兽药残留对肠道微生物群系和人类健康的影响-99页-WN7.pdf
THE IMPACT OF VETERINARY DRUG RESIDUES ON THE GUT MICROBIOME AND HUMAN HEALTHA FOOD SAFETY PERSPECTIVEFOOD SAFETY AND QUALITY SERIES 20ISSN 24151173FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONSROME,2023THE IMPACT OF VETERINARY DRUG RESIDUES ON THE GUT MICROBIOME AND HUMAN HEALTHA FOOD SAFETY PERSPECTIVERequired citation:FAO.2023.The impact of veterinary drug residues on the gut microbiome and human health A food safety perspective.Food Safety and Quality Series,No.20.Rome.https:/doi.org/10.4060/cc5301enThe designations employed and the presentation of material in this information product do not imply the expression of any opinion whatsoever on the part of the Food and Agriculture Organization of the United Nations(FAO)concerning the legal or development status of any country,territory,city or area or of its authorities,or concerning the delimitation of its frontiers or boundaries.The mention of specific companies or products of manufacturers,whether or not these have been patented,does not imply that these have been endorsed or recommended by FAO in preference to others of a similar nature that are not mentioned.ISSN 2415-1173 PrintISSN 2664-5246 OnlineISBN 978-92-5-137809-0 FAO,2023,last updated 03/06/2023Some rights reserved.This work is made available under the Creative Commons Attribution-Non Commercial-ShareAlike 3.0 IGO licence(CC BY-NC-SA 3.0 IGO;https:/creativecommons.org/licenses/by-nc-sa/3.0/igo/legalcode).Under the terms of this licence,this work may be copied,redistributed and adapted for non-commercial purposes,provided that the work is appropriately cited.In any use of this work,there should be no suggestion that FAO endorses any specific organization,products or services.The use of the FAO logo is not permitted.If the work is adapted,then it must be licensed under the same or equivalent Creative Commons licence.If a translation of this work is created,it must include the following disclaimer along with the required citation:“This translation was not created by the Food and Agriculture Organization of the United Nations(FAO).FAO are not responsible for the content or accuracy of this translation.The original English edition shall be the authoritative edition”.Disputes arising under the licence that cannot be settled amicably will be resolved by mediation and arbitration as described in Article 8 of the licence except as otherwise provided herein.The applicable mediation rules will be the mediation rules of the World Intellectual Property Organization http:/www.wipo.int/amc/en/mediation/rules and any arbitration will be conducted in accordance with the Arbitration Rules of the United Nations Commission on International Trade Law(UNCITRAL).Thirdparty materials.Users wishing to reuse material from this work that is attributed to a third party,such as tables,figures or images,are responsible for determining whether permission is needed for that reuse and for obtaining permission from the copyright holder.The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user.Sales,rights and licensing.FAO information products are available on the FAO website(www.fao.org/publications)and can be purchased through publications-salesfao.org.Requests for commercial use should be submitted via:www.fao.org/contact-us/licence-request.Queries regarding rights and licensing should be submitted to:copyrightfao.org.Cover photographs from left to right:FAO/Luis Tato;FAO/Hoang Dinh Nam;FAO/K.PurevraqchaaDesign and layout:studio Pietro BartoleschiiiiCONTENTSAcknowledgements.vAbbreviations and Acronyms.viiExecutive summary.ixCHAPTER 1INTRODUCTION.1CHAPTER 2WHAT IS THE GUT MICROBIOME?.5CHAPTER 3STUDY OF THE MICROBIOME.11Models.11Analytical considerations-sampling and sample preparation.14Analytical methods.15Standardization and best practices.17CHAPTER 4GUT MICROBIOME,HUMAN AND PHARMACEUTICALS INTERACTIONS.19Effects of the microbiome on drugs.19Effect of drugs on the microbiome.20Antimicrobial resistance.21Health implications derived from drug-induced microbiome disturbances.23CHAPTER 5STUDY OF VETERINARY DRUG RESIDUES AND THE MICROBIOME.25In vitro studies.25In vivo studies.30Antimicrobials.30Glucocorticosteroids and production aids.36Insecticide residues.36CHAPTER 6GUT MICROBIOME AND HEALTH EFFECTS.39ivBIBLIOGRAPHY.58ANNEXESI.MICROBIOTA MEMBERS ALTERED BY EXPOSURE TO THERAPEUTICAL DOSES OF ANTIBIOTICS .73II.GUT MICROORGANISMS FOUND TO HAVE INCREASED ANTIBIOTIC RESISTANCE.74III.IN VIVO STUDIES EVALUATING THE EFFECTS OF DRUGS ON THE GUT MICROBIOTA AND HOST HEALTH.76IV.IN VIVO STUDIES EVALUATING THE EFFECTS OF INSECTICIDES ON THE GUT MICROBIOTA AND HOST HEALTH.80TABLES1.JECFA veterinary drug functional classes.12.Effect of select antibiotics administered orally on the gastrointestinal microbiota.21FIGURE1.Conditions and physiological activities in the gastrointestinal tract.7CHAPTER 7THE MICROBIOME IN VETERINARY DRUG RESIDUE RISK ASSESSMENT.43CHAPTER 8POTENTIAL OF THE GUT MICROBIOME IN THE ASSESSMENT OF VETERINARY DRUGS.47From microbial isolates to microbiota.47Microbiome function,gastrointestinal location and host impact.49Alterations of concern or normal microbial fluctuation.49From associations to causality.50The omics in risk assessment.51Additional considerations.51CHAPTER 9RESEARCH GAPS AND NEEDS .53CHAPTER 10CONCLUSION.57vACKNOWLEDGEMENTSThe research and drafting of the publication were carried out by Carmen Diaz-Amigo(Food Systems and Food Safety Division ESF,FAO)and the literature search and preliminary analysis by Susan Vaughn Grooters(ESF)under the technical leadership and guidance of Catherine Bessy,Senior Food Safety Officer(ESF).The support and guidance of Markus Lipp,Senior Food Safety Officer(ESF),and the technical inputs and insights provided by Vittorio Fattori,Food Safety Officer(ESF),during the entire process of the publications development are gratefully recognized.FAO is grateful to the expert Mark Feeley(Consultant,Canada)for his insightful comments and recommendations to improve the draft.Finally,special thanks go out to Karel Callens Senior Advisor to Chief Economist,Governance and Policy Support Unit(DDCG,FAO)and Fanette Fontaine,Science Policy Advisor(DDCG),for their pioneer initiative at FAO bringing attention to and starting a dialogue on the impact of microbiomes in food systems.FAO/Ishara KodikaraviiABBREVIATIONS AND ACRONYMSADIacceptable daily intakeDNAdeoxyribonucleic acidDGGEdenaturing gradient gel electrophoresisEMAEuropean Medicines AgencyFDAUnited States Food and Drug AdministrationGIgastrointestinalHFAhuman flora associatedJECFAJoint Expert Committee on Food AdditivesIHMSinternational Human Microbiome StandardsITSinternal transcribed spacermADImicrobiological ADIMDCminimum disruptive concentrationMICminimal inhibitory concentrationmRNAmessenger RNANOAECno-observable adverse effect concentrationNODnon-obese diabeticNOECno observed effect concentrationNOELno observed effect levelOIEWorld Organization for Animal HealthPCRpolymerase chain reactionRNAribonucleic acidrRNAribosomal RNASCFAshort-chain fatty acidsSHIMEsimulator of human intestinal microbial ecosystemVICHVeterinary International Conference on HarmonizationWHOWorld Health Organizationviii FAO/Luis Tato Sergei GaponixEXECUTIVE SUMMARYVeterinary drugs are administered to treat and prevent diseases in food-producing animals.These compounds may leave residual amounts in food products(e.g.meat,milk,eggs),especially if drugs are not used as approved(e.g.doses or dosing frequencies,off-label uses)or when clearance periods are not followed.The risk assessment of veterinary drug residues is typically conducted to evaluate their safety and determine health-based values.These assessments consider both toxicological and microbiological data.The development of omic technologies,including culture-independent analytical approaches(16S rRNA gene sequencing,shotgun metagenomics,transcriptomics,proteomics,metabolomics)has enabled the holistic evaluation of complex biological systems.These include,for example,the gut microbiome,human physiology or microbiomehost interactions.The human gut microbiome is comprised of trillions of microorganisms(bacteria,fungi,viruses and archaea),and its composition and function are highly influenced by various factors(e.g.diet,age,lifestyle,host genetics,environmental conditions along and across the gastrointestinal tract).The gut microbiome influences some physiological activities,e.g.immune system development and metabolism.However,there are concerns about the potential of residual veterinary drug in food to disturb the gut microbiome and the microbiomehost interactions,and whether these lead to short and long-term health consequences.This review aims to evaluate the current knowledge about the effects of veterinary drug residues on the gut microbiome.It also assesses the scientific evidence on the influence of microbiome disturbances on health.Limited research has focused on evaluating low residue levels of a few antibiotics on the faecal microbiota.These studies were primarily conducted in vitro and dependent on traditional bacteria cultures.They evaluated the capacity of antimicrobials to(1)disrupt the microbial barrier and the susceptibility to pathogen colonization,and(2)select for resistant bacteria.Effects were dose-dependent.All these studies,of relevance for food safety,were used to determine health-based values.However,most did not use the most modern holistic technologies(omics).Moreover,these research studies were microbe-centric and lacked consideration of host parameters.However,most research on drugs and the gut microbiome is clinically relevant,as they evaluate treatment regimens(single therapeutical or subtherapeutic doses,schedule and duration)and drug combinations most commonly used in human medicine.Human clinical studies were not considered in database queries.Contrary to the research using low residue levels,most research evaluating therapeutical or subtherapeutic doses is conducted in vivo in rodents.The interest in early exposure is also reflected by the numerous research studies on this topic.Based on study conditions,most of the findings report microbial alterations and increased risk x xfor the development of metabolic disorders.Another common research focus is the increased susceptibility to gastrointestinal infections following microbiota disturbances caused by antimicrobial treatments.In general,the microbiota effects reported are very diverse in some cases contradicting because the studies are designed differently(e.g.drugs,doses,exposure periods,models)and analytical methodologies are very heterogeneous.For these reasons,assay reproducibility inter-study comparability cannot be assessed.The lack of methodology standardization is a common observation in microbiome research.Moreover,the relationship between microbiome disturbances and health effects is associative or speculative in all the cases included in this review.In the absence of confirmed causality and mechanisms showing how the gut microbiome modulates health disorders,it is very difficult to incorporate microbiome data in risk assessments.FAO/Giulio Napolitano FAO/Hkun Lat1CHAPTER 1INTRODUCTIONVeterinary drugs include a large class of chemical agents defined in the Codex Procedural Manual as“any substance applied or administered to any food-producing animal,such as meat or milk-producing animals,poultry,fish or bees,whether used for therapeutic,prophylactic,or diagnostic purposes,or for modification of physiological functions or behavior”(Codex Alimentarius,2018a).Hundreds of different drugs are used in veterinary medicine for treating and managing food-producing animals.The Joint Expert Committee on Food Additives(JECFA)evaluates the safety of veterinary drug residues in food,grouped into 13 functional classes based on their functional activity(Table 1).Some veterinary drugs may fall into several classes.For example,an adrenoreceptor agonist may also be classified as a production aid,or an antimicrobial may also have antiprotozoal properties(Codex Alimentarius,2018b).TABLE 1 JECFA VETERINARY DRUG FUNCTIONAL CLASSESAdrenoceptor agonistAntiprotozoal agentProduction aidBetaadrenoceptor blocking agentGlucocorticosteroidTranquilizing agentAnthelminthic agentGrowth promoterTrypanocideAntifungal agentInsecticideVeterinary drug,unclassifiedAntimicrobial agentSource(italics):Codex Alimentarius.2018b.Codex Veterinary Drug Residue in Food Online Database.In:Codex Alimentarius.Rome.Cited September 2019.https:/www.fao.org/faowhocodexalimentarius/codextexts/dbs/vetdrugs/enVeterinary drugs may be administered orally,including as a supplement to feed and water,injected intravenously or intramuscularly,intramammary,subcutaneously,by aerosol,applied topically on the skin,or in the case of fish,via immersion.Drugs can reach the environment via the disposal of human or animal waste(including manure)or water run-off.In addition,some antimicrobial agents,such as antibiotics(e.g.gentamycin,tetracyclines,oxalinic acid)and anti-fungal compounds,are also applied to fruits,vegetables,grains and pulses to control plant diseases.Therefore,terrestrial and aquatic animals and plants may be unintentionally exposed to drugs from environmental sources such as grazing on contaminated pastures,water or soil contamination.Environmental exposure in food-producing animals is not specifically considered or discussed in this review but is important as a consideration in the One Health paradigm.2THE IMPACT OF VETERINARY DRUG RESIDUES ON THE GUT MICROBIOME AND HUMAN HEALTH A FOOD SAFETY PERSPECTIVEDepending upon the pharmacokinetic properties of a specific drug,the drug preparation,and the route of administration,the drug is absorbed from the administration site and distributed systemically throughout the tissues of the animals body.Such tissues include but are not limited to muscle,fat,organs(e.g.kidney,liver and lungs)and animal products such as milk,dairy products,eggs and honey.Drug residues may concentrate in certain parts of an animals body following administration;for example,certain fat-soluble drugs may be sequestered in adipose tissue or concentrated in the liver or kidneys,where they are metabolized and eliminated.Notably,injection sites may have higher concentrations of drug residues than surrounding skeletal muscle.Eventually,drugs are metabolized to variable extents and eliminated from the food animal.For fish,the environmental temperature may also impact the metabolism and excretion rates.The relationship between the time of the last administration of a particular drug and the amount of drug residue present in any tissue depends upon multiple factors,including the dose and route of administration of the drug,the drug pharmacokinetics,the animal species and the health status of the animal.The withdrawal period,from the last drug administration until slaughter,is often established by governme
