The gut–joint axis in osteoarthritis: integrating microbiota-driven metaflammation and immunosenescence

Apr 10, 2026International immunopharmacology

How Gut Bacteria May Link Inflammation and Aging Immune Cells to Osteoarthritis

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Gut microbiota imbalance is closely related to the clinical manifestations of osteoarthritis (OA).

The gut-joint axis may serve as a critical pathway linking gut microbiota, inflammation, and aging processes in OA.
Imbalances in gut microbiota could weaken gut barrier integrity and trigger inflammation that exacerbates OA symptoms.
Microbiota-driven processes may contribute to both metaflammation and Immunosenescence, influencing the progression of OA.
A unified framework incorporating microbiota, gut barrier function, inflammation, aging, and phenotypic expression may help explain the clinical diversity observed in OA.
This framework may facilitate the development of biomarker-based strategies for patient classification and targeted treatments in OA management.

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Osteoarthritis (OA) has traditionally been viewed as a mechanical degenerative disease, but in recent years, the paradigm has gradually shifted from "mechanical wear and tear degenerative disease" to a complex condition driven by systemic low-grade inflammation and Immunosenescence. As a key linking pathway between gut microbiota, metaflammation, and Immunosenescence, the gut-joint axis has attracted widespread attention. The composition of gut microbiota and its metabolites influences the occurrence and development of OA by regulating gut barrier function and systemic inflammation levels. Numerous animal models and clinical studies have confirmed that gut microbiota imbalance is closely related to the clinical manifestations of OA. The mechanisms of microbiota-driven metaflammation and Immunosenescence jointly promote the pathological process of OA, revealing its heterogeneity and complexity. This article proposes a core hypothesis: the gut-joint axis acts as a key upstream pathway in which gut microbiota imbalance weakens gut barrier integrity and triggers microbiota-driven metaflammation. This process further accelerates inflammaging, thereby amplifying the inflammatory response and structural degeneration of the cartilage-synovium-subchondral-bone unit. To integrate dispersed evidence and better explain the clinical heterogeneity of OA, we construct a unified framework of "microbiota, barrier, inflammation, aging, and phenotype," correlating microbial functional outputs with key phenotypes such as inflammation dominance, metaflammation, aging-driven changes, and pain hypersensitivity. This framework provides a theoretical basis for biomarker-based patient stratification and combination strategies targeting both microbiota and anti-aging interventions. It also offers a roadmap for advancing OA precision management and the development of disease-modifying treatments.

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The gut–joint axis in osteoarthritis: integrating microbiota-driven metaflammation and immunosenescence

Abstract

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