Infant gut microbiome altered before type 1 diabetes onset

Last Updated: 2015-02-16

By Will Boggs MD

NEW YORK (Reuters Health) - Changes in the makeup of the infant gut microbiome precede the development of type 1 diabetes, researchers have found.

"Our study provides the first evidence that the gut microbiome is altered prior to the onset of type 1 diabetes (T1D) relative to healthy controls," Dr. Ramnik J. Xavier from Broad Institute of MIT and Harvard in Cambridge, Massachusetts, told Reuters Health by email. "This raises the possibility that certain aspects of the microbiome can be used as a biomarker for disease diagnosis, prognosis, timing."

The notion that microbial exposure can influence the pathogenesis T1D is well established in mouse models, Dr. Xavier and colleagues write in the February 11 issue of the journal Cell Host & Microbe. But there have been limited studies of the human microbiome in T1D.

The team assessed the composition of the gut microbiota in a longitudinal cohort of 33 HLA-matched infants genetically predisposed to T1D and followed from birth to age three years. Eleven of these infants seroconverted to serum autoantibody positivity, and four of these developed T1D within the time frame of the study.

Age proved to be the strongest driver of the composition of the infant gut microbiome, the researchers found. But there was a "remarkable" stability in the metabolic pathway coding potential of the microbiome despite dramatic shifts of taxonomic composition throughout infancy.

Despite the variability in the gut microbiome through infancy, about 10% of the bacterial strains were maintained in the infant gut from birth until three years of age, according to the report.

The microbiome of infants that went on to develop T1D showed a significant drop in diversity, with a relative overabundance of pathobiont-like species and a relative underabundance of bacteria that are commonly depleted in the inflammatory state.

Infants who seroconverted but had not yet developed T1D showed an intermediate abundance of these organisms between that of nonconverters and T1D cases.

Prior to clinical onset of T1D, gut microbial gene content showed an increase in the multiple sugar transport system and a decrease in the biosynthesis of a number of amino acids.

The researchers found a positive correlation between Blautia and Ruminococcus, both of which were increased in abundance in T1D cases, with triglycerides and branch-chain amino acids, "possibly indicating that these microbe-metabolite relationships cooperatively impact T1D progression."

"Although the alterations to the microbiota that we observed may be related to impaired glucose metabolism in the prediabetic stage," the investigators say, "these results suggest that the T1D-associated microbiota that becomes established prior to disease onset may actively promote a metabolic environment in the gut that is permissive to inflammation and promotes pathogenesis."

"Studies with much larger cohorts of prospectively-tracked individuals will be required to establish which are the strongest biomarkers and how effectively they may predict disease," Dr. Xavier said. "The temporality of the shift in microbiome composition also raises the possibility of a causal relationship between the gut microbiome and T1D onset. Therefore we hope our work motivates further studies on the mechanistic relationships between the gut microbiome and T1D."

What causes the shifts in gut microbiome composition and metabolism in the first place? Dr. Xavier speculated, "It is likely the result of additive influences from diet, other environmental factors involving hygiene, and genetics. This study is not powered to provide a conclusive answer to this question, but we are in the process of analyzing much bigger cohorts of infants in which we test the influence of the hygiene hypothesis on the development of T1D."

The authors caution that "all children in this cohort carry T1D-predisposing HLA alleles and are restricted to the countries of Finland and Estonia, and are therefore not necessarily representative of genetically 'normal' infants in other regions of the world."

Dr. Li Wen from Yale University School of Medicine in New Haven, Connecticut, who recently reviewed the role of gut microbiota in the development of diabetes and obesity, said "the gut microbiome could be used as a biomarker for T1D prediction and prevention."

"We know that the destruction of islet beta cells has occurred already before the clinical onset of T1D in the mouse model, which may lead to a metabolic change in the host that might affect the gut microbiome through reducing the diversity," Dr. Wen, who was not part of the new research, told Reuters Health by email. "NOD mice also express reduced bacterial diversity at the prediabetes stage."

"Fecal transplant might be a promising approach for prevention," Dr. Wen said, "although this is not likely to gain great favor in the prospective population that could be treated. Perhaps more promisingly, it might be also be a good adjunct to insulin therapy to improve diabetes control."

SOURCE: http://bit.ly/1zlpDJr

Cell Host Microbe 2015;17:260-73.