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Review
. 2025 May 19;22(1):20.
doi: 10.1186/s12979-025-00514-y.

Gut-vitamin D interplay: key to mitigating immunosenescence and promoting healthy ageing

Affiliations
Review

Gut-vitamin D interplay: key to mitigating immunosenescence and promoting healthy ageing

Hammad Ullah. Immun Ageing. .

Abstract

Background: Immunosenescence is the loss and change of immunological organs, as well as innate and adaptive immune dysfunction with ageing, which can lead to increased sensitivity to infections, age-related diseases, and cancer. Emerging evidence highlights the role of gut-vitamin D axis in the regulation of immune ageing, influencing chronic inflammation and systemic health. This review aims to explore the interplay between the gut microbiota and vitamin D in mitigating immunosenescence and preventing against chronic inflammation and age-related diseases.

Main text: Gut microbiota dysbiosis and vitamin D insufficiency accelerate immunosenescence and risk of chronic diseases. Literature data reveal that vitamin D modulates gut microbiota diversity and composition, enhances immune resilience, and reduce systemic inflammation. Conversely, gut microbiota influences vitamin D metabolism to promote the synthesis of active vitamin D metabolites with implications for immune health.

Conclusions: These findings underscore the potential of targeting gut-vitamin D axis to modulate immune responses, delay the immune ageing, and mitigate age-related diseases. Further research is needed to integrate vitamin D supplementation and microbiome modulation into strategies aimed at promoting healthy ageing.

Keywords: Gut microbiota; Healthy ageing; Immune ageing; Immunosenescence; Vitamin D.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: Hammad Ullah is the guest editor for the topical collection ‘Micronutrients and immune ageing’ published in Immunity & Ageing. The peer-review of this paper was therefore overseen by an independent member of the editorial board while the submission was subject to the exact same review process as applied to any other manuscript.

Figures

Fig. 1
Fig. 1
Cytochrome P450-mediated metabolism of vitamin D
Fig. 2
Fig. 2
Schematic representation of the interplay between vitamin D and gut microbiota, emphasizing its impact on immune responses. Vitamin D (both D2 and D3 isoforms) is metabolized into its active form, 1,25(OH)₂D, which interacts with VDR and RXR to regulate transcription and translation of target genes. The downstream effects include increased production of antimicrobial peptides (e.g., cathelicidin and β-defensin), enhanced mucosal immunity, and improved epithelial barrier integrity through the upregulation of tight junction proteins (e.g., ZO-1, ZO-2, claudin-1). These actions modulate gut microbiota composition and diversity, decrease gut permeability, and reduce translocation of lipopolysaccharides (LPS) into the bloodstream. Additionally, vitamin D modulates both innate and adaptive immune responses, further mitigating inflammatory processes and restoring gut homeostasis, thereby preventing dysbiosis and systemic inflammation. VDR, vitamin D receptor; RXR, retinoid X receptor; VDRE, vitamin D response elements; mRNA, messenger RNA; ZO-1, zonula occludens-1; ZO-2, zonula occludens-2; TLR, toll-like receptors; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; LPS, lipopolysaccharide

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