Stalled gut microbiome development triples risk for type 1 diabetes in children
· News-MedicalType 1 diabetes affects more than 9 million people worldwide, including 1.8 million children and adolescents. While the disease is thought to be driven by complex genetic factors, researchers are also examining the influence of environmental exposures, including how the population of microorganisms living in the gut develops. A new prospective study led by investigators from Mass General Brigham, the Broad Institute of MIT and Harvard, and Harvard T.H. Chan School of Public Health found that children at high genetic risk of type 1 diabetes whose gut microbiome development plateaued early had about three times the risk of developing the disease compared with children whose microbiomes continued to mature. The study also found that the children's genetics influenced how strongly microbiome maturation was related to disease risk. Their results are published in Nature Metabolism.
Daniel Wang, MD, ScD, co-corresponding author, associate scientist, Channing Division of Network Medicine, Mass General Brigham Department of MedicineThe disease burden of type 1 diabetes is substantial for children and their families, requiring careful management of insulin, exercise and diet from a very early age."
Wang is also an assistant professor at Harvard Medical School and in the Department of Nutrition at Harvard Chan School and an associate member at the Broad Institute. "Understanding the role of microbiome development in diabetes progression could lead to early prediction and prevention strategies, giving us more options to delay or even prevent the clinical manifestation of this disease."
This longitudinal observational study, known as the TEDDY Study, followed 887 children at high genetic risk for type 1 diabetes and analyzed more than 12,000 stool samples collected during their first six years of life, tracking how each child's gut microbiome matured over time. Participants came from Finland, Germany, Sweden and the U.S.
In type 1 diabetes, the immune system begins attacking insulin-producing cells years before symptoms appear. To account for this, the researchers counted a child as having developed the disease process when blood tests first detected this attack or when they were diagnosed with type 1 diabetes.
The study identified three distinct microbiome maturational patterns. In participants with an early-matured microbiome, the gut microbiome changed substantially within the first year of life, with a rich and diverse population of gut bacteria. In participants with a late-matured microbiome, gut development started more slowly than in those with the early-matured pattern. Around age 1, the gut bacteria had changed little and had lower bacterial diversity, but the microbiome caught up later. For those with an early-plateaued microbiome, gut development started slowly but never caught up. The microbiome still had low bacterial diversity during the first three years of life.
Children whose microbiome development stalled early, plateauing rather than continuing to mature, had about three times the risk of developing type 1 diabetes or the immune attack that precedes it, compared with children whose microbiomes matured on a standard schedule. Results were similar when the researchers looked at the early immune stage and clinical diagnosis separately. This result was only apparent through repeated sampling over time and would likely have been missed in a single microbiome snapshot.
The researchers were interested not only in risk prediction but also in the microbiome's biology and the influence of genetics.
The patterns also reflected differences in what the bacteria were equipped to do. Children with the early-matured microbiome shifted sooner from having milk-adapted bacteria such as Bifidobacterium toward having species that break down dietary fiber, a sign of readiness for a more varied diet. The early-plateaued microbiome remained oriented toward digesting milk sugars even after solid foods were introduced and relied on a narrower set of species to carry out key functions.
"Genetic background can change how much a given maturation pattern matters for risk, so combining microbiome and genetic information gives a more accurate picture," said lead author Danyue Dong, PhD, a postdoctoral research fellow in the Channing Division of Network Medicine at Mass General Brigham. "By analyzing interactions between the microbiome and host genetics, we found genetic variants, particularly those involved in antimicrobial and antiviral immune responses, that shaped how strongly the late-matured pattern was related to disease risk. The early-plateaued pattern, by contrast, carried higher risk regardless of genetic background."
As this research continues to develop, Wang and Dong envision a future in which gut microbiome testing could be incorporated into pediatrician visits during the first years of life, a potentially critical window for microbiome-directed prevention strategies, such as dietary supplements, if such approaches prove effective in clinical trials.
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