The authors detail how a balanced microbiome (eubiosis) sustains immune tolerance and systemic health, while dysbiosis disturbs gut barrier integrity and promotes inflammatory cascades. This section underscores Toll-like receptors, the gut-lung axis, and short-chain fatty acids (SCFAs) as mediators of microbiome–immune dialogue. Case studies link microbiota composition to diseases ranging from COVID-19 and chronic lung conditions to autoimmune disorders, mental health, and even zoonotic infections like leptospirosis. These findings emphasize the microbiome's systemic reach beyond the gut.
Microbiota and DNA Integrity
The review reveals direct and indirect genotoxic effects of microbial metabolites. Colibactin, typhoid toxin, and cytolethal distending toxins from pathogens such as E. coli, Shigella, and Salmonella induce double-strand breaks and interfere with host DNA repair. Moreover, the review links microbial influences to tumor suppressor modulation, notably p53 degradation, and associates dysbiosis with colorectal carcinogenesis through epigenetic modifications. These insights stress the microbiome's role in either preserving or disrupting DNA stability, a key factor in aging.
Immunosenescence and Dysbiosis: A Synergistic Deterioration
Aging leads to immunosenescence, characterized by weakened gut-associated lymphoid tissue (GALT) and declining naive T cells, dendritic cells (DCs), and regulatory T cells. Dysbiosis accelerates these changes, skewing DC function toward proinflammatory states. Chronic inflammation becomes self-sustaining, with senescent immune cells promoting further dysbiosis. The authors highlight SCFAs' role in preserving gut barrier function and modulating immune responses, offering a feedback mechanism that, when disrupted, contributes to age-related immune decline and systemic diseases.
Cellular and Molecular Pathways: Inflammaging and Barrier Dysfunction
Inflammaging, the chronic low-grade inflammation characteristic of aging, is exacerbated by gut permeability, senescent epithelial cells, and activated immune cells releasing cytokines. The imbalance between anti-inflammatory Tregs and pro-inflammatory Th17 cells intensifies tissue damage and fibrosis. At the neuro-immunological level, the gut-brain axis bridges dysbiosis with neurodegeneration, linking microbial imbalance to conditions like Alzheimer's disease. SCFA depletion and endotoxin elevation further drive systemic inflammation and epigenetic disruptions, compounding aging processes.
DNA Damage–Inflammation Feedback Loop
Inflammation and DNA damage engage in a reciprocal relationship: reactive oxygen species and cytokines like TNF-α exacerbate genotoxicity, while the DNA damage response itself activates pro-inflammatory pathways (e.g., NF-κB signaling). This bidirectional loop contributes to both genomic instability and immune dysfunction. SCFAs again play a restorative role by enhancing DNA repair through epigenetic mechanisms (e.g., histone acetylation and DNA methylation), showcasing potential therapeutic avenues.
Future Directions: Research and Personalized Interventions
Despite promising correlations, the review acknowledges limitations in current research. Inter-individual microbiome variability, lack of longitudinal studies, and underexplored mechanistic pathways complicate universal conclusions. Nonetheless, multi-omics technologies (metagenomics, metabolomics, etc.) hold promise in identifying microbial markers and tailoring interventions. The authors advocate for targeted microbiome modulation—via probiotics, diet, or pharmacological agents—to reduce DNA damage, modulate inflammation, and promote healthy aging.
Conclusion
The interplay between the gut microbiome, immune aging, and DNA repair defines a critical axis in human longevity. Dysbiosis disrupts immune equilibrium and accelerates senescence, while pro-inflammatory states exacerbate DNA damage and genomic instability. Targeting the microbiome with therapeutic interventions, especially SCFA-promoting strategies, may offer a potent means of extending healthspan. Future research must clarify causal mechanisms and translate findings into scalable, personalized treatments for age-related disorders.
Full text:
https://www.xiahepublishing.com/2472-0712/ERHM-2024-00046
The study was recently published in the Exploratory Research and Hypothesis in Medicine .
Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.
