收稿日期: 2024-05-27
网络出版日期: 2024-11-26
基金资助
国家自然科学基金项目(32170064)
Effects of Bupropion Hydrochloride on Resistome of Gut Microbiota in SD Rats
Received date: 2024-05-27
Online published: 2024-11-26
Supported by
the National Natural Science Foundation of China(32170064)
为探究抗抑郁药盐酸安非他酮对肠道菌群耐药组的影响，选用SD大鼠为研究对象，分别采用16S rRNA扩增子及宏基因组测序技术，分析盐酸安非他酮对大鼠粪便和盲肠内容物菌群及其耐药组的影响，并挖掘之间的关联。结果表明：粪便和盲肠内容物样本中主要抗生素耐药基因（ARGs）类型包括杆菌肽类、四环素、万古霉素及大环内酯-林可酰胺-链菌素类（MLS）等。与对照组（HC）相比，盐酸安非他酮灌胃干预组（Bup-PO）提高了大鼠粪便和盲肠内容物样本中细菌ARG总丰度，但仅在粪便样本中达到显著性差异。在ARG类型上，相比于HC组，Bup-PO组显著提高了粪便样本中氨基糖苷类、杆菌肽类、莫匹罗星、利福霉素类、四环素、万古霉素6类耐药基因类型的相对丰度，且增加了万古霉素抗性基因的种类。在盲肠内容物样本中，Bup-PO组显著提高了四环素、柔红霉素和磷霉素3类耐药基因类型的相对丰度。在ARG亚型上，在粪便样中，相比于HC组，Bup-PO组显著提高了万古霉素（vanAG、vanRI、vanSA、vanSI），四环素（tetM、tetO、tet32），杆菌肽类（bceA、bcrA）和利福霉素类（ rpoB）耐药基因的相对丰度。在盲肠内容物样本中，灌胃盐酸安非他酮给药对ARGs的影响与粪便样本中有所不同，表现为降低了大环内酯-林可酰胺-链菌素类（lmrB）耐药基因的相对丰度，但提高了另一种大环内酯-林可酰胺-链菌素类（macB）耐药基因的相对丰度丰度。同时，灌胃给药盐酸安非他酮还提高了四环素（tetW）和柔红霉素（drrA）耐药基因的相对丰度。以上结果表明，盐酸安非他酮干预有增加大鼠肠道菌群抗生素耐药性的风险。UCG-005和norank_ f__norank_o__Clostridia_UCG-014是大鼠粪便和盲肠内容物菌群的主要细菌属，相关性分析结果表明，UCG-005可能是四环素、利福霉素类、莫匹罗星、杆菌肽类、万古霉素耐药基因的潜在细菌宿主，而norank_ f__norank_o__Clostridia_UCG-014可能是柔红霉素耐药基因的细菌宿主，它们在盐酸安非他酮给药后增加可能是导致这6种类型耐药基因丰度增加的原因。
闫鹤 , 陈春霞 , 刘宗保 , 李佳林 , 詹诗皿 . 盐酸安非他酮对SD大鼠肠道菌群耐药组的影响[J]. 华南理工大学学报(自然科学版), 2025 , 53(10) : 155 -173 . DOI: 10.12141/j.issn.1000-565X.240258
To investigate the impact of the antidepressant bupropion hydrochloride on the gut microbiome resistome, this study employed Sprague-Dawley (SD) rats as model organisms. Using both 16S rRNA amplicon sequencing and metagenomic sequencing approaches, it systematically analyzed the drug’s effects on microbial communities and their resistome profiles in both fecal and cecal contents. Furthermore, it conducted comprehensive correlation analyses to elucidate potential relationships between these alterations. The results show that prevalent types of ARGs in the feces and cecum samples include bacitracin, tetracycline, vancomycin, and macrolides-lincomycin-streptogramin (MLS). Compared to the control group (HC), the bupropion hydrochloride gavage intervention group (Bup-PO) shows increased total abundance of bacterial antibiotic resistance genes (ARGs) in both fecal and cecal content samples, with statistically significant differences observed only in fecal samples. In terms of ARG types, the Bup-PO group demonstrates significantly increased relative abundance of six antibiotic resistance gene classes in fecal samples compared to the HC group, including: aminoglycoside resistance genes, bacitracin resistance genes, mupirocin resistance genes, rifamycin resistance genes, tetracycline resistance genes, Vancomycin resistance genes. Notably, the treatment group also shows an expansion in the diversity of vancomycin resistance gene variants. In cecum samples, the Bup-PO group significantly increases the relative abundance of 3 resistance gene types, tetracycline, daunorubicin, and fosfomycin. On ARG subtypes, in fecal samples, compared to the HC group, the Bup-PO group significantly increases the relative abundance of vancomycin (vanAG, vanRI, vanSA, vanSI), tetracycline (tetM, tetO, tet32), bacitracin (bceA, bcrA) and rifampicin (rpoB) resistance genes. In cecum samples, the effect of gavage bupropion on ARGs differs from that in fecal samples, with gavage intervention of bupropion causing fluctuations in the relative abundance of the MLS class of resistance genes, decreasing the abundance of lmrB but increasing the abundance of macB. Concurrently, bupropion hydrochloride intervention via oral gavage significantly increased the relative abundance of tetracycline (tetW) and daunorubicin (drrA) resistance genes. The above results suggest that bupropion intervention has the risk of increasing antibiotic resistance in rat’s gut microbiota. UCG-005 and norank__f__norank__o_Clostridia_UCG-014 are the major bacterial genera of the rat intestinal flora, and correlation analyses suggest that UCG-005 may be a potential host for tetracycline, rifampicin, mupirocin, and bacitracin, vancomycin resistance genes, while norank_f__norank__o_Clostridia_UCG-014 may be a potential bacterial host for daunorubicin resistance genes, and their increase after bupropion intervention may be responsible for the increased abundance of these six types of resistance genes.
| [1] | LAXMINARAYAN R， SRIDHAR D， BLASER M，et al ．Achieving global targets for antimicrobial resistance［J/OL］．Science，2016，353（6302）：874-875. |
| [2] | 桑金慧，何振杰，余相宇，等 ．基于宏基因组学分析安徽地区畜禽粪便微生物耐药性特征［J/OL］．中国微生态学杂志，2024，36（1）：29-40. |
| SANG Jinhui， HE Zhenjie， YU Xiangyu，et al ．Macrogenomics-based analysis of microbial resistance of microbes in pig and chicken faeces in Anhui region［J］．Chinese Journal of Microecology，2024，36（1）：29-40. | |
| [3] | DING P， LU J， WANG Y，et al ．Antidepressants promote the spread of antibiotic resistance via horizontally conjugative gene transfer［J/OL］．Environmental Microbiology，2022，24（11）：5261-5276. |
| [4] | MURRAY C J， IKUTA K S， SHARARA F，et al ．Global burden of bacterial antimicrobial resistance in 2019：a systematic analysis［J/OL］．Lancet，2022，399（10325）：629-655. |
| [5] | GOOSSENS H， FERECH M， STICHELE R V，et al ．Outpatient antibiotic use in Europe and association with resistance：a cross-national database study［J］．Lancet，2005，365（9459）：579-587. |
| [6] | LARSSON D G J， FLACH C F ．Antibiotic resistance in the environment［J/OL］．Nature Reviews．Microbiology，2022，20（5）：257-269. |
| [7] | QIU Z， YU Y， CHEN Z，et al ．Nanoalumina promotes the horizontal transfer of multiresistance genes mediated by plasmids across genera［J/OL］．Proceedings of the National Academy of Sciences，2012，109（13）：4944-4949. |
| [8] | WANG X， CHEN Z， MU Q，et al ．Ionic liquid enriches the antibiotic resistome，especially efflux pump genes，before significantly affecting microbial community structure［J/OL］．Environmental Science & Technology，2020，54（7）：4305-4315. |
| [9] | WANG Y， LU J， MAO L，et al ．Antiepileptic drug carbamazepine promotes horizontal transfer of plasmid-borne multi-antibiotic resistance genes within and across bacterial genera［J/OL］．The ISME Journal，2019，13（2）：509-522. |
| [10] | KIM S， COVINGTON A， PAMER E G ．The intestinal microbiota：antibiotics，colonization resistance， and enteric pathogens［J/OL］．Immunological Reviews，2017，279（1）：90-105. |
| [11] | SCHMIDT H D， SHELTON R C， DUMAN R S ．Functional biomarkers of depression：diagnosis，treatment，and pathophysiology［J/OL］．Neuropsychopharmacology，2011，36（12）：2375-2394. |
| [12] | FRIEDRICH M J ．Depression is the leading cause of disability around the world［J/OL］．The Journal of the American Medical Association，2017，317（15）：1517. |
| [13] | 高鑫磊，贾艾楠，刘敏 ．1990年和2019年中国分省精神障碍伤残负担分析［J］．中华精神科杂志，2023，56（1）：40-46. |
| GAO Xinlei， JIA Ainan， LIU Min，et al ．The burden of disability associated with mental disorders in China by province between 1990 and 2019［J］．Chinese Journal of Psychiatry，2023，56（1）：40-46. | |
| [14] | DREW L ．How antidepressants help bacteria resist antibiotics［J/OL］．Nature，2023，doi：10.1038/d41586-023-00186-y . |
| [15] | CIPRIANI A， FURUKAWA T A， SALANTI G，et al ．Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder：a systematic review and network meta-analysis［J/OL］．Lancet，2018，391（10128）：1357-1366. |
| [16] | WANG Y， YU Z， DING P，et al ．Antidepressants can induce mutation and enhance persistence toward multiple antibiotics［J/OL］．Proceedings of the National Academy of Sciences，2023，120（5）：e2208344120/1-12. |
| [17] | ADU M K， WALLACE L J， LARTEY K F，et al ．Prevalence and correlates of likely major depressive disorder among the adult population in ghana during the COVID-19 pandemic［J/OL］．International Journal of Environmental Research and Public Health，2021，18（13）：7106/1-19. |
| [18] | VERMA S， MISHRA A ．Depression，anxiety，and stress and socio-demographic correlates among general Indian public during COVID-19［J/OL］．International Journal of Social Psychiatry，2020，66（8）：756-762. |
| [19] | SUNA S G， DIDEM K， ERYILMAZ M ．The effects of antidepressants fluoxetine，sertraline，and amitriptyline on the development of antibiotic resistance in acinetobacter baumannii［J/OL］．Archives of Microbiology，2022，204（4）：230/1-10. |
| [20] | SHI D， HAO H， WEI Z，et al ．Combined exposure to non-antibiotic pharmaceutics and antibiotics in the gut synergistically promote the development of multi-drug-resistance in Escherichia coli ［J/OL］．Gut Microbes，2022，14（1）：2018901/1-17. |
| [21] | JIN M， LU J， CHEN Z，et al ．Antidepressant fluoxetine induces multiple antibiotics resistance in Escherichia coli via ROS-mediated mutagenesis［J/OL］．Environment International，2018，120：421-430. |
| [22] | OU J， ELIZALDE P， GUO H B，et al ．TCA and SSRI antidepressants exert selection pressure for efflux-dependent antibiotic resistance mechanisms in Escherichia coli［J/OL］．mBio，2022，13（6）：e02191-22/1-20. |
| [23] | WANG Y， HU Y， CAO J，et al ．Antibiotic resistance gene reservoir in live poultry markets［J/OL］．The Journal of Infection，2019，78（6）：445-453. |
| [24] | VICH VILA A， COLLIJ V， SANNA S，et al ．Impact of commonly used drugs on the composition and metabolic function of the gut microbiota［J/OL］．Nature Communications， 2020，11（1）：362/1-11. |
| [25] | ZHANG W， QU W， WANG H，et al ．Antidepressants fluoxetine and amitriptyline induce alterations in intestinal microbiota and gut microbiome function in rats exposed to chronic unpredictable mild stress［J/OL］．Translational Psychiatry，2021，11（1）：131/1-16. |
| [26] | ZUNG W W K， BRODIE H K H， FABRE L，et al ．Comparative efficacy and safety of bupropion and placebo in the treatment of depression［J/OL］．Psychopharmacology，1983，79（4）：343-347. |
| [27] | JEFFERSON J W， PRADKO J F， MUIR K T ．Bupropion for major depressive disorder：pharmacokinetic and formulation considerations［J］．Clinical Therapeutics，2005，27（11）：1685-1695. |
| [28] | JORENBY D E， HAYS J T， RIGOTTI N A，et al ．Efficacy of varenicline，an α 4β2 nicotinic acetylcholine receptor partial agonist，vs placebo or sustained-release bupropion for smoking Cessation：a randomized controlled trial［J/OL］．The Journal of the American Medical Association，2006，296（1）：56-63. |
| [29] | FOLEY K F， DESANTY K P， KAST R E ．Bupropion：pharmacology and therapeutic applications［J］．Expert Review of Neurotherapeutics，2006，6（9）：1249-1265. |
| [30] | VARSHOSAZ J， MINAIYAN M， ZAKI M R，et al ．In vitro/in vivo evaluation of agar nano spheres for pulmonary delivery of bupropion HCl［J/OL］．Drug Delivery，2016：23（6）：1948-1954. |
| [31] | LAIZURE S C， DEVANE C L， STEWART J T，et al ．Pharmacokinetics of bupropion and its major basic metabolites in normal subjects after a single dose［J/OL］．Clinical Pharmacology and Therapeutics，1985，38（5）：586-589. |
| [32] | STAHL S M， PRADKO J F， HAIGHT B R，et al ．A review of the neuropharmacology of bupropion，a dual norepinephrine and dopamine reuptake inhibitor［J］．Primary Care Companion to the Journal of Clinical Psychiatry，2004，6（4）：159-166. |
| [33] | 周道友 ．不同剂量盐酸安非他酮与帕罗西汀治疗抑郁症的临床对照研究［J］．医学与哲学（临床决策论坛版），2009，30（9）：34-35，51. |
| ZHOU Daoyou. Study of different dose of bupropion hydrochloride and paroxetine in treatment of depression［J］．Medicine & Philosophy，2009，30（9）：34-35，51. | |
| [34] | CARROLL F I， BLOUGH B E， MASCARELLA S W，et al ．Bupropion and bupropion analogs as treatments for CNS disorders［M/OL］．Advances in Pharmacology，2014，69：177-216. |
| [35] | BALLESTA A， ORIO L， ARCO R，et al ．Bupropion，a possible antidepressant without negative effects on alcohol relapse［J/OL］．European Neuropsychopharmacology，2019，29（6）：756-765. |
| [36] | CHEN S， ZHOU Y， CHEN Y，et al ．Fastp：an ultra-fast all-in-one FASTQ preprocessor［J/OL］．Bioinformatics （Oxford，England），2018，34（17）：i884-i890. |
| [37] | LI H， DURBIN R ．Fast and accurate short read alignment with burrows-wheeler transform［J/OL］．Bioinformatics （Oxford， England），2009，25（14）：1754-1760． |
| [38] | BUCHFINK B， XIE C， HUSON D H ．Fast and sensitive protein alignment using DIAMOND［J/OL］．Nature Methods，2015，12（1）：59-60. |
| [39] | LIU Z， KLüMPER U， LIU Y，et al ．Metagenomic and metatranscriptomic analyses reveal activity and hosts of antibiotic resistance genes in activated sludge［J/OL］．Environment International，2019，129：208-220. |
| [40] | HU Y， YANG X， QIN J，et al ．Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota［J/OL］．Nature Communications，2013，4（1）：2151/1-7. |
| [41] | MA L， XIA Y， LI B，et al ．Metagenomic assembly reveals hosts of antibiotic resistance genes and the shared resistome in pig， chicken， and human feces［J/OL］．Environmental Science & Technology，2016，50（1）：420-427. |
| [42] | YAO Y， LIU Z， YIP K K，et al ．Cross-regional scale pollution of freshwater biofilms unveiled by antibiotic resistance genes［J/OL］．Science of the Total Environment，2022，818（19）：151835/1-12. |
| [43] | LI B， YANG Y， MA L，et al ．Metagenomic and network analysis reveal wide distribution and co-occurrence of environmental antibiotic resistance genes［J/OL］．The ISME Journal，2015，9（11）：2490-2502. |
| [44] | CHEN B， YUAN K， CHEN X，et al ．Metagenomic analysis revealing antibiotic resistance genes （ARGs） and their genetic compartments in the Tibetan environment［J/OL］．Environmental Science & Technology，2016，50（13）：6670-6679. |
| [45] | MACKELPRANG R， WALDROP M P， DEANGELIS K M，et al ．Metagenomic analysis of a permafrost microbial community reveals a rapid response to thaw［J/OL］．Nature，2011，480（7377）：368-371. |
| [46] | MA L， LI B， ZHANG T ．New insights into antibiotic resistome in drinking water and management perspectives：a metagenomic based study of small-sized microbes［J/OL］．Water Research，2019，152：191-201. |
| [47] | QIU T， HUO L， GUO Y，et al ．Metagenomic assembly reveals hosts and mobility of common antibiotic resistome in animal manure and commercial compost［J/OL］．Environmental Microbiome，2022，17（1）：42/1-15. |
| [48] | 钱璟，吴哲元，朱泳璋，等 ．上海市崇明区猪-土壤界面微生态与抗生素耐药性相关性分析［J/OL］．中国微生态学杂志，2024，36（2）：135-146. |
| QIAN Jing， WU Zheyuan， ZHU Yongzhang，et al ．Correlation between microecology and antibiotic resistance at the pig-soil interface in Chongming District，Shanghai，China［J/OL］．Chinese Journal of Microecology，2024，36（2）：135-146. | |
| [49] | FENG J， LI B， JIANG X，et al ．Antibiotic resistome in a large-scale healthy human gut microbiota deciphered by metagenomic and network analyses［J/OL］．Environmental Microbiology，2018，20（1）：355-368. |
| [50] | BUNGAU S， TIT D M， BEHL T，et al ．Aspects of excessive antibiotic consumption and environmental influences correlated with the occurrence of resistance to antimicrobial agents［J/OL］．Current Opinion in Environmental Science & Health，2021，19：100224/1-6. |
| [51] | ZHANG R M， LIU X， WANG S L，et al ．Distribution patterns of antibiotic resistance genes and their bacterial hosts in pig farm wastewater treatment systems and soil fertilized with pig manure［J/OL］．Science of the Total Environment，2021，758：143654/1-7. |
| [52] | PAN X， QIANG Z，BEN W，et al ．Residual veterinary antibiotics in swine manure from concentrated animal feeding operations in shandong province，China［J/OL］．Chemosphere，2011，84（5）：695-700. |
| [53] | SHENG S， LI X， ZHAO S，et al ．Effects of levodopa on gut bacterial antibiotic resistance in Parkinson's disease rat［J/OL］．Frontiers in Aging Neuroscience，2023， 15：1122712/1-12. |
| [54] | AMMAM F， MEZIANE-CHERIF D， MENGIN-LECREULX D，et al ．The functional vanGCd cluster of clostridium difficile does not confer vancomycin resistance［J/OL］．Molecular Microbiology，2013，89（4）：612-625. |
| [55] | ARIAS C， COURVALIN P， REYNOLDS P ． vanC cluster of vancomycin-resistant Enterococcus gallinarum BM4174［J/OL］．Antimicrobial Agents and Chemotherapy，2000，44（6）：1660-1666. |
| [56] | COURVALIN P ．Vancomycin resistance in gram-positive cocci［J/OL］．Clinical Infectious Diseases： An Official Publication of the Infectious Diseases Society of America，2006，42 （）：S25-S34. |
| [57] | KAPLAN E L ．Vancomycin in infants and children： a review of pharmacology and indications for therapy and prophylaxis［J/OL］．Journal of Antimicrobial Chemotherapy，1984，14（）：59-66. |
| [58] | WILHELM M P ．Vancomycin［J/OL］．Mayo Clinic Proceedings，1991，66（11）：1165-1170. |
| [59] | ARIAS C A， MURRAY B E ．The rise of the Enterococcus：beyond vancomycin resistance［J/OL］．Nature Reviews．Microbiology，2012，10（4）：266-278. |
| [60] | STANLEY D， GEIER M S， CHEN H，et al ．Comparison of fecal and cecal microbiotas reveals qualitative similarities but quantitative differences［J/OL］．BMC Microbiology，2015，15：51. |
| [61] | CHE Y， XIA Y， LIU L，et al ．Mobile antibiotic resistome in wastewater treatment plants revealed by Nanopore metagenomic sequencing［J/OL］．Microbiome，2019，7（1）：44. |
| [62] | HE L Y， HE L K， LIU Y S，et al ．Microbial diversity and antibiotic resistome in swine farm environments［J/OL］．Science of the Total Environment，2019，685：197-207. |
| [63] | WEI B， XU Q L， ZHANG B，et al ．Comparative study of Sargassum fusiforme polysaccharides in regulating cecal and fecal microbiota of high-fat diet-fed mice［J/OL］．Marine Drugs，2021，19（7）：364/1-11. |
| [64] | TANCA A， MANGHINA V， FRAUMENE C，et al ．Metaproteogenomics reveals taxonomic and functional changes between cecal and fecal microbiota in mouse［J/OL］．Frontiers in Microbiology，2017，8：391/1-12. |
| [65] | SUN C H， LIU H Y， LIU B，et al ．Analysis of the gut microbiome of wild and captive Père david's deer［J/OL］．Frontiers in Microbiology，2019，10：2331/1-9. |
| [66] | HAWORTH S E， WHITE K S， C?Té S D，et al ．Space，time and captivity： quantifying the factors influencing the fecal microbiome of an alpine ungulate［J/OL］．FEMS Microbiology Ecology，2019，95（7）：fiz095. |
| [67] | LI J G， WANG C D， TANG Z H，et al ．The gut bacterial community composition of wild Cervus albirostris （white-lipped deer） detected by the 16S ribosomal RNA gene sequencing［J/OL］．Current Microbiology，2017，74（9）：1100-1107. |
| [68] | COUCH C E， STAGAMAN K， SPAAN R S，et al ．Diet and gut microbiome enterotype are associated at the population level in african buffalo［J/OL］．Nature Communications，2021，12（1）：2267/1-11. |
| [69] | SUN G， ZHANG H， WEI Q，et al ．Comparative analyses of fecal microbiota in European mouflon （Ovis orientalis musimon） and blue sheep （Pseudois nayaur） living at low or high altitudes［J/OL］．Frontiers in Microbiology，2019，10：1735/1-15. |
| [70] | LI Y， YAN Y， FU H，et al ．Does diet or macronutrients intake drive the structure and function of gut microbiota？［J/OL］．Frontiers in Microbiology，2023，14：1126189/1-13. |
| [71] | ZHANG B， WAN Y， ZHOU X，et al ．Characteristics of serum metabolites and gut microbiota in diabetic kidney disease［J/OL］．Frontiers in Pharmacology，2022，13：872988/1-17. |
| [72] | WANG D， ZHOU Y， ZHAO J，et al ．Oral yak whey protein can alleviate UV-induced skin photoaging and modulate gut microbiota composition［J/OL］．Foods，2024，13（16）：2621/1-14. |
| [73] | RAINERI S， SHERRIFF J A， THOMPSON K S J，et al ．Pharmacologically induced weight loss is associated with distinct gut microbiome changes in obese rats［J/OL］．BMC Microbiology，2022，22（1）：91/1-21. |
| [74] | SONG E J， SHIN N R， JEON S，et al ．Impact of the herbal medicine，Ephedra sinica stapf，on gut microbiota and body weight in a diet-induced obesity model［J/OL］．Frontiers in Pharmacology，2022，13：1042833/1-11. |
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