Gut microbiome and metabolic activity in type 1 diabetes: An analysis based on the presence of GADA

Objective Type 1 diabetes (T1D) progression is affected by circulating glutamic acid decarboxylase antibody (GADA) that persist for many years. This study aimed at investigating whether and how the gut microbiome and its correlated metabolites change in T1D with the presence of GADA. Methods We used a radiobinding assay to measure GADA titers and identify the 49 T1D patients with GADA+ and 52 T1D patients with GADA-. The fresh feces and serum were analyzed using 16S rRNA gene sequencing and GC/MS. Then gut microbiome and serum metabolites were compared between the GADA+ patients and the GADA- patients. The association between gut microbial community and metabolites was assessed using the Spearman’s rank correlation. Results The gut microbiome in diversity, composition, and function differed between these two groups. The abundance of genus Alistipes, Ruminococcus significantly increased in patients with GADA+ compared to that observed in the samples of GADA-. There were 54 significantly altered serum metabolites associated with tryptophan metabolism, phenylalanine, and tyrosine biosynthesis in individuals with GADA+ compared with those of GADA-For the serum metabolites, compared with those of GADA-, there were 54 significantly different metabolites with tryptophan metabolism, phenylalanine, and tyrosine and tryptophan biosynthesis decreased in individuals with GADA+. The abundance of Alistipes was positively correlated with altered metabolites involved in tryptophan metabolism. Conclusion We demonstrate that T1D patients with GADA+ are characterised by aberrant profiles of gut microbiota and serum metabolites. The abundance of Alistipes disturbances may participate in the development of T1D patients with GADA by modulating the host’s tryptophan metabolism. These findings extend our insights into the association between the gut microbiota and tryptophan metabolism and GADA and might be targeted for preventing the development of T1D.

[1]  J. Xia,et al.  MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights , 2021, Nucleic Acids Res..

[2]  C. Tsentidis,et al.  Associated Autoimmunity in Type 1 Diabetes and Latent Autoimmune Diabetes of Adults: The Role of Glutamic-Acid Decarboxylase Autoantibodies. , 2021, Diabetes research and clinical practice.

[3]  Xia Li,et al.  Residual β-cell function after 10 years of autoimmune type 1 diabetes: prevalence, possible determinants, and implications for metabolism , 2021, Annals of translational medicine.

[4]  K. Herold,et al.  A little help from residual β cells has long-lasting clinical benefits. , 2021, The Journal of clinical investigation.

[5]  M. Atkinson,et al.  Modulation of Leukocytes of the Innate Arm of the Immune System as a Potential Approach to Prevent the Onset and Progression of Type 1 Diabetes , 2021, Diabetes.

[6]  T. Baydar,et al.  Neopterin and biopterin levels and tryptophan degradation in patients with diabetes , 2020, Scientific Reports.

[7]  O. Pedersen,et al.  Gut microbiota profile and selected plasma metabolites in type 1 diabetes without and with stratification by albuminuria , 2020, Diabetologia.

[8]  P. Kris-Etherton,et al.  Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity , 2020, Gut microbes.

[9]  R. Knight,et al.  A Universal Gut-Microbiome-Derived Signature Predicts Cirrhosis. , 2020, Cell metabolism.

[10]  P. Wearsch,et al.  The Genus Alistipes: Gut Bacteria With Emerging Implications to Inflammation, Cancer, and Mental Health , 2020, Frontiers in Immunology.

[11]  Guixia Wang,et al.  Evaluating the Causal Role of Gut Microbiota in Type 1 Diabetes and Its Possible Pathogenic Mechanisms , 2020, Frontiers in Endocrinology.

[12]  Yan Ni,et al.  M2IA: a web server for microbiome and metabolome integrative analysis , 2020, Bioinform..

[13]  Ke Zhang,et al.  Clostridium species as probiotics: potentials and challenges , 2020, Journal of Animal Science and Biotechnology.

[14]  Mark S. Anderson,et al.  Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes , 2019, Diabetes Care.

[15]  Y. Seo,et al.  Comparative Analysis of Fecal Microbiota Composition Between Rheumatoid Arthritis and Osteoarthritis Patients , 2019, Genes.

[16]  William A. Walters,et al.  Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2 , 2019, Nature Biotechnology.

[17]  Stuart M. Brown,et al.  Type 1 Diabetes: an Association Between Autoimmunity, the Dynamics of Gut Amyloid-producing E. coli and Their Phages , 2019, Scientific Reports.

[18]  Gang Yu,et al.  M2IA: a Web Server for Microbiome and Metabolome Integrative Analysis , 2019, bioRxiv.

[19]  U. Röhrig,et al.  Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond , 2019, Nature Reviews Drug Discovery.

[20]  C. Huttenhower,et al.  The human gut microbiome in early-onset type 1 diabetes from the TEDDY study , 2018, Nature.

[21]  F. Tinahones,et al.  Gut Microbiota Differs in Composition and Functionality Between Children With Type 1 Diabetes and MODY2 and Healthy Control Subjects: A Case-Control Study , 2018, Diabetes Care.

[22]  T. R. Licht,et al.  Microbial tryptophan catabolites in health and disease , 2018, Nature Communications.

[23]  Hong-Hong Zhang,et al.  Gut microbiota profiling in Han Chinese with type 1 diabetes. , 2018, Diabetes research and clinical practice.

[24]  W. Jia,et al.  Incidence of type 1 diabetes in China, 2010-13: population based study , 2018, British Medical Journal.

[25]  Eric A. Franzosa,et al.  Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation. , 2017, Cell host & microbe.

[26]  Å. Lernmark,et al.  Genetic and Environmental Interactions Modify the Risk of Diabetes-Related Autoimmunity by 6 Years of Age: The TEDDY Study , 2017, Diabetes Care.

[27]  E. Bonifacio,et al.  Type 1 diabetes mellitus , 2017, Nature Reviews Disease Primers.

[28]  H. Deng,et al.  Demographic and clinical characteristics of patients with type 1 diabetes mellitus: A multicenter registry study in Guangdong, China , 2016, Journal of diabetes.

[29]  Hanns-Ulrich Marschall,et al.  Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. , 2016, Cell metabolism.

[30]  Xin-Hua Xiao,et al.  Imbalance of Fecal Microbiota at Newly Diagnosed Type 1 Diabetes in Chinese Children , 2016, Chinese medical journal.

[31]  Paul J. McMurdie,et al.  DADA2: High resolution sample inference from Illumina amplicon data , 2016, Nature Methods.

[32]  Tommi Vatanen,et al.  The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. , 2015, Cell host & microbe.

[33]  R. Leslie,et al.  Latent Autoimmune Diabetes in Adults With Low-Titer GAD Antibodies: Similar Disease Progression With Type 2 Diabetes , 2014, Diabetes Care.

[34]  J. Krischer,et al.  The Prediction of Type 1 Diabetes by Multiple Autoantibody Levels and Their Incorporation Into an Autoantibody Risk Score in Relatives of Type 1 Diabetic Patients , 2013, Diabetes Care.

[35]  F. Tinahones,et al.  Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study , 2013, BMC Medicine.

[36]  M. Ciorba,et al.  Serum Analysis of Tryptophan Catabolism Pathway: Correlation With Crohn's Disease Activity , 2012, Inflammatory bowel diseases.

[37]  Aleksandar Milosavljevic,et al.  Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. , 2011, Gastroenterology.

[38]  S. Salzberg,et al.  FLASH: fast length adjustment of short reads to improve genome assemblies , 2011, Bioinform..

[39]  A. Rizzo,et al.  Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. , 2011, Gastroenterology.

[40]  C. Huttenhower,et al.  Metagenomic biomarker discovery and explanation , 2011, Genome Biology.

[41]  O. Kordonouri,et al.  GADA positivity at onset of type 1 diabetes is a risk factor for the development of autoimmune thyroiditis , 2011, Pediatric diabetes.

[42]  R. Paroni,et al.  Increased intestinal permeability precedes clinical onset of type 1 diabetes , 2006, Diabetologia.

[43]  M. Burns,et al.  Case-Control Study , 2020, Definitions.

[44]  S. Leeder,et al.  A population based study , 1993, The Medical journal of Australia.

[45]  R. Beiko,et al.  Predicting the Functional Potential of the Microbiome from Marker Genes Using PICRUSt. , 2018, Methods in molecular biology.