Colonic epithelial hypoxia remains constant during the progression of diabetes in male UC Davis type 2 diabetes mellitus rats

IF 3.7 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Brian D Piccolo, James L Graham, Leslie Tabor-Simecka, Christopher E Randolph, Becky Moody, Michael S Robeson, Ping Kang, Renee Fox, Renny Lan, Lindsay Pack, Noah Woford, Laxmi Yeruva, Tanya LeRoith, Kimber L Stanhope, Peter J Havel
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Abstract

Introduction Colonocyte oxidation of bacterial-derived butyrate has been reported to maintain synergistic obligate anaerobe populations by reducing colonocyte oxygen levels; however, it is not known whether this process is disrupted during the progression of type 2 diabetes. Our aim was to determine whether diabetes influences colonocyte oxygen levels in the University of California Davis type 2 diabetes mellitus (UCD-T2DM) rat model. Research design and methods Age-matched male UCD-T2DM rats (174±4 days) prior to the onset of diabetes (PD, n=15), within 1 month post-onset (RD, n=12), and 3 months post-onset (D3M, n=12) were included in this study. Rats were administered an intraperitoneal injection of pimonidazole (60 mg/kg body weight) 1 hour prior to euthanasia and tissue collection to estimate colonic oxygen levels. Colon tissue was fixed in 10% formalin, embedded in paraffin, and processed for immunohistochemical detection of pimonidazole. The colonic microbiome was assessed by 16S gene rRNA amplicon sequencing and content of short-chain fatty acids was measured by liquid chromatography-mass spectrometry. Results HbA1c % increased linearly across the PD (5.9±0.1), RD (7.6±0.4), and D3M (11.5±0.6) groups, confirming the progression of diabetes in this cohort. D3M rats had a 2.5% increase in known facultative anaerobes, Escherichia–Shigella , and Streptococcus (false discovery rate <0.05) genera in colon contents. The intensity of pimonidazole staining of colonic epithelia did not differ across groups (p=0.37). Colon content concentrations of acetate and propionate also did not differ across UCD-T2DM groups; however, colonic butyric acid levels were higher in D3M rats relative to PD rats (p<0.01). Conclusions The advancement of diabetes in UCD-T2DM rats was associated with an increase in facultative anaerobes; however, this was not explained by changes in colonocyte oxygen levels. The mechanisms underlying shifts in gut microbe populations associated with the progression of diabetes in the UCD-T2DM rat model remain to be identified. Data are available in a public, open access repository. Data are available upon reasonable request. Data and coding will be made available upon reasonable request to the corresponding author.
雄性加州大学戴维斯分校 2 型糖尿病大鼠的结肠上皮缺氧在糖尿病发展过程中保持不变
引言 据报道,结肠细胞氧化细菌衍生的丁酸盐可通过降低结肠细胞的氧含量来维持协同厌氧菌群;但这一过程是否会在 2 型糖尿病发展过程中受到破坏尚不清楚。我们的目的是确定糖尿病是否会影响加州大学戴维斯分校 2 型糖尿病(UCD-T2DM)大鼠模型中结肠细胞的氧含量。研究设计和方法 本研究纳入了糖尿病发病前(PD,n=15)、发病后 1 个月内(RD,n=12)和发病后 3 个月内(D3M,n=12)年龄匹配的雄性 UCD-T2DM 大鼠(174±4 天)。在对大鼠实施安乐死和收集组织以估算结肠氧含量之前 1 小时,给大鼠腹腔注射吡咪唑(60 毫克/千克体重)。结肠组织用 10% 福尔马林固定,石蜡包埋,并进行免疫组化检测。通过 16S 基因 rRNA 扩增子测序评估结肠微生物组,并通过液相色谱-质谱法测量短链脂肪酸的含量。结果 HbA1c % 在 PD 组(5.9±0.1)、RD 组(7.6±0.4)和 D3M 组(11.5±0.6)呈线性增长,证实了糖尿病在该组群中的进展。D3M 组大鼠结肠内容物中已知的兼性厌氧菌、埃希氏菌和链球菌(假发现率<0.05)增加了 2.5%。各组结肠上皮的波尼哒唑染色强度没有差异(P=0.37)。UCD-T2DM组大肠内容物中乙酸盐和丙酸盐的浓度也没有差异;但是,D3M组大鼠的大肠丁酸水平高于PD组大鼠(P<0.01)。结论 UCD-T2DM 大鼠糖尿病的进展与兼性厌氧菌的增加有关;但是,结肠细胞氧水平的变化并不能解释这一点。与 UCD-T2DM 大鼠模型糖尿病进展相关的肠道微生物种群变化的内在机制仍有待确定。数据可在公开、开放的资源库中获取。如有合理要求,可提供数据。如有合理要求,可向通讯作者提供数据和编码。
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来源期刊
BMJ Open Diabetes Research & Care
BMJ Open Diabetes Research & Care Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
9.30
自引率
2.40%
发文量
123
审稿时长
18 weeks
期刊介绍: BMJ Open Diabetes Research & Care is an open access journal committed to publishing high-quality, basic and clinical research articles regarding type 1 and type 2 diabetes, and associated complications. Only original content will be accepted, and submissions are subject to rigorous peer review to ensure the publication of high-quality — and evidence-based — original research articles.
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