Long-term high-fat diet and long-term high-refined-carbohydrate diet induce alterations in the splenic TCRβ CDR3 repertoire and peripheral multi-compartmental immune parameters in mice

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Abstract
Background: High-fat diet (HFD) and high-refined carbohydrate diet (HRCD) are closely associated with elevated risks of chronic inflammation, autoimmune diseases, and infectious diseases. However, the molecular alterations of the immune system following long-term intervention with these two diets remain unclear. Methods: 3-month-old young male mice were used as the animal model and received long-term intervention with HFD or HRCD until 14 months of age. Comparative analyses were performed on the pathological characteristics of immune organs, immune cell subsets, serum proteomics, and TCRβ CDR3 repertoire characteristics detected by next-generation sequencing. Results: Both dietary interventions led to increased body weight and caused similar splenic pathological damage in mice. Their effects on the immune system were dominated by peripheral alterations with mild central changes. Meanwhile, both diets led to increased clonal concentration, decreased uniformity, depletion of low-frequency clones, and expansion of mid-frequency clones in the splenic TCRβ CDR3 repertoire while also identifying a clonotype CSSRAGGLNSDYTF whose abundance in both the thymus and spleen was significantly higher in the HFD and HRCD groups than in the Control group. In contrast, the specific mechanisms underlying immune regulation differed significantly between the two diets. HFD significantly upregulated the levels of serum IL-6, IL-10, TNF-α and FAS, altered the proportion of splenic T cell subsets, and strongly affected splenic TRBJ gene usage and CDR3 length distribution. HRCD predominantly increased IL-17A levels and the proportion of DCs. Conclusion: This study preliminarily demonstrates that HFD and HRCD can induce similar pathological phenotypes but distinct molecular immune mechanisms, both showing more pronounced alterations in the spleen than in the thymus under the parameters examined.

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