Gut microbiome development may help predict type 1 diabetes in children at high risk

Mass General Brigham researchers found that children at high genetic risk of type 1 diabetes whose gut microbiome maturation stalled early had three times the risk of developing the disease, suggesting potential for detection and prevention strategies.

Type 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.

“The 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,” said co-corresponding author Daniel Wang, MD, ScD, associate scientist with the Channing Division of Network Medicine in the Mass General Brigham Department of Medicine. 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.”

This study provides strong prospective evidence linking gut microbiome development and type 1 diabetes, but it cannot establish cause and effect, and further study is needed, including clinical trials to test potential interventions. Because the study used data from children at high risk for developing type 1 diabetes, additional research is needed to see whether the results apply to the general population.

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.

Authorship: Additional authors include Meir J. Stampfer, Aaron M. Walsh, Tommi Vatanen, George Weingart, Mondher Khdhiri, Kendra Vehik, Eric A. Franzosa, Curtis Huttenhower, and members of the TEDDY Study Group.

Disclosures: Curtis Huttenhower serves on the scientific advisory boards of Zoe Nutrition, Empress Therapeutics, and Seres Therapeutics.

Funding: This study was funded in part by the National Institutes of Health (U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, HHSN267200700014C, UL1 TR000064, UL1 TR002535, R00DK119412, R01NR01999, R01AG077489, RF1AG083764, U54AG089325, R01DK149250 and U19AI110820), the Centers for Disease Control and Prevention, and Breakthrough T1D.

Paper cited: Dong D et al. “Gut Microbiome Maturation in Early Childhood Interacts with Host Genetics to Predict Type 1 Diabetes Risk,”  Nature Metabolism  DOI: 10.1038/s42255-026-01614-9

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