The Role of the Human Gut Microbiome in Type 1 Diabetes

The human microbiome – which is the sum of all the microorganism that live in conjunction with the human body – includes eukaryotes, archaea, bacteria as well as the viruses and phages that infect them. Not that many years ago a systematic study of the entire microbiome in any context would have been nearly impossible. Now, with the advancement of DNA sequencing technologies and associated metagenomics techniques, huge amounts of data about human microbiomes have been collected. With the goal of systematizing such investigations the NIH Common Fund Human Microbiome Project (HMP) was established in 2008. A summary report of the NIH workshop on 10 years of results of the first phase of the HMP project (HMP1) was published in the 2017 NIH-wide workshop report on “The Human Microbiome: Emerging Themes at the Horizon of the 21st Century”. Phase 2 of the HMP, also known as Integrative Human Microbiome Project (iHMP), was launched in 2014 with expanded data sets and a definition of the baseline of the human microbial diversity in a greater population study size and multiple body-site contexts. A report on the second wave of data from the expanded HMP (also termed HMP I-II) can be found in the Lloyd-Price et al. paper (2017). The iHMP also encompasses three major sub-projects focusing on health and disease areas around i) pregnancy & preterm birth, ii) onset of Inflammatory Bowel Disease, and iii) onset of Type 2 diabetes.

Type 1 diabetes

The incidence of both type 1 (T1D) and type 2 (T2D) diabetes have risen steeply in the world since the end of World War II. T1D is an autoimmune disease striking predominantly the young which is characterized by immune-system mediated destruction of insulin-producing β-cells of the pancreas. T1D proceeds with an inflammatory component where β-cells are inflamed, called insulitis (Tsalamandris et al., 2019). The hypothesis that intestinal microbiota may play an important role in the development of T1D has been around for some time (Siljander et al., 2019). It appears that the role of the gut in T1D is complex and mediated through a combination of resident immune cells, functions of the local epithelium and mucous membranes in concert with the gut microbiome.

Image credits: Moreno-Indias et al., 2014.

The TEDDY studies

The Environmental Determinants of Diabetes in the Young (TEDDY) study – TEDDY is a large multicentre study into the causes of T1D. It is formed by a consortium of several clinical centers located in both the US and Europe and the data is being analyzed collaboratively. TEDDY is monitoring >7,000 children from birth to age 15 via the clinical centers, gathering biospeciemens as well as clinical and personal data from neonates and parents. Late in 2018 two key Nature papers describing some key findings of this study were published. One paper (Stewart et al., 2018) focused on the temporal developmental facets of microbiomes in young patients and controls, while the second paper (Vatanen et al., 2018) summarized some key findings with respect to microbiome changes in patients with T1D.

1. Stewart et al. (2018) described that the gut microbiome goes through three phases following birth. This observation was obtained by combining information from 16S rRNA and metagenomic sequencing followed by statistical analysis to show how microbiome features cluster. The first stage is a so-termed developmental phase which lasts from month 3 to 14. The second, transitional phase, runs from months 15 to 20, followed by the so-called stable phase consisting of months 31 to 46. One key parameter most significantly impacting the overall structure of the microbiome clustering was receipt of breast milk, both with regard to timing and exclusivity versus other nutrition. A second feature that contributed to microbiome structure, during the developmental phase, was birth mode. Lastly, it was also found that environmental factors such as geographical location and exposure to pets correlated with changes in microbiome diversity in both developmental and transitional phases.

Image credit:  Stewart et al., 2018.

• Vatanen et al. (2018) found that microbiomes of matched case-control children versus study children that went on to develop T1D or islet autoimmunity (IA), have more genes for fermentation and short chain fatty acid (SCFA) production. Interestingly, the bacterial taxa harboring these genes were varied geographically suggesting these functions are more tightly linked to T1D than the individual taxonomy of the microbiomes. Infant microbiomes were broadly dominated in the first year of life by three species of Bifidobacterium and/or multiple members of the Proteobacteria phylum. Furthermore, in breast fed infants genes for breakdown of human milk oligosaccharide (HMO) were noticeably prevalent. Together with other evidence from human studies and in T1D mouse model this supports the theory of proactive effect of SCFA in human T1D early-onset.

T1D high-level lessons

The conclusions from both Stewart et al. and Vatanen et al. (two publications of a significant and growing body of literature based on the TEDDY study) are consistent with observed trends in microbiomes in patients with T1D gleaned from other smaller studies summarized in a 2019 review by Abdellatif and Sarvetnick. The conclusions can be summarized as follows:

• Higher proportions of C-section births are correlated with increased T1D,
• Multiple early uses of antibiotics are correlated with increased T1D,
• Breast feeding is correlated with reduced T1D incidence, and
• Exposure to a wider variety of microbial antigens is correlated with reduced occurrence of T1D.

T2D also displays links to the microrbiome

Like T1D, T2D is a disease with genetic, inflammatory, immunological, and environmental components, and it appears that the microbiome may also have an influence on T2D genesis and rates of incidence. While a detailed elaboration of the T2D correlation is beyond our scope here it suffices to say that there is evidence that gut microbiome differences do exist between lean and obese study subjects and obesity is a known risk factor for T2D (Tsalamandris et al., 2019). It is thought that the gut microbiome may both directly and indirectly affect the host immune system and has the potential to contribute to metabolic changes and inflammation that characterize the onset of diabetes.

Companies active in the microbiome and metagenomics sector

Among the companies working in microbiome science, Microbiome Insights specifically focuses on developing capabilities useful in T1D investigations. Microbiome Insights is a leader in providing end-to-end services for microbiome DNA sequencing and bioinformatics. This privately held company was formed by University of British Columbia (UBC) professors Dr. Brett Finlay, Dr. Bill Mohn, and CEO Malcolm Kendall in 2015. The company offers a range of microbiome services, including both shallow and deep shotgun metagenomic sequencing for taxonomic profiling and functional analysis. They also offer 16S RNA sequencing and qPCR for total bacterial quantitation. In addition, the company performs short chain fatty acids (SCFA) and calprotectin quantification in fecal samples.

Pendulum Therapeutics is a microbiome company that applies the discoveries of high-resolution, long-read DNA sequencing to the development of microbiome interventions targeting both chronic and rare diseases. Founded in 2012 and based in San Francisco, CA Pendulum Therapeutics’ current pipeline includes pre-clinical and clinical trials focused on novel microbiome interventions in key areas, including diabetes and IBS.

Additional companies active in the area of microbiome analytical services, research, and development of potential therapeutics are listed below.

CosmosID is a bioinformatics company focused on rapid identification of microorganisms in metagenomic samples. Founded in 2007 and based in Rockville MD near Washington D.C. Cosmos founder Rita R. Cowell is a professor at University of Maryland. The company is privately held and provides next generation sequencing and bioinformatics services. Focused on microbiome analysis with rapid identification and characterization of microorganisms, Cosmos ID offers cloud-based metagenomics application based on Genbook their proprietary microbial genetics database which contains nearly 160K phylogenetically organized genomes and gene sequences, and capable of identifying bacteria, virus, fungi, and protists. Their sequencing services include shotgun, 16S rRNA, ITS, metatranscriptomics, and long-read sequencing.

CoreBiome provides fast, accurate genomic profiles of microbial communities to customers in pharmaceutical, agriculture, and academic research. CoreBiome is a small company that was founded in July 2016, with its headquarters in Minneapolis-St Paul. It is now a wholly owned subsidiary of OraSure Technologies, Inc. after having been acquired in early 2019. CoreBiome offers microbiome sequencing and analysis services of medical, environmental, and agricultural samples which includes shotgun and 16S rRNA sequencing. Subsequent analysis and annotation is available through Core Analysis™ tools.

Kaleido Biosciences – a public company with its headquarters in Boston, MA and trading on the Nasdaq with symbol KLDO – designs and analyzes microbiome systems and provides adaptive solutions. Kaleido Biosciences focuses on the development of products called Microbiome Metabolic Therapies (MMTs). Initial work on MMTs involve small molecule glycans that will be orally administered to affect the gut microbiome function. First glycan candidates (KB195 and KB174) are for the treatment of hyperammonemia caused by either urea cycle disorders or hepatic encephalopathy. Kaleido Biosciences uses a so-called human-centric approach which employs ex vivo screening of microbiomes from healthy volunteers followed by ex vivo testing of patient microbiome.

Seres Therapeutics, a privately held company, founded in 2010 by Flagship Pioneering and located in Cambridge, MA is trying to create new medicines based on the human microbiome which uses live bacteria to treat diseases resulting from dysbiosis of the microbiome. Seres has two Ecobiotic® drug designs in early clinical trial; SER-287 for ulcerative colitis and SER-109 for recurrent C. difficile Infection. The company’s areas of focus are in infectious disease and inflammatory/immunology (including immuno-oncology).

Second Genome was founded in 2009 and is located in San Francisco. Second Genome focuses on the discovery and development of therapeutics and offers a pipeline of microbiome modulators that impact infection, immunity and metabolic diseases. Specifically, their scientific staff works on inflammatory disease such as IBD, immune-oncology in enhancing checkpoint therapy effectiveness, metabolic diseases which includes onalcoholic steatohepatitis (NASH), and central nervous system disorders such as autism spectrum disorders (ASD) that demonstrates a gut microbiome involvement. Second Genome claims to have the world’s largest dynamic, curated database (SGKnowledgeBase™) and a suite of software, hardware, and data science capabilities that allows the company to accurately identify microbial biology in health and disease.

References

Abdellatif and Sarvetnick, Current understanding of the role of gut dysbiosis in type 1 diabetes. (2019) J Diabetes, Aug;11(8):632-644.

Lloyd-Price et al., Strains, functions and dynamics in the expanded Human Microbiome Project. (2017) Nature, Oct 5;550(7674):61-66.

Siljander et al., Microbiome and type 1 diabetes. (2019) EBioMedecine, Aug;46:512-521.

Stewart et al., Temporal development of the gut microbiome in early childhood from the TEDDY study. (2018) Nature, Oct;562(7728):583-588.

Tsalamandris et al., The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. (2019) Eur Cardiol, Apr;14(1):50-59.

Vatanen et al., The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. (2018) Nature, Oct;562(7728):589-594.

2017 NIH-wide microbiome workshop writing team, 2017 NIH-wide workshop report on the “The Human Microbiome: Emerging Themes at the Horizon of the 21st Century.” (2019) Microbiome, Feb 26;7(1):32.