Age‐mediated gut microbiota dysbiosis promotes the loss of dendritic cells tolerance

• Published in: Aging cell 2023-06, Vol.22 (6), p.e13838-n/a
• Main Authors: Bashir, Hilal, Singh, Sanpreet, Singh, Raghwendra Pratap, Agrewala, Javed N., Kumar, Rashmi
• Format: Article
• Language: English
• Subjects: Age; Aging; Aldehyde dehydrogenase; Animals; Antibiotics; Antigens; Arginase; Bone marrow; CD4 antigen; Cytokines; Cytokines - metabolism; Dendritic cells; Dendritic Cells - metabolism; Dysbacteriosis; dysbiosis; Dysbiosis - metabolism; Gastrointestinal Microbiome; gut microbiota; immune response; Immune system; Immune Tolerance; Immunological tolerance; Inflammatory diseases; Interferon regulatory factor 4; Interleukin 10; Interleukin 12; Interleukin 4; Interleukin 6; Intestinal microflora; Lactobacillus plantarum; Lymphocytes; Lymphocytes T; Metabolic pathways; Mice; Microbiota; NF-κB protein; Nitric oxide; Pathogens; T-Lymphocytes, Regulatory - metabolism; tolerance; Transforming growth factor-b; Tumor necrosis factor-α; Variance analysis; γ-Interferon
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13838

The old age‐related loss of immune tolerance inflicts a person with a wide range of autoimmune and inflammatory diseases. Dendritic cells (DCs) are the sentinels of the immune system that maintain immune tolerance through cytokines and regulatory T‐cells generation. Aging disturbs the microbial composition of the gut, causing immune system dysregulation. However, the vis‐à‐vis role of gut dysbiosis on DCs tolerance remains highly elusive. Consequently, we studied the influence of aging on gut dysbiosis and its impact on the loss of DC tolerance. We show that DCs generated from either the aged (DCOld) or gut‐dysbiotic young (DCDysbiotic) but not young (DCYoung) mice exhibited loss of tolerance, as evidenced by their failure to optimally induce the generation of Tregs and control the overactivation of CD4+ T cells. The mechanism deciphered for the loss of DCOld and DCDysbiotic tolerance was chiefly through the overactivation of NF‐κB, impaired frequency of Tregs, upregulation in the level of pro‐inflammatory molecules (IL‐6, IL‐1β, TNF‐α, IL‐12, IFN‐γ), and decline in the anti‐inflammatory moieties (IL‐10, TGF‐β, IL‐4, IDO, arginase, NO, IRF‐4, IRF‐8, PDL1, BTLA4, ALDH2). Importantly, a significant decline in the frequency of the Lactobacillus genus was noticed in the gut. Replenishing the gut of old mice with the Lactobacillus plantarum reinvigorated the tolerogenic function of DCs through the rewiring of inflammatory and metabolic pathways. Thus, for the first time, we demonstrate the impact of age‐related gut dysbiosis on the loss of DC tolerance. This finding may open avenues for therapeutic intervention for treating age‐associated disorders with the Lactobacillus plantarum. Age, gut dysbiosis and loss of DC tolerance. DCs obtained from either the old or antibiotics (Abx) induced gut dysbiosis in young but not control young groups of mice exhibited loss of tolerance. This was demonstrated by their failure to optimally expand the pool of Tregs, control the overactivation of CD4+ T cells, upregulation of NF‐κB and pro‐inflammatory cytokines and decline in the anti‐inflammatory molecules. A significant drop in the frequency of the Lactobacillus genus is noticed in the gut. Replenishing the gut of old mice with Lactobacillus plantarum (LP) revived the tolerogenic function of DCs through the rewiring of inflammatory and metabolic pathways.