Bifidobacterium and the Gut–Immune Axis: Mechanistic Insights and Therapeutic Potential

Ranjith Balakrishnan ¹, Rajasekaran Subbarayan ^1,2*, Rupendra Shrestha ^3*, Loganathan Krishnamoorthy ⁴, Arunkumar Radhakrishnan ⁶

1. Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India

2. Centre for Herbal Pharmacology and Environmental Sustainability, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India

3. Department of Natural and Applied Sciences, Nexus Institute of Research and Innovation (NIRI), Lalitpur, Nepal

4. Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
5. Department of Pharmacology, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India

Publications: Microbiological Research, 128686 doi: 10.1016/j.micres.2026.128686

Abstract – Gut–immune axis is a bidirectional network that links the intestinal microbiota to host immune homeostasis. Among commensal microbes, Bifidobacterium species are prominent modulators of mucosal and systemic immunity through strain-specific metabolic, structural, and receptor-mediated mechanisms. This narrative review synthesizes mechanistic, preclinical, and clinical evidence on how Bifidobacterium influences immune regulation, epithelial barrier integrity, and inflammation, emphasizing strain specificity and host context. Bifidobacterium exerts immunomodulatory effects through acetate production, exopolysaccharides, tryptophan-derived indoles, and extracellular vesicles, which regulate dendritic cells, macrophage polarization, secretory IgA, tight junction integrity, and Treg/Th17 balance. These effects are highly strain-dependent and are influenced by diet, obesity, host genetics, and disease state. Preclinical and clinical evidence suggests potential benefits in antibiotic-associated dysbiosis, inflammatory bowel disease, cancer therapy response, early life immune maturation, and selected metabolic and neuroimmune disorders, although the outcomes remain heterogeneous. Bifidobacterium should be viewed as a diverse group of immunomodulatory microbes rather than a uniform probiotic genus. Its therapeutic potential depends on the strain selection, host context, and ecological interactions within the gut microbiome. Precision and strain-resolved approaches supported by multi-omics and clinical validation are required to translate these perspectives into routine practice.

Cite: Ramesh A, Subbarayan R, Shrestha R, Krishnamoorthy L, Radhakrishnan A. Bifidobacterium and the Gut–Immune Axis: Mechanistic Insights and Therapeutic Potential. Microbiological Research. 2026:128686.