, such as short-chain fatty acids, influence immune cell development, inflammatory regulation, and immune homeostasis. It emphasizes recent advances in metagenomics, metabolomics, and single-cell sequencing that have uncovered novel mechanisms of microbiota-driven immune modulation. The discussion also addresses the microbiome’s role in early-life immune education and its implications for autoimmune diseases, inflammation, and cancer immunotherapy, offering insights into emerging microbiome-based therapeutic strategies.  \nCitation: Ghosh N, Sinha K. Guardians within: Cross-talk between the gut microbiome and host immune system. World J Gastrointest Pathophysiol 2025; 16(4): 111245  \nURL: [https://www.wjgnet.com/2150-5330/full/v16/i4/111245.htm](https://www.wjgnet.com/2150-5330/full/v16/i4/111245.htm)  \nDOI: [https://dx.doi.","cbCaiqiqXNWD7Iq3","https://ap.wps.com/l/cbCaiqiqXNWD7Iq3","pdf",3089453,"English","# Abstract\n# Key Words\n# Core Tip\n# Introduction","[{\"question\":\"What is the focus of the review on the gut microbiome and host immunity?\",\"answer\":\"It focuses on how gut microbial communities cross-talk with the host immune system, shaping immune cell differentiation, inflammatory regulation, and immune homeostasis.\"},{\"question\":\"Which immune cell types and microbial metabolites are highlighted?\",\"answer\":\"Innate and adaptive immune cells are discussed, including macrophages, dendritic cells, natural killer cells, innate lymphoid cells, T cells, and B cells. Gut microbiota-derived metabolites such as short-chain fatty acids are emphasized.\"},{\"question\":\"How do current advances support microbiome-based therapeutic strategies?\",\"answer\":\"Recent advances in metagenomics, metabolomics, and single-cell sequencing provide deeper insights into the microbiota-immune axis, enabling new avenues for therapies targeting immune-mediated diseases and optimizing health through microbiome modulation.\"}]","Guardians within - Cross-talk between the gut microbiome and host immune system | PDF",1790566535]