Microbial Determinants of Dementia Risk in Type 2 Diabetics of Mexican Descent Living in South Texas: A Pilot Study

Type 2 diabetes (T2D) is a common antecedent of pathological neurodegeneration and accompanying dementia, including Alzheimer's Disease (AD). However, relatively little is known regarding mechanistic links between metabolic and neurodegenerative disorders. We recently completed a pilot clinical study focusing on individuals of Mexican descent living in Southern Texas - a population with increased prevalence of co-morbid T2D and early onset AD - with the working hypothesis that diet-driven shifts in gut microbiome composition contribute to T2D and AD susceptibility and pathophysiology in this population. Gastrointestinal symptom rating scale (GSRS) survey data from study participants provided evidence supporting an altered gut microbial ecology in subjects with T2D (sT2D) compared to healthy controls without T2D (HC), despite no significant differences in dietary preferences. Metagenomic 16S rRNA gene amplicon sequencing of twelve stool samples revealed that T2D gut communities are less diverse than those of HC, as determined by alpha diversity metrics. Furthermore, we observed a significant decrease in the abundance of the immunomodulatory short-chain fatty acid-producing taxa and increased abundance of a known pathobiont in gut microbiomes of sT2D. Our results suggest that characterization of the gut microbiome of individuals with T2D could be used to identify key actors among disease state microbiota which may exacerbate or accelerate neurodegenerative disorders and may point toward novel microbiome-targeted immunotherapeutic approaches for treating neuroinflammation in AD.

2型糖尿病（Type 2 diabetes, T2D）是病理性神经退行性病变及伴随性痴呆（包括阿尔茨海默病，Alzheimer's Disease, AD）的常见前驱病因。然而，目前学界对代谢性疾病与神经退行性疾病之间的机制性关联仍知之甚少。我们近期完成了一项针对居住在德克萨斯州南部的墨西哥裔人群的先导临床研究——该群体的2型糖尿病与早发性阿尔茨海默病共病患病率较高——研究的核心工作假说为：饮食驱动的肠道菌群组成改变，会影响该群体的2型糖尿病、阿尔茨海默病易感性及其病理生理过程。研究参与者的胃肠道症状评定量表（Gastrointestinal symptom rating scale, GSRS）调查数据表明，与无2型糖尿病的健康对照（Healthy Controls, HC）相比，2型糖尿病患者（sT2D）的肠道微生物生态存在显著改变，且两组的饮食偏好并无明显差异。对12份粪便样本开展宏基因组16S rRNA基因扩增子测序后发现，通过α多样性指标（alpha diversity metrics）评估，2型糖尿病患者的肠道菌群群落多样性显著低于健康对照群体。此外，我们还观察到，2型糖尿病患者肠道菌群中，具备免疫调节功能的产短链脂肪酸菌群丰度显著降低，而已知的致病共生菌（pathobiont）丰度则明显升高。本研究结果提示，对2型糖尿病患者的肠道菌群进行特征分析，可用于识别疾病状态下菌群中可能加重或加速神经退行性疾病进程的关键类群，同时也可为治疗阿尔茨海默病的神经炎症提供全新的菌群靶向免疫治疗思路。