HLA‐C ∗ 0304 Associates With Beneficial Gut Microbiota and Later Onset of Type 1 Diabetes in Pediatric Cohorts

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Objective To investigate whether human leukocyte antigens (HLAs) influence gut microbiota composition and contributes to delayed type 1 diabetes mellitus (T1DM) onset in children. Methods This multicenter cross‐sectional study included 106 newly diagnosed pediatric T1DM patients (age <18 years) and 69 healthy controls from nine Chinese cities. Gut microbiota was profiled via whole‐metagenome shotgun sequencing, and HLA alleles were genotyped by PCR sequence‐based typing. Participants were stratified by HLA‐risk scores. Statistical analyses included α/β‐diversity metrics, linear discriminant analysis effect size analysis (LEfSe), and Spearman correlation adjusted for confounders. Results Principal coordinates analysis (PCoA) exposed discernible disparities in gut microbiota structures within the high‐HLA‐risk T1DM cohort relative to both high‐ and low‐HLA‐risk control groups ( R 2 = 0.0562, p = 0.003 and R 2 = 0.0343, p = 0.003). HLA‐C ∗ 0304 carriers exhibited delayed T1DM onset compared to noncarriers (adjusted R 2 = 0.225, p = 0.017). High‐HLA‐risk T1DM patients showed distinct microbiota divergence from controls ( R 2 = 0.0562, p = 0.003), driven by reduced Lachnospiraceae and Blautia (butyrate producers) in noncarriers. Conversely, HLA‐C ∗ 0304‐positive T1DM patients had enriched Blautia ( p = 0.005) and Lachnospiraceae ( p = 0.039), alongside lower opportunistic pathogens ( Citrobacter ; p < 0.05). High‐HLA‐risk patients also displayed lower fasting C‐peptide levels than low‐risk counterparts (0.19 ± 0.14 vs. 0.26 ± 0.19 µg/mL, p = 0.029). Conclusions Our study demonstrates that specific HLA class I subtypes (e.g., C ∗ 0304) may modulate T1DM onset through selective enrichment of beneficial gut microbiota. Elucidating the mechanisms by which HLA variants regulate mucosal immunity and coordinate HLA‐microbiota‐immune interactions holds significant potential for developing targeted interventions against T1DM pathogenesis.

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