PO.BCS01.10 · 生物信息与计算

通过计算机建模和体内研究探讨无限制使用抗生素、肠道微生物组失衡与化学致癌物对肝脏和肾脏的毒性

Exploring unrestricted antibiotic use gut microbiome imbalance and chemical carcinogens in liver and kidneys toxicity through computer modeling and in vivo study

编号 4200 展板 27 时间 4/21 09:00–12:00 区域 Section 4 主讲 Chinedum Udekwu, BS;MS

分会场 Integrative Computational Approaches 2

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作者与单位 Authors & Affiliations

Solomon Owumi¹, Dooshima A. Bagu², Joseph Chimezie³, Esther M. Pius¹, Uche O. Arunsi⁴, Jesutosin O. Babalola⁵, Ayomide P. Akomolafe⁶, Chima Amadi⁷, Chinedum Udekwu⁸, Adegboyega K. Oyelere⁹, E. Oluwabunmi Olapade-Olaopa¹⁰, Olorunseun O. Ogunwobi¹

¹University of Ibadan, Ibadan, Nigeria,²Dooshima Bagu, Ibadan, Nigeria,³Joseph Chimezie, Ibadan, Nigeria,⁴Chemistry Biochemistry, Georgia Institute of Technology, Georgia Institute of Technology, GA,⁵Biochemistry, University of Ibadan, Ibadan, Nigeria,⁶University of Nebraska, Omaha, NE,⁷Dedra Nutraceuticals and Biotechnology Initiative, ABuja, Nigeria,⁸Chemistry Biochemistry, Michigan State University, East Lansing, MI,⁹Georgia Institute of Technology, Atlanta, GA,¹⁰Surgery, University of Ibadan, Ibadan, Nigeria

摘要 Abstract

中文摘要

肠道微生物群对人体健康至关重要，可被抗生素破坏，这已被证明与癌症等疾病相关。食物受黄曲霉毒素B1（AFB1）和二乙基亚硝胺（DEN）污染（两者均为强效肝脏致癌物）会增加肝癌风险。本研究探讨无限制使用常见抗生素（氨苄西林和环丙沙星）如何影响肠道微生物，结合AFB1和DEN的膳食联合暴露，以及大鼠肝脏和肾脏毒性的发生。采用分子对接（MD）和网络毒理学研究AFB1、DEN、AMP和CPX如何通过与参与氧化还原和保护性细胞通路的关键枢纽蛋白相互作用而引起肝肾毒性。使用分子对接评估了STAT3和EGFR的配体取向和结合能。肠道微生物分析显示，AMP和CPX诱导抗生素驱动的菌群失调，抑制有益的革兰阳性菌（如乳酸杆菌），并促进机会性革兰阴性菌（如大肠埃希菌、肺炎克雷伯菌和铜绿假单胞菌）的生长。这些变化导致产生影响肝脏免疫系统的有毒代谢物。在致癌物存在的情况下，AMP和CPX的协同作用可能在共同处理组中促进致癌。STAT3、EGFR、MAPK8、IKBKB、MMP2、MET和NOS2被鉴定为重要的枢纽基因。AFB1（-8.5 kcal/mol）、CPX（-7.8 kcal/mol）和AMP（-7.6 kcal/mol）对EGFR显示出高亲和力，表明其在EGFR信号调节中可能具有协同作用。对雄性Wistar大鼠的体内研究表明，共同处理降低了体重、肝脏和肾脏重量，升高了血清肝转氨酶、肌酐和尿素，降低了抗氧化酶，并增加了炎症标志物、脂质过氧化、甲胎蛋白和caspase-3活性，同时肝脏和肾脏中的IL-10降低。数据表明，AMP和CPX引起肠道菌群失调，并与AFB1和DEN一起产生协同的肝肾毒性作用，这可能与致癌的发生相关。

查看英文原文 English abstract

The gut microbiota, vital for human health, can be disrupted by antibiotics, which has been linked to diseases such as cancer. Contamination of food with Aflatoxin B 1 (AFB 1 ) and Diethylnitrosamine (DEN), both strong liver carcinogens, increases liver cancer risk. This study examines how unrestricted use of common antibiotics (Ampicillin and Ciprofloxacin) affects gut microbes, combined dietary exposure to AFB 1 and DEN, and the development of liver and kidney toxicity in rats. Molecular Docking (MD) and Network Toxicology were used to investigate how AFB 1 , DEN, AMP, and CPX cause hepatorenal toxicity by interacting with key hub proteins involved in redox and protective cellular pathways. Ligand orientation and binding energies for STAT3 and EGFR were assessed using molecular docking. Gut microbial analysis shows that AMP and CPX induce antibiotic-driven dysbiosis, suppressing beneficial gram-positive bacteria like Lactobacillus and promoting the growth of opportunistic gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. These changes result in toxic metabolite production affecting the hepatic immune system. In the presence of carcinogens, AMP and CPX synergy may contribute to carcinogenesis in co-treated groups. STAT3, EGFR, MAPK8, IKBKB, MMP2, MET, and NOS2 were identified as important hub genes. AFB 1 (-8.5 kcal/mol), CPX (-7.8 kcal/mol), and AMP (-7.6 kcal/mol) showed high affinity for EGFR, indicating a possible synergistic role in EGFR signalling modulation. In vivo studies in male Wistar rats showed that co-treatment reduced body, liver, and kidney weights, raised serum hepatic transaminases, creatinine, and urea, decreased antioxidant enzymes, and increased inflammation markers, lipid peroxidation, alpha-fetoprotein, and caspase-3 activity, alongside reduced IL-10 in the liver and kidney. The data indicate that AMP and CPX cause gut dysbiosis and, together with AFB 1 and DEN, have a synergistic hepatorenal toxic effect that may be relevant in the onset of carcinogenesis.

利益披露 Disclosure

S. Owumi, None.. D. A. Bagu, None.. J. Chimezie, None.. E. M. Pius, None.. U. O. Arunsi, None.. J. O. Babalola, None.. A. P. Akomolafe, None.. C. Amadi, None.. C. Udekwu, None.. A. K. Oyelere, None.. E. O. Olapade-Olaopa, None.. O. O. Ogunwobi, None.

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