獸藥殘留對腸道微生物群系和人類健康的影響

20FOODSAFETYANDQUALITYSERIESISSN2415?1173THEIMPACT

OFVETERINARYDRUGRESIDUESONTHEGUTMICROBIOMEANDHUMANHEALTHA

FOODSAFETYPERSPECTIVETHEIMPACT

OFVETERINARYDRUGRESIDUESONTHEGUTMICROBIOMEANDHUMANHEALTHA

FOODSAFETYPERSPECTIVEFOODANDAGRICULTURE

ORGANIZATION

OFTHEUNITEDNATIONSROME,2023Requiredcitation:FAO.2023.

The

impact

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on

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microbiome

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human

health

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A

food

safetyperspective.FoodSafetyandQualitySeries,No.20.Rome./10.4060/cc5301enThe

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?FAO/K.PurevraqchaaDesignandlayout:studioPietroBartoleschiCONTENTSAcknowledgements

vAbbreviationsandAcronymsviiExecutivesummaryixCHAPTER1INTRODUCTION

1CHAPTER2WHAT

IS

THE

GUT

MICROBIOME?

5CHAPTER3STUDY

OF

THE

MICROBIOME11Models

11Analyticalconsiderations-

samplingandsamplepreparation

14Analyticalmethods

15Standardizationandbestpractices

17CHAPTER4GUT

MICROBIOME,

HUMAN

AND

PHARMACEUTICALS

INTERACTIONS19Effectsofthemicrobiomeondrugs

19Effectofdrugsonthemicrobiome

20Antimicrobialresistance

21Healthimplicationsderivedfromdrug-inducedmicrobiomedisturbances

23CHAPTER5STUDY

OF

VETERINARY

DRUG

RESIDUES

AND

THE

MICROBIOME25Invitrostudies

25Invivostudies

30Antimicrobials

30Glucocorticosteroidsandproductionaids

36Insecticideresidues

36CHAPTER6GUT

MICROBIOME

AND

HEALTH

EFFECTS

39iiiCHAPTER7THE

MICROBIOME

IN

VETERINARY

DRUG

RESIDUE

RISK

ASSESSMENT

43CHAPTER8POTENTIAL

OF

THE

GUT

MICROBIOME

IN

THE

ASSESSMENT

OF

VETERINARY

DRUGS

47Frommicrobialisolatestomicrobiota

47Microbiomefunction,gastrointestinallocationandhostimpact

49Alterationsofconcernornormalmicrobial?uctuation

49Fromassociationstocausality

50Theomicsinriskassessment

51Additionalconsiderations

51CHAPTER9RESEARCH

GAPS

AND

NEEDS

53CHAPTER10CONCLUSION57BIBLIOGRAPHY

58ANNEXESI.

MICROBIOTA

MEMBERS

ALTERED

BY

EXPOSURE

TOTHERAPEUTICAL

DOSES

OF

ANTIBIOTICS

73II.

GUT

MICROORGANISMS

FOUND

TO

HAVE

INCREASED

ANTIBIOTIC

RESISTANCE

74III.

IN

VIVO

STUDIES

EVALUATING

THE

EFFECTS

OF

DRUGSON

THE

GUT

MICROBIOTA

AND

HOST

HEALTH

76IV.

IN

VIVO

STUDIES

EVALUATING

THE

EFFECTS

OF

INSECTICIDESON

THE

GUT

MICROBIOTA

AND

HOST

HEALTH

80TABLES1.

JECFA

veterinarydrugfunctionalclasses

12.

Effectofselectantibioticsadministeredorallyonthegastrointestinalmicrobiota21FIGURE1.

Conditionsandphysiologicalactivitiesinthegastrointestinaltract

7ivACKNOWLEDGEMENTSThe

research

and

drafting

of

the

publication

were

carried

out

by

Carmen

Diaz-Amigo

(Food

Systems

and

Food

Safety

Division

[ESF],

FAO)

and

the

literaturesearch

and

preliminary

analysis

by

Susan

Vaughn

Grooters

(ESF)

under

the

technicalleadershipandguidanceofCatherineBessy,

SeniorFoodSafetyOf?cer(ESF).ThesupportandguidanceofMarkusLipp,SeniorFoodSafetyOf?cer(ESF),andthe

technical

inputs

and

insights

provided

by

VittorioFattori,

Food

Safety

Of?cer(ESF),

during

the

entire

process

of

the

publication’s

development

are

gratefullyrecognized.FAO

is

grateful

to

the

expert

Mark

Feeley

(Consultant,

Canada)

for

his

insightfulcommentsandrecommendationstoimprovethedraft.Finally,special

thanks

go

out

to

Karel

Callens

Senior

Advisor

to

Chief

Economist,Governance

and

Policy

Support

Unit

(DDCG,

FAO)

and

Fanette

Fontaine,

SciencePolicy

Advisor

(DDCG),

for

their

pioneer

initiative

at

FAO

bringing

attention

toandstartingadialogueontheimpactofmicrobiomesinfoodsystems.vABBREVIATIONS

AND

ACRONYMSADI

acceptabledailyintakeDNA

deoxyribonucleicacidDGGE

denaturinggradientgelelectrophoresisEMA

EuropeanMedicinesAgencyFDA

UnitedStatesFoodandDrugAdministrationGI

gastrointestinalHFA

human?oraassociatedJECFA

JointExpertCommitteeonFoodAdditivesIHMS

internationalHumanMicrobiomeStandardsITS

internaltranscribedspacermADI

microbiologicalADIMDC

minimumdisruptiveconcentrationMIC

minimalinhibitoryconcentrationmRNA

messengerRNANOAEC

no-observableadverseeffectconcentrationNOD

non-obesediabeticNOEC

noobservedeffectconcentrationNOEL

noobservedeffectlevelOIE

World

OrganizationforAnimalHealthPCR

polymerasechainreactionRNA

ribonucleicacidrRNA

ribosomalRNASCFA

short-chainfattyacidsSHIME

simulatorofhumanintestinalmicrobialecosystemVICH

VeterinaryInternationalConferenceonHarmonizationWHO

World

HealthOrganizationviiviiiEXECUTIVE

SUMMARYVeterinary

drugsareadministeredtotreatandpreventdiseasesinfood-producinganimals.

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

ordosing

frequencies,

off-label

uses)

or

when

clearance

periods

are

not

followed.The

risk

assessment

of

veterinary

drug

residues

is

typically

conducted

to

evaluatetheir

safety

and

determine

health-based

values.

These

assessments

consider

bothtoxicological

and

microbiological

data.

The

development

of

omic

technologies,includingculture-independentanalyticalapproaches(16SrRNAgenesequencing,shotgun

metagenomics,

transcriptomics,

proteomics,

metabolomics)

has

enabled

theholistic

evaluation

of

complex

biological

systems.

These

include,

for

example,

thegutmicrobiome,humanphysiologyormicrobiome–hostinteractions.Thehumangut

microbiome

is

comprised

of

trillions

of

microorganisms

(bacteria,

fungi,

virusesand

archaea),

and

its

composition

and

function

are

highly

in?uenced

by

variousfactors

(e.g.

diet,

age,

lifestyle,

host

genetics,

environmental

conditions

along

andacross

the

gastrointestinal

tract).

The

gut

microbiome

in?uences

some

physiologicalactivities,

e.g.

immune

system

development

and

metabolism.

However,

there

areconcerns

about

the

potential

of

residual

veterinary

drug

in

food

to

disturb

the

gutmicrobiome

and

the

microbiome–host

interactions,

and

whether

these

lead

to

shortandlong-termhealthconsequences.Thisreviewaimstoevaluatethecurrentknowledgeabouttheeffectsofveterinarydrugresiduesonthegutmicrobiome.Italsoassessesthescienti?cevidenceonthein?uenceofmicrobiomedisturbancesonhealth.Limited

research

has

focused

on

evaluating

low

residue

levels

of

a

few

antibiotics

onthe

faecal

microbiota.

These

studies

were

primarily

conducted

in

vitro

and

dependenton

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,

ofrelevance

for

food

safety,

were

used

to

determine

health-based

values.

However,most

did

not

use

the

most

modern

holistic

technologies

(omics).

Moreover,

theseresearch

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

humanmedicine.

Human

clinical

studies

were

not

considered

in

database

queries.

Contraryto

the

research

using

low

residue

levels,

most

research

evaluating

therapeutical

orsubtherapeutic

doses

is

conducted

in

vivo

in

rodents.

The

interest

in

early

exposureis

also

re?ected

by

the

numerous

research

studies

on

this

topic.

Based

on

studyconditions,

most

of

the

?ndings

report

microbial

alterations

and

increased

riskixfor

the

development

of

metabolic

disorders.

Another

common

research

focus

isthe

increased

susceptibility

to

gastrointestinal

infections

following

microbiotadisturbancescausedbyantimicrobialtreatments.In

general,

the

microbiota

effects

reported

are

very

diverse

–

in

some

casescontradicting

–

because

the

studies

are

designed

differently

(e.g.

drugs,

doses,exposure

periods,

models)

and

analytical

methodologies

are

very

heterogeneous.

Forthese

reasons,

assay

reproducibility

inter-study

comparability

cannot

be

assessed.The

lack

of

methodology

standardization

is

a

common

observation

in

microbiomeresearch.Moreover,

therelationshipbetweenmicrobiomedisturbancesandhealtheffects

is

associative

or

speculative

in

all

the

cases

included

in

this

review.

In

theabsence

of

con?rmed

causality

and

mechanisms

showing

how

the

gut

microbiomemodulates

health

disorders,

it

is

very

dif?cult

to

incorporate

microbiome

data

inriskassessments.xCHAPTER1INTRODUCTIONVeterinary

drugs

include

a

large

class

of

chemical

agents

defined

in

the

CodexProcedural

Manual

as

“any

substance

applied

or

administered

to

any

food-producinganimal,

such

as

meat

or

milk-producing

animals,

poultry,

?sh

or

bees,

whetherused

for

therapeutic,

prophylactic,

or

diagnostic

purposes,

or

for

modi?cation

ofphysiological

functions

or

behavior”

(Codex

Alimentarius,

2018a).

Hundreds

ofdifferent

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

functionalclassesbasedontheirfunctionalactivity(Table

1).Someveterinarydrugsmayfallinto

several

classes.

For

example,

an

adrenoreceptor

agonist

may

also

be

classi?edas

a

production

aid,

or

an

antimicrobial

may

also

have

antiprotozoal

properties(CodexAlimentarius,2018b).TABLE

1

JECFA

VETERINARY

DRUG

FUNCTIONAL

CLASSESAdrenoceptor

agonistBeta?adrenoceptor

blocking

agentAnthelminthic

agentAntiprotozoal

agentGlucocorticosteroidGrowth

promoterInsecticideProduction

aidTranquilizing

agentTrypanocideAntifungal

agentVeterinary

drug,

unclassi?edAntimicrobial

agentSource

(italics):

Codex

Alimentarius.

2018b.

Codex

Veterinary

Drug

Residue

in

Food

Online

Database.

In:

Codex

Alimentarius.

Rome.

CitedSeptember2019./fao?who?codexalimentarius/codex?texts/dbs/vetdrugs/enVeterinary

drugs

may

be

administered

orally,

including

as

a

supplement

to

feed

andwater,

injected

intravenously

or

intramuscularly,

intramammary,

subcutaneously,

byaerosol,

applied

topically

on

the

skin,

or

in

the

case

of

?sh,

via

immersion.

Drugscan

reach

the

environment

via

the

disposal

of

human

or

animal

waste

(includingmanure)

or

water

run-off.

In

addition,

some

antimicrobial

agents,

such

as

antibiotics(e.g.

gentamycin,

tetracyclines,

oxalinic

acid)

and

anti-fungal

compounds,

are

alsoappliedtofruits,vegetables,grainsandpulsestocontrolplantdiseases.Therefore,terrestrial

and

aquatic

animals

and

plants

may

be

unintentionally

exposed

to

drugsfrom

environmental

sources

such

as

grazing

on

contaminated

pastures,

water

orsoil

contamination.

Environmental

exposure

in

food-producing

animals

is

notspeci?cally

considered

or

discussed

in

this

review

but

is

important

as

a

considerationintheOneHealthparadigm.1THE

IMPACT

OF

VETERINARY

DRUG

RESIDUES

ON

THE

GUT

MICROBIOME

AND

HUMAN

HEALTHA

FOODSAFETYPERSPECTIVEDepending

upon

the

pharmacokinetic

properties

of

a

specific

drug,

the

drugpreparation,

and

the

route

of

administration,

the

drug

is

absorbed

from

theadministration

site

and

distributed

systemically

throughout

the

tissues

of

theanimal’s

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,

eggsand

honey.

Drug

residues

may

concentrate

in

certain

parts

of

an

animal’s

bodyfollowing

administration;

for

example,

certain

fat-soluble

drugs

may

be

sequesteredin

adipose

tissue

or

concentrated

in

the

liver

or

kidneys,

where

they

are

metabolizedand

eliminated.

Notably,

injection

sites

may

have

higher

concentrations

of

drugresidues

than

surrounding

skeletal

muscle.

Eventually,

drugs

are

metabolized

tovariable

extents

and

eliminated

from

the

food

animal.

For

?sh,

the

environmentaltemperaturemayalsoimpactthemetabolismandexcretionrates.Therelationshipbetween

the

time

of

the

last

administration

of

a

particular

drug

and

the

amountof

drug

residue

present

in

any

tissue

depends

upon

multiple

factors,

including

thedose

and

route

of

administration

of

the

drug,

the

drug

pharmacokinetics,

the

animalspecies

and

the

health

status

of

the

animal.

The

withdrawal

period,

from

the

lastdrug

administration

until

slaughter,

is

often

established

by

governmental

authoritiestoavoidtherisksthatdrugresiduesmayposetohumans.Drugs

are

used

to

treat,

control

or

prevent

diseases.

They

are

also

used

as

growthpromoters.

For

example,

antibiotics

have

been

used

at

subtherapeutic

levels

topromote

animal

growth,

although

this

practice

is

strictly

controlled

or

banned

inmany

countries.

When

drugs

are

not

used

as

approved

(e.g.

in

different

species

ofanimals,

at

different

doses

or

dosing

frequencies,

or

at

different

administration

ratesfor

off-label

treatment

of

diseases),

residue

levels

present

in

tissue

can

be

differentthan

expected.

Drugs

may

be

used

for

purposes

other

than

approved

or

prescribedfor

several

reasons:

a

genuine

lack

of

awareness

of

the

proper

use

by

some

farmers,deliberate

deviation

from

the

intended

use

(e.g.

unavailability

of

approved

drugs),as

well

as

a

lack

of

regulation

or

monitoring

oversight

by

government

authorities.Such

practices

may

be

of

concern

in

developing

countries

(Muaz

et

al.,

2018).When

used

in

food-producing

animals,

these

factors

may

result

in

residues

in

foodfor

human

consumption.

Veterinary

drug

residues

have

been

found

not

only

indifferent

products

of

animal

origin

(e.g.

milk,

meat,

eggs,

organ

tissues,

?sh,

shrimps)but

also

in

vegetables

(Chen,

Ying

and

Deng,

2019).

Residues

of

veterinary

drugsin

food

may

frequently

exceed

national

or

international

standards

(Bacanli

andBasaran,

2019).

National

monitoring

programmes

are

in

place

to

survey

compliancewith

regulatory

limits

for

veterinary

drug

residues

and

to

verify

the

effectivenessof

veterinary

drug

management

and

best

practices.

The

latest

reports

from

theUnited

States

of

America

(USDA,

2019),

the

European

Union

(EFSA,

2021)

andAustralia

(Australian

Department

of

Agriculture

Water

and

the

Environment,

2020)indicate

compliance

in

over

99.6

percent

of

samples.

However,

the

frequency

ofveterinarydrugresiduesfoundinfoodmaybehigherindevelopingcountriesdueto

inappropriate

use

of

antimicrobials

in

the

veterinary

sector

and

the

lack

of

strictregulatory

and

enforcement

frameworks

(Ayukekbong,

Ntemgwa

and

Atabe,

2017).2INTRODUCTIONVeterinary

drug

residues

ingested

through

food

products

(meat,

milk,

dairy,

eggs,etc.)

that

are

not

absorbed

in

the

gastrointestinal

tract

may

remain

in

contact

withthe

human

gastrointestinal

microbiota.

Moreover,

drug

residues

ingested

andabsorbedcanbemetabolizedbythehostandreleasedbacktotheintestine,wherethey

can

further

interact

with

the

gut

microbiome.

The

physico-chemical

andpharmacokineticpropertiesofadrugarefactorsthatwilldeterminehowthedrugwillaffectthehumangastrointestinalmicrobiome.This

review

addresses

the

current

status

of

the

human

gastrointestinal

microbiomein

the

context

of

human

health

and

risk

assessment

of

veterinary

drug

residues.

Itwill

discuss

de?nitions,

tools

and

methodologies

used

to

evaluate

the

microbiome.It

also

includes

published

in

vitro

or

in

vivo

studies

aimed

at

assessing

the

exposureofthehumangutmicrobiometoveterinarydrugresidues.Theeffectofveterinarydrugs

on

the

gut

microbiota

of

food-producing

animals

is

out

of

the

scope

of

thisdocument.Theimpactofpharmaceuticalsusedattherapeuticdosesonthehumangutmicrobiomeisbrie?ydiscussed.3THE

IMPACT

OF

VETERINARY

DRUG

RESIDUES

ON

THE

GUT

MICROBIOME

AND

HUMAN

HEALTHA

FOODSAFETYPERSPECTIVE4CHAPTER2WHAT

IS

THE

GUTMICROBIOME?The

gut

microbiome

is

a

dynamic

microbial

network

composed

of

bacteria,fungi,

viruses,

protozoa

and

archaea

living

in

a

symbiotic

relationship

with

thehost

(Durack

and

Lynch,

2018).

Microbiota

is

another

term

that

also

refers

tomicrobial

populations.

Microbiome

and

microbiota

are

terms

commonly

usedinterchangeably

due

to

the

lack

of

consensus

de?nitions.

In

general,

microbiotarefers

to

the

group

of

individual

microbes

within

the

microbial

community

and

itstaxonomical

structure.

The

microbiome

is

a

more

complex

entity

that,

in

addition

tothenotionofmicrobiota,alsoencompassesthefunctionanddynamicswithinthispopulation.

The

most

popular

de?nition

describes

the

microbiome

as

the

collectivemicrobial

genomes

that

live

at

speci?c

body

sites,

e.g.

skin

and

gastrointestinaltract

(Turnbaugh

et

al.,

2007).

A

more

recent

proposal

de?nes

a

microbiome

as

“acharacteristic

microbial

community

occupying

a

reasonable,

well-de?ned

habitatwith

distinct

physio-chemical

properties”

(Berg

et

al.,

2020,

p.

17).

It

is

essential

tounderstandthemicrobiomeasapopulationwithinade?nedfunctionalecosystemandnotonlythesumofdifferentindividualmicrobes.Most

research

on

the

gut

microbiota

focuses

on

the

bacterial

population.

The

mostabundant

phyla

are

Firmicutes

and

Bacteroidetes,

accounting

for

over

90

percentof

this

microbial

group

(Almeida

et

al.,

2019;

Cani

and

Delzenne,

2007).

Minorphyla

include

Actinobacteria

and

Proteobacteria,

among

others

less

abundant

(Qinet

al.,

2010).

However,

less

is

known

about

other

microbiota

members,

such

asviruses

and

fungi,

as

well

as

their

interaction

and

overall

role

within

the

complexmicrobiome

network

and

microbiome–host

relationship.

The

viral

community,alsoknownasthevirome,outnumberthebacterialcells10:1andarecomposedofDNA

and

ribonucleic

acid

(RNA)

viruses

infecting

bacteria

(e.g.

bacteriophages),archaeaandeukaryoticvirusesaswellasretroviruses(Mukhopadhyaetal.,2019).Although

poorly

understood,

gut

bacteriophages

are

the

most

abundant

type

ofviruses

and

are

known

to

shape

the

intestinal

microbial

composition,

drive

bacterialdiversity1

and

facilitate

horizontal

gene

transfer

(Sutton

and

Hill,

2019).

The

fungal1the

variety

and

abundance

of

species

in

a

de?ned

unit

of

study

(Magurran,Taxonomical

diversity

refers

to2013).

It

has

two

components:

richness

(total

number

of

species

in

the

unit

of

study)

and

evenness(relativedifferencesintheabundanceofvariousspeciesinthecommunity)(Young

andSchmidt,2008).5THE

IMPACT

OF

VETERINARY

DRUG

RESIDUES

ON

THE

GUT

MICROBIOME

AND

HUMAN

HEALTHA

FOODSAFETYPERSPECTIVEcommunity,also

described

as

mycobiome,

is

present

in

the

lower

part

of

the

gut

inlower

numbers

than

bacteria.

However,

it

has

been

less

studied

than

the

bacterialcommunity.

The

role

of

the

mycobiome

in

the

microbiome

and

its

interaction

withthe

host

has

gained

interest

more

recently

(Richard

and

Sokol,

2019;

Santus,

Devlinand

Behnsen,

2021).

It

has

been

reported

that

the

mycobiome

contributes

to

immunehomeostasis

and

when

altered,

it

can

contribute

to

chronic

in?ammatory

disorders,such

as

in?ammatory

bowel

disease

(Gutierrez

et

al.,

2022;

Iliev

and

Leonardi,2017).

Limited

research

indicates

that

Archaea,

another

understudied

microbiomecomponent,

possibly

contributes

to

host

homeostasis

and

in?ammatory

boweldisease(Houshyaretal.,2021;Mohammadzadehetal.,2022).The

gut

microbiome

starts

taking

shape

early

in

life,

commencing

at

birth

uponexposure

to

the

mother

and

the

environment,

and

it

continues

to

evolve,

forminga

complex

ecosystem

in

the

gastrointestinal

tract

(Arrieta

et

al.,

2