Microbial Determinants of Dementia Risk in Type 2 Diabetics of Mexican Descent

Microbial Determinants of Dementia Risk in Type 2 Diabetics of Mexican Descent

Type 2 diabetes (T2D) predisposes individuals to neurodegeneration and dementia, including Alzheimer's Disease (AD); yet the link between metabolic and neurodegenerative disorders remains unknown. Here, the investigators will study a well-defined human population with increased prevalence and early onset of both T2D and AD, individuals of Mexican descent living in South Texas. The study will begin to explore the possibility that disruption of the structure of the bacterial community residing in the gut in type 2 diabetic individuals of Mexican descent living in South Texas is directly related to the increased prevalence of early onset AD in this population. In this study, the investigators will perform gene sequencing on DNA isolated from fecal samples to identify and compare the populations of bacteria living in individuals with T2D versus non-diabetic controls. The investigators will analyze the findings to determine if the community structure of the gut microbiome of individuals of Mexican descent with T2D is significantly altered compared to that of non-diabetics within the same population. The investigators' findings could lead to the identification of early indicators of dementia onset as well as novel therapies for treating metabolic and neurodegenerative diseases.

Type 2 diabetes (T2D) as a common antecedent of pathological neurodegeneration and dementia, including Alzheimer's Disease (AD); yet the mechanistic link between metabolic and neurodegenerative disorders remains unresolved. Here, the investigators will study a well-defined human population with increased prevalence and early onset of both T2D and AD, individuals of Mexican descent living in South Texas. The study will lay critical groundwork toward addressing the investigators' overarching hypothesis that dysbiosis of the gut microbiome in type 2 diabetic individuals of Mexican descent living in South Texas is causally related to the increased prevalence of comorbid, early onset AD in this population. In this study, the investigators will perform state-of-the-art metagenomic 16S ribosomal RNA (rNRA) gene sequencing and bioinformatic analysis on fecal samples collected from type 2 diabetic and non-diabetic control individuals of Mexican descent to test the working hypothesis that the community structure of the gut microbiome of individuals of Mexican descent with T2D is significantly altered compared to that of nondiabetics within the same population. To the investigators' knowledge, this multidisciplinary pilot study will be the first to investigate the gut microbial community structure of type 2 diabetic versus that of nondiabetic individuals of Mexican descent. Furthermore, it has the potential to provide mechanistic insight into how T2D predisposes individuals to the neuropathology and cognitive impairment characteristic of AD and to identify a novel class of interventions that target the host gut microbiome for the prevention of early onset AD in a predisposed population, as well as the population at large.

Human subjects will be recruited through the University of Texas Medical Branch at Galveston (UTMB) Endocrinology and pre-screened to confirm that the potential participants meet established inclusion and exclusion criteria as either T2D or nondiabetic controls, as defined in the UTMB human subjects protocol associated with this project. Pre-screened participants that meet the defined criteria will be invited to attend an appointment with a study coordinator held at the UTMB Clinical Research Center. Consented and enrolled study participants will be asked to complete medical history, dietary preference, and gastrointestinal function questionnaires and instructed as to how to use the provided OMNIgene-GUT RNA (OMR)-200 fecal sample collection kit (DNA GenoTek). Participants will submit the collected fecal sample via shipment of a pre-paid and labeled shipping envelope. Samples will be deidentified and stored at -80oC in the Buffington Lab prior to shipment to the Baylor College of Medicine Center for Metagenomic and Microbiome Research (CMMR) for metagenomic 16S rRNA gene sequencing. Briefly, bacterial genomic DNA will be extracted using the MagAttract PowerSoil Kit (Qiagen) and the 16S ribosomal DNA (rDNA) V4 region will be amplified by polymerase chain reaction (PCR) and sequenced on the MiSeq platform (Illumina). 16S rRNA gene read pairs will be demultiplexed based on unique molecular barcodes added to primers used for amplification and reads will be merged using USEARCH. 16S rRNA gene sequences will be clustered into Operational Taxonomic Units (OTUs) using the UPARSE algorithm and mapped to an optimized version of the SILVA database to determine taxonomies. The investigators will then use a custom script developed by the CMMR to construct a rarefied OTU table for downstream analyses of alpha-diversity, beta-diversity, and phylogenetic trends to identify any changes in community structure between type 2 diabetic and non-diabetic individuals of Mexican descent enrolled in the study.

Inclusion Criteria:

Type 2 Diabetic Inclusion Criteria

1. Male or female with a diagnosis of type 2 diabetes.
2. Ages 50 to 70 years.
3. Mexican descent living in Texas.
4. Participant is willing and able to give informed consent for participation in the study.

Non-Diabetic Control Inclusion Criteria

1. Male or female without history of type 2 diabetes.
2. Ages 50 to 70 years.
3. Mexican descent living in Texas.
4. Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

Type 2 Diabetic Exclusion Criteria

1. Hypertension that is not controlled by greater than 2 medications.
2. Chronic kidney disease, CKD greater than 3.
3. History of coronary bypass or stint placement.
4. Current pregnancy.
5. Subjects with a history of inflammatory bowel disease, Celiac disease or active diverticular disease.
6. Other medical condition or medication administration deemed exclusionary by the study investigators.

Non-Diabetic Control Exclusion Criteria

1. Hypertension that is not controlled by greater than 2 medications.
2. Chronic kidney disease, CKD greater than 3.
3. History of coronary bypass or stint placement.
4. Current pregnancy.
5. Subjects with a history of inflammatory bowel disease, Celiac disease or active diverticular disease.
6. Other medical condition or medication administration deemed exclusionary by the study investigators.