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Hindawi Publishing CorporationGastroenterology Research and PracticeVolume 2011, Article ID 971938, 16 pagesdoi:10.1155/2011/971938

Review Article

Probiotics, Nuclear Receptor Signaling, andAnti-Inflammatory Pathways

Sonia S. Yoon1 and Jun Sun1, 2

1 Division of Gastroenterology and Hepatology, Department of Medicine, Strong Memorial Hospital,University of Rochester Mediacal Center, University of Rochester, Rochester, NY 14642, USA

2 Department of Microbiology and Immunology, University of Rochester, P.O. Box 646,601 Elmwood Avenue, Rochester, NY 14642, USA

Correspondence should be addressed to Jun Sun, jun [email protected]

Received 2 February 2011; Revised 28 March 2011; Accepted 19 May 2011

Academic Editor: Genevieve B. Melton-Meaux

Copyright © 2011 S. S. Yoon and J. Sun. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

There is increased investigation of the human microbiome as it relates to health and disease. Dysbiosis is implicated in variousclinical conditions including inflammatory bowel disease (IBD). Probiotics have been explored as a potential treatment for IBDand other diseases. The mechanism of action for probiotics has yet to be fully elucidated. This paper discusses novel mechanismsof action for probiotics involving anti-inflammatory signaling pathways. We highlight recent progress in probiotics and nuclearreceptor signaling, such as peroxisome-proliferator-activated receptor gamma (PPARγ) and vitamin D receptor (VDR). We alsodiscuss future areas of investigation.

1. Introduction

Probiotics are ingestible microorganisms with health bene-fits. Increased interest in the intestinal microbiome and itseffect on health and disease is evidenced by the concomi-tant increase in peer-reviewed clinical trials investigatingprobiotics as therapy since 1999 [1]. Studies of the varioussignaling pathways involved in the response to bacteria andinflammation have led to a more detailed understanding ofmechanisms and actions of probiotics. This paper discussesprogress in understanding how probiotics contribute tointestinal mucosal function, particularly in relation to anti-inflammatory signaling pathways.

2. Intestinal Microflora

The intestinal microflora, as a whole, serves importantfunctions in metabolism, intestinal epithelial cell functionand health, immunity, and inflammatory signaling [2, 3].Recently, there has been increasing interest in the role ofthe intestinal microflora and its total genetic composition,together referred to as the microbiome in the development,

maintenance, and perpetuation of various clinical condi-tions, both intestinal and extraintestinal.

Dysbiosis has been implicated in various clinical condi-tions including atopy, irritable bowel syndrome (IBS), col-orectal cancer, alcoholic liver disease in animal and humanstudies, obesity and other metabolic disorders, and chronicinflammatory diseases such as IBD [4–11]. Decreaseddiversity of the intestinal microbiota was seen in fecalsamples obtained from children who subsequently developedallergic disease [6, 7]. Altered microbiota composition incolon cancer patients when compared to patients withnormal colonoscopies and in patients with IBS comparedto unaffected patients has also been demonstrated [5, 9].Alcohol feeding resulted in enteric bacterial overgrowth ina mouse model [8]. The role of the microbiota in obesityhas been extensively studied and carefully reviewed in theliterature [12, 13]. Microbial composition in IBD patientswith ulcerative colitis (UC) or Crohn’s disease (CD) as com-pared to unaffected individuals has been studied and showsdecreased diversity [4, 14–19]. This altered microflora mayhave significant implications for the intestinal milieu, with asyet incompletely understood effects. The pathogenesis of IBD

2 Gastroenterology Research and Practice

likely involves a combination of factors including intestinaldysbiosis in conjunction with environmental factors in agenetically susceptible host [20].

Based on the concept of a dysregulated or dysfunctionalmicrobiota in disease, various methods to attenuate theeffects of an altered microbiome have been attempted.

3. Probiotics

“Probiotics” were first described in the literature by Lillyand Stillwell in 1965 as growth-promoting factors producedby certain microorganisms [21] although it may have beendescribed as early as 1908 [22]. Recently, probiotics weredefined as “live organisms which, when consumed in ade-quate amounts as part of food, confer a health benefit on thehost” (Report of a Joint FAO/WHO Expert Consultation onEvaluation of Health and Nutritional Properties of Probioticsin Food Including Powder Milk with Live Lactic AcidBacteria (October 2001), “Health and Nutritional Propertiesof Probiotics in Food Including Powder Milk with LiveLactic Acid Bacteria”, Food and Agriculture Organizationof the United Nations, World Health Organization). Themechanisms of action of probiotics include immune modu-lation, direct effect on commensal and pathogenic bacteria toinhibit infection and restore homeostasis, and modificationof pathogenic toxins and host products [23]. The efficacy ofprobiotics in various clinical conditions both in the pediatricand adult patient population has been extensively studiedand carefully reviewed [1, 19, 24–32].

Rectal infusion of normal stool via enemas to treatpseudomembranous colitis has been described as early as1958 [70]. Infusion of stool via nasogastric tube to thesmall intestine or via colonoscopy to the colon for CDADhas also been described and shows high response rates[71–74]. A recent study showed that fecal bacteriotherapywas effective in relief of clinical symptoms in a patientwith recurrent CDAD and that this was accompanied bythe repopulation of the diseased intestinal microbiota withbeneficial species that were diminished pretreatment [75].Other methods to supply live, nonpathogenic organisms tothe intestinal microbiota in AAD and CDAD include orallyadministered probiotics. The efficacy of various probioticformulations in AAD and CDAD has been extensivelystudied and carefully reviewed [1]. A recent study showedthat the probiotics Lactobacillus acidophilus and Lactobacilluscasei were well tolerated and effective in reducing therisk of the development of AAD and CDAD [76]. Theutility of the probiotic yeast Saccharomyces boulardii for avariety of conditions including traveler’s diarrhea, enteralnutrition-associated diarrhea, AAD, and CDAD has beeninvestigated, and according to a recent meta-analysis, strongevidence exists for advocating its use in traveler’s diarrheaand AAD [77]. Recent trials using Bifidobacterium bifidumand Saccharomyces boulardii demonstrated improvement inclinical IBS symptoms and quality of life [78, 79], and severalreviews of the evidence for the utility of probiotics in IBShave been published [80–82].

For IBD therapy, treatment with different strains ofprobiotics has shown varied results. Small trials have shown

promise for probiotic use in the induction and maintenanceof remission in UC. VSL#3 has been shown to be safe andeffective in the treatment of acute mild to moderately activeUC [83]. Patients with mild to moderate UC unresponsive toconventional therapy achieved a combined induction remis-sion/response rate of 77% with treatment with VSL#3 [84].E. coli Nissle 1917 was found to be effective and equivalent tomesalazine in maintaining remission in UC [85]. In anotherstudy, Lactobacillus rhamnosus GG (LGG) was equivalent tomesalazine in the maintenance of remission in UC, however,appeared to be more effective in prolonging the relapse-free time [86]. Evidence also exists for the role of probioticsin prophylaxis of pouchitis after surgery in UC patientsas well as induction of remission in chronic pouchitis[87, 88].

Studies of probiotic use in induction and maintenanceof remission and prevention of postoperative recurrencein CD have been less consistent than those for UC. Asmall study of LGG for the prevention of recurrence aftersurgery in CD did not show any improvement over placebo[89]; however, Saccharomyces boulardii appears useful inmaintaining remission in CD [90, 91]. The progress in theuse of probiotics for IBD has been carefully reviewed [92, 93];however, there remains a relative lack of well-designed, large,randomized, placebo-controlled trials.

Several barriers exist to advocating broad use of probi-otics in clinical practice, not least of which is the considerableheterogeneity in the experimental designs with respect tospecies and strains of probiotics and the various animalmodels utilized [94]. Although clinical trials examining therole of probiotics in the treatment and/or prevention of AAD,CDAD, IBD including UC, CD, and pouchitis, necrotizingenterocolitis, infectious gastroenteritis, radiation-inducedenteritis, and colitis, IBS and various atopic diseases havebeen reported [1, 24, 25, 28, 29, 31, 87, 95–97]; in manycases, results have been inconsistent, and large, well-designedtrials are lacking. An additional complicating factor pertainsto issues of quality control. Determining whether a commer-cially available probiotic actually contains the live organismsit purports to contain and determining if there is rationalselection of component probiotic strains in “cocktails” areissues that must be considered [22]. Future research to refinetechniques to accurately identify “normal” and “diseased”microbiota and to further elucidate the specific effects andmechanisms of actions of individual probiotic strains will aidin optimizing therapeutic efficacy.

4. Mechanisms for Probiotics inAnti-Inflammation

There has been and continues to be considerable research indelineating the underlying mechanisms by which probioticsexert their beneficial effects. The mechanisms regulating thefunction of probiotics are very diverse. It is well accepted thatprobiotics use distinct cellular and molecular mechanisms,including blocking pathogenic bacterial effects, regulat-ing immune responses, and altering intestinal epithelialhomeostasis by promoting cell survival, enhancing barrierfunction, and stimulating protective responses [32].

Gastroenterology Research and Practice 3

Table 1 outlines representative publications on probioticmechanisms of actions. The probiotic-host interaction iscomplex and further complicated by the fact that certainprobiotic effects appear to be species and strain specific.Different probiotics have been shown to exert both pro-inflammatory [98] and anti-inflammatory effects on den-dritic cells [99]. A recent study demonstrated that the anti-inflammatory effect of certain lactobacilli is via NOD2-mediated signaling [100]. NOD2/CARD15 is a member ofa superfamily of genes involved in intracellular bacterialrecognition and has been identified as an important suscep-tibility gene for CD [101, 102]. The authors speculate thatthe inconsistent clinical results of lactobacilli use in patientswith CD may be related to a relative deficiency of NOD2.Probiotic effect on the innate immune responsive pathwaysincluding toll-like receptor (TLR), nuclear factor kappa B(NF-κB), mitogen-activated protein kinase (MAPK), c-JunNH2-terminal kinase (JNK) has been extensively investigated(Table 1). Activation of specific TLRs also appears to bespecies specific [47, 48]. The action of E. coli Nissle 1917 onCaco-2 cells was found to be mediated by flagellin possiblyvia a TLR pathway [103]. The probiotic-induced effect on theNF-κB signaling pathway is well represented in the literatureand is generally characterized by inhibition (Table 1).

Defective epithelial barrier function has been implicatedin IBD and can predict relapse during clinical remission[104–109]. One way by which probiotics have been shownexert their action is by stabilizing tight junctions (TJs)and enhancing barrier function of intestinal epithelial cells(Table 1).

Abnormal STAT/suppressor of cytokine signaling(SOCS) signaling has been demonstrated in CD patients[110], and probiotics are also shown to modulate the JAK-STAT signaling in human placental trophoblast cells [111].Increasing evidence further demonstrates that metabolism,xenobiotics, and nuclear receptor signaling are involved inthe action of probiotics [67, 68].

Induction of heat shock proteins (HSPs) and endogenousantimicrobial peptides (defensins) via activation of NF-κB,MAPK, and JNK has also been linked to probiotic action [35,41, 43]. Since defensins are implicated in the pathogenesis ofIBD, increased expression by probiotics provides a possiblemechanism for clinical efficacy seen in certain IBD patientsand deserves further study.

5. Defensins and Nuclear Receptor Signaling

Defensins are a class of endogenous antimicrobial peptidesinvolved in innate immunity which is highly evolutionarilyconserved and represents a primary line of defense againstvarious microbial pathogens [112–114]. Antimicrobial pep-tides are widely distributed throughout the animal and plantkingdom, and despite their evolutionary heritage, remaineffective antimicrobial agents [114]. This is due, in largepart, to their mechanism of action involving membranedisruption and pore formation, which is not easily exploitedby pathogens to confer resistance [112–115]. Importantantimicrobial peptides in humans include defensins, cathe-licidins, lysozymes, and other antimicrobial antiproteases

[116]. There are three known defensin subfamilies; α and βdefensins are expressed mainly in immune cells and epithelialcells while the θ defensin is found mainly in immune cellsof the Rhesus macaque [117, 118]. In the gastrointestinaltract, β defensin expression is seen in multiple sites, whereasα defensin expression is largely in the small intestine[119]. In the uninflamed colon, human β defensin 1 isthe predominant defensin and human β defensin 2 and 3are induced with inflammation or infection [120]. In micelacking functional cryptidins (murine α defensins), increasedsurvival and virulence of orally administered bacteria wereseen and intestinal peptide preparations had decreasedantimicrobial activity [121].

The possible role of a deficiency in defensins in thepathogenesis of IBD has been proposed [116, 122]. ThePaneth cells of the small intestine are the major source ofendogenous antimicrobials, including α defensins [102]. Inaddition, The Paneth cells have been shown to express NOD2[123]. In patients with ileal CD, human α defensin 5 and6 production is reduced, and this effect is magnified inthose patients with a concomitant NOD2 mutation [124].For β defensins, CD patients with colonic disease exhibitnormal levels of β defensin 2 and 3 whereas UC patientshave increased levels, suggesting a role of failure of β defensininduction in the pathogenesis of CD [125]. Constitutivehuman β defensin 1 expression is reduced in CD patientswith colonic involvement independent of inflammation,and recently, the maintenance of constitutive β defensinexpression was shown to be activated by the nuclear receptorperoxisome-proliferator-activated receptor gamma (PPARγ)[122].

Further contributing to the effect of a defensin defi-ciency in the pathogenesis of IBD may be the diminisheddiversity of the intestinal microbiota seen in IBD patients.The interaction of commensal bacteria with antimicrobialpeptide synthesis is not well understood; however, it hasbeen suggested that commensal bacteria provide chronicstimulation of epithelial cells to produce antimicrobialpeptides at levels sufficient to kill microbial pathogens [114,126].

Probiotics, but not fecal isolates, have been shown toinduce human β defensin 2 in intestinal epithelial cells [41,42]. Wehkamp et al. and Schlee et al. have reported thatNF-κB and activator protein-1 (AP-1) mediate inductionof human β defensin 2 in intestinal epithelial cells by theprobiotic E. coli Nissle 1917 and VSL#3 [41, 42].

Interestingly, nuclear receptors are known to regulate theexpressions of defensins [122, 127]. Nuclear receptors rep-resent a class of intracellular transcription factors activatedby ligands which can directly interact with DNA; as a result,nuclear receptors play significant roles in the regulation ofmetabolic, reproductive, developmental, and immune pro-cesses [128–131]. Nuclear receptors regulate transcriptionalactivity by several distinct mechanisms, including “ligand-dependent transactivation, ligand-independent repression,and ligand-dependent transrepression” although the rangeof transcriptional activities of each nuclear receptor variesand even the transcriptional effects of a single nuclearreceptor may be cell specific [132]. A detailed discussion


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inW

Tbu

tn

otT

LR2-

orT

LR4-

knoc

kou

tm

ice

(ii)

EC

Nre

sult

edin

redu

ctio

nof

inte

rfer

on(I

FN)-γ

secr

etio

nin

TL

R2

knoc

kou

t(i

ii)

Cyt

okin

ese

cret

ion

was

alm

ost

un

dete

ctab

lean

dn

otm

odu

late

dby

EC

Nin

TLR

-4-k

noc

kou

tm

ice

(iv)

Incr

ease

dT

LR2

and

TLR

4pr

otei

nex

pres

sion

and

NF-κB

acti

vity

via

TL

R2

and

TL

R4

was

seen

wit

hE

CN

and

hum

anT

-cel

lcoc

ult

ure

[48]


Ta

ble

1:C

onti

nu

ed.

Invo

lved

path

way

sP

robi

otic

sIn

vitr

osy

stem

Invi

vosy

stem

Sum

mar

yR

ef.

MA

PK

(p38

/ER

K)

(i)

LP(i

i)L

c(i

)M

ice

per

iton

eal

mac

roph

ages

(i)

LPst

ron

gly

indu

ced

IL-1

0an

dw

eakl

yin

duce

dIL

-12;

Lcst

ron

gly

indu

ced

IL-1

2an

dw

eakl

yin

duce

dIL

-10

(ii)

LP,c

ompa

red

toLc

,dem

onst

rate

dm

ore

rapi

dan

dst

ron

gac

tiva

tion

ofM

AP

Ks,

espe

cial

lyof

ER

K(i

ii)

Blo

ckin

gL

P-in

duce

dE

RK

acti

vati

onre

sult

edin

decr

ease

dIL

-10

prod

uct

ion

and

incr

ease

dIL

-12

prod

uct

ion

(iv)

Com

bin

edst

imu

lati

onw

ith

LPan

dL

cre

sult

edin

syn

ergi

stic

indu

ctio

nof

IL-1

0pr

odu

ctio

n;t

his

was

trig

gere

dby

the

key

fact

ors:

cell

wal

ltei

choi

cac

idan

dlip

otei

choi

cac

ids

(v)

Teic

hoi

c-ac

id-i

ndu

ced

IL-1

0pr

odu

ctio

nw

asm

edia

ted

byT

LR2-

depe

nde

nt

ER

Kac

tiva

tion

[49]

MA

PK

(p38

/ER

K)

Tig

ht

jun

ctio

ns

(TJ)

(i)

LGG

(i)

CaC

o-2

(i)

LGG

-pro

duce

dso

lubl

epr

otei

ns

(p40

and

p75)

dim

inis

hed

the

hydr

ogen

-per

oxid

e-in

duce

dde

crea

sein

TE

Ran

din

crea

sein

inu

linpe

rmea

bilit

yan

din

duce

din

crea

sein

mem

bran

etr

ansl

ocat

ion

ofpr

otei

nki

nas

eC

(PK

C)

beta

I,P

KC

epsi

lon

,an

dle

velo

fph

osph

o-E

RK

1/2

inth

ede

terg

ent-

inso

lubl

efr

acti

ons

(ii)

LGG

-pro

duce

dso

lubl

epr

otei

ns

(p40

and

p75)

prev

ente

dhy

drog

en-p

erox

ide-

indu

ced

redi

stri

buti

onof

occl

udi

n,z

onu

laoc

clu

den

s(Z

O)-

1,E

-cad

her

in,a

nd

beta

-cat

enin

from

inte

rcel

lula

rju

nct

ion

san

dth

eir

diss

ocia

tion

from

the

dete

rgen

t-in

solu

ble

frac

tion

s(i

ii)

p40-

and

p75-

med

iate

dre

duct

ion

ofhy

drog

en-p

erox

ide-

indu

ced

tigh

tju

nct

ion

disr

upt

ion

and

inu

linp

erm

eabi

lity

was

atte

nu

ated

byU

0126

(aM

AP

kin

ase

inh

ibit

or)

[50]

MA

PK

(p38

/ER

K)

TJ

(i)

B.i

nfan

tis

(i)

T84

(i)

IL-1

0,IL

-1de

fici

ent

mic

e

(i)

B.i

nfan

tis-

con

diti

oned

med

ium

(BiC

M)

incr

ease

dT

ER

,ZO

-1,a

nd

occl

udi

nex

pres

sion

and

decr

ease

dcl

audi

n-2

expr

essi

on;t

his

was

asso

ciat

edw

ith

incr

ease

dph

osph

o-E

RK

and

decr

ease

dph

osph

o-p3

8(i

i)T

NF-α

-an

dIF

N-γ

-in

duce

ddr

ops

inT

ER

and

rear

ran

gem

ent

ofT

Jpr

otei

ns

wer

epr

even

ted

byB

iCM

(iii

)In

hib

itio

nof

ER

Kat

ten

uat

edth

epr

otec

tion

from

TN

F-α

and

IFN

-γan

dpr

even

ted

BiC

M-i

ndu

ced

incr

ease

inT

ER

(iv)

Invi

vo,o

ralB

iCM

redu

ced

colo

nic

perm

eabi

lity,

inIL

-10-

defi

cien

tm

ice,

lon

g-te

rmB

iCM

decr

ease

dco

lon

ican

dsp

len

icIF

N-γ

secr

etio

n,a

tten

uat

edin

flam

mat

ion

,an

dn

orm

aliz

edco

lon

icpe

rmea

bilit

y

[51]

TJ

(i)

LPM

B45

2(i

)C

aCo-

2

(i)

LPM

B45

2in

crea

sed

TE

Rac

ross

Cac

o-2

cell

mon

olay

ers

indo

se-d

epen

den

tm

ann

er(i

i)A

lter

edex

pres

sion

ofse

vera

ltig

ht-

jun

ctio

n-r

elat

edge

nes

(in

clu

din

goc

clu

din

and

asso

ciat

edpl

aqu

epr

otei

ns)

was

seen

inre

spon

seto

LPM

B45

2(i

ii)LP

MB

452

cau

sed

chan

ges

inge

ne

expr

essi

onle

vels

oftu

bulin

and

prot

easo

me

(iv)

LPM

B45

2-tr

eate

dce

llssh

owed

incr

ease

dfl

uor

esce

nce

inte

nsi

tyof

the

fou

rti

ght

jun

ctio

npr

otei

ns

wh

enco

mpa

red

tou

ntr

eate

dco

ntr

ols

[52]

Gastroenterology Research and Practice 7T

abl

e1:

Con

tin

ued

.

Invo

lved

path

way

sP

robi

otic

sIn

vitr

osy

stem

Invi

vosy

stem

Sum

mar

yR

ef.

TJ

PK

C(i

)LP

(i)

CaC

o-2

(i)

Un

con

juga

ted

bilir

ubi

n(U

CB

)ca

use

dde

crea

sed

PK

Cac

tivi

ty,s

erin

eph

osph

oryl

ated

occl

udi

ng,

and

ZO

-1le

vels

(ii)

Hig

hco

nce

ntr

atio

ns

ofU

CB

cau

sed

cyto

toxi

city

and

decr

ease

dT

ER

(iii

)Tr

eatm

ent

wit

hL

Pm

itig

ated

the

effec

tsof

UC

Bon

TE

Ran

dap

opto

sis,

prev

ente

dab

erra

nt

expr

essi

onan

dre

arra

nge

men

tof

TJ

prot

ein

s,an

dpa

rtia

llyre

stor

edP

KC

acti

vity

and

seri

ne

phos

phor

ylat

edT

Jpr

otei

nle

vels

[53]

TJ

(i)

LPD

SM26

48(i

)C

aCo-

2

(i)

LPD

SM26

48re

duce

dth

ede

lete

riou

seff

ect

ofE

sche

rich

iaco

li(e

nte

ropa

thog

enic

E.c

oli(

EP

EC

))O

127:

H6

(E23

48/6

9)on

TE

Ran

dad

her

ence

wit

hsi

mu

ltan

eou

sor

prio

rco

cult

ure

com

pare

dw

ith

EP

EC

incu

bati

onal

one

[54]

TJ

TL

R(i

)LP

(i)

CaC

o-2

(i)

Hu

man

(i)

LPin

duce

dtr

ansl

ocat

ion

ofZ

O-1

toth

eT

Jre

gion

inan

invi

tro

mod

el,b

ut

the

effec

tson

occl

udi

nw

ere

min

orco

mpa

red

wit

heff

ects

seen

invi

vo(i

i)L

Pac

tiva

ted

TL

R2

sign

alin

g,an

dtr

eatm

ent

wit

hT

LR

2ag

onis

tPa

m(3

)-C

ys-S

K4(

PC

SK),

incr

ease

dfl

uor

esce

nt

stai

nin

gof

occl

udi

nin

the

TJ

(iii

)P

hor

bol-

este

r-in

duce

ddi

sloc

atio

nof

ZO

-1an

doc

clu

din

and

asso

ciat

edin

crea

sein

epit

hel

ialp

erm

eabi

lity

wer

eat

ten

uat

edw

ith

pret

reat

men

tw

ith

LPor

PC

SK

[55]

TJ

(i)

B.b

ifidu

m(i

)R

ats

(i)

B.b

ifidu

mde

crea

sed

the

inci

den

ceof

nec

roti

zin

gen

tero

colit

is(N

EC

),n

orm

aliz

edIL

-6,m

uci

n-3

,an

dT

ff3

leve

lsin

the

ileu

mof

NE

Cra

ts,a

nd

nor

mal

ized

the

expr

essi

onan

dlo

caliz

atio

nof

TJ

and

adh

eren

sju

nct

ion

(AJ)

prot

ein

sin

the

ileu

mco

mpa

red

wit

han

imal

sw

ith

NE

C(i

i)B

.bifi

dum

did

not

affec

tre

duce

dm

uci

n-2

prod

uct

ion

inth

eN

EC

rats

[56]

TJ

(i)

VSL

#3(i

)B

AL

B/c

mic

e

(i)

VSL

#3tr

eatm

ent

prev

ente

dth

ein

crea

sein

epit

hel

ialp

erm

eabi

lity

inac

ute

colit

is,d

ecre

ase

inex

pres

sion

and

redi

stri

buti

onof

occl

udi

n,Z

O-1

,an

dcl

audi

n-1

,cla

udi

n-3

,cla

udi

n-4

,an

dcl

audi

n-5

,an

din

crea

seof

epit

hel

ial

apop

toti

cra

tio

[57]

TJ

(i)

Lr(i

i)L

a(i

)M

ice

(i)

Pre

trea

tmen

tw

ith

com

bin

atio

nof

Lran

dL

asi

gnifi

can

tly

prev

ente

dde

crea

sein

the

mem

bran

e-bo

un

dA

TPa

ses

and

redu

ced

expr

essi

onof

tigh

tju

nct

ion

prot

ein

sin

the

mem

bran

e[5

8]

TJ

(i)

B.l

acti

s42

0(i

i)B

.lac

tis

HN

019

(iii

)L

aN

CFM

(iv)

L.sa

livar

ius

Ls-3

3

(i)

CaC

o-2

(i)

B.l

acti

s42

0an

dE

sche

rich

iaco

liO

157:

H7

(EH

EC

)su

per

nat

ant

had

oppo

site

effec

tsin

tigh

tju

nct

ion

inte

grit

y;B

.lac

tis

420

sup

ern

atan

tpr

otec

ted

the

tigh

tju

nct

ion

sfr

omE

HE

C-i

ndu

ced

dam

age

wh

enad

min

iste

red

befo

reE

HE

Csu

pern

atan

t(i

i)E

HE

Can

dpr

obio

tics

had

reve

rse

effec

tsu

pon

cycl

o-ox

ygen

ase

expr

essi

on

[59]

TJ

(i)

EC

N(i

)B

AL

B/c

mic

e

(i)

EC

Nco

lon

izat

ion

ofgn

otob

ioti

cm

ice

resu

lted

inu

preg

ula

tion

ofZ

O-1

mR

NA

and

prot

ein

leve

lsin

IEC

s(i

i)E

CN

adm

inis

trat

ion

redu

ced

loss

ofbo

dyw

eigh

tan

dco

lon

shor

ten

ing

inD

SS-t

reat

edm

ice

(iii

)E

CN

inoc

ula

tion

amel

iora

tes

the

infi

ltra

tion

ofth

eco

lon

wit

hle

uko

cyte

s

[60]

TJ

PK

C(i

)E

CN

(i)

T84

(i)

EP

EC

wit

hE

CN

coin

cuba

tion

:add

itio

nof

EC

Naf

ter

EP

EC

infe

ctio

nre

stor

edba

rrie

rin

tegr

ity

and

abol

ish

edba

rrie

rdi

sru

ptio

n(i

i)E

CN

alte

red

the

expr

essi

on,d

istr

ibu

tion

ofZ

O-2

prot

ein

and

ofdi

stin

ctP

KC

isot

ypes

;ZO

-2ex

pres

sion

was

incr

ease

din

para

llelt

oit

sre

dist

ribu

tion

tow

ards

the

cell

bou

nda

ries

(iii

)E

CN

indu

ces

rest

orat

ion

ofa

disr

upt

edep

ith

elia

lbar

rier

;th

isis

tran

smit

ted

byP

KC

zeta

sile

nci

ng

and

ZO

-2re

dist

ribu

tion

[61]


Ta

ble

1:C

onti

nu

ed.

Invo

lved

path

way

sP

robi

otic

sIn

vitr

osy

stem

Invi

vosy

stem

Sum

mar

yR

ef.

TJ

(i)

LGG

(i)

MD

CK

-1,T

84

(i)

EH

EC

-in

duce

dde

crea

sein

elec

tric

alre

sist

ance

and

the

incr

ease

inba

rrie

rp

erm

eabi

lity

assa

ysw

ere

atte

nu

ated

bypr

obio

tic

pret

reat

men

t(i

i)LG

Gpr

otec

ted

epit

hel

ialm

onol

ayer

sag

ain

stE

HE

C-i

ndu

ced

redi

stri

buti

onof

clau

din

-1an

dZ

O-1

prot

ein

s(i

ii)

Hea

t-in

acti

vate

dLG

Gdi

dn

otaff

ect

EH

EC

bin

din

gor

disr

upt

ion

ofba

rrie

rfu

nct

ion

[62]

JAK

/STA

TM

AP

K(p

38/E

RK

)

(i)

Stre

ptoc

occu

sth

erm

ophi

lus

(ii)

La

(i)

HT

29/c

l.19A

(ii)

Cac

o-2,

(i)

Stre

ptoc

occu

sth

erm

ophi

lus

(ST

)/La

orth

eco

mm

ensa

lBac

tero

ides

thet

aiot

aom

icro

n(B

T)

prev

ente

dth

eT

NF-α

-an

dIF

N-γ

-in

duce

dre

duct

ion

inT

ER

and

incr

ease

inep

ith

elia

lper

mea

bilit

y(i

i)ST

/La

orB

Tpr

even

ted

IFN

-γin

hib

itio

nof

agon

ist-

stim

ula

ted

chlo

ride

secr

etio

n(i

ii)

ST/L

aor

BT

rest

orat

ion

ofC

l(-)

secr

etio

nw

asbl

ocke

dby

inh

ibit

ors

ofp3

8M

AP

K,E

RK

1,2,

and

PI3

K(i

v)ST

/La

pret

reat

men

tre

vers

edth

eIF

N-γ

-in

duce

ddo

wn

regu

lati

onof

the

cyst

icfi

bros

istr

ansm

embr

ane

con

duct

ance

regu

lato

r(C

FTR

)an

dth

eN

KC

C1

cotr

ansp

orte

r(v

)T

he

effec

tsof

ST/L

aor

BT

onT

ER

and

per

mea

bilit

yw

ere

pote

nti

ated

bya

Jan

us

kin

ase

(JA

K)

inh

ibit

orbu

tn

otby

p38,

ER

K1,

2,or

PI3

Kin

hib

itio

n(v

i)R

edu

ced

acti

vati

onof

supp

ress

orof

cyto

kin

esi

gnal

ing

(SO

CS)

3an

dST

AT

1,3

was

seen

only

inpr

obio

tic-

trea

ted

epit

hel

ialc

ells

expo

sed

tocy

toki

nes

[63]

JAK

/STA

TN

F-κB

(i)

LcS

(i)

RA

W26

4.7

(ii)

LI-

LP

MC

(iii

)U

C-P

BM

C

(i)

SAM

P1/

Yit

mic

e

(i)

LcS

impr

oved

chro

nic

ileit

isin

SAM

P1/

Yit

mic

e(i

i)L

csim

prov

edm

uri

ne

chro

nic

colit

is,a

nd

this

was

asso

ciat

edw

ith

decr

ease

dIL

-6pr

odu

ctio

nby

larg

ein

test

inal

lam

ina

prop

ria

mon

onu

clea

rce

lls(

LI-L

PM

Cs)

and

dow

nre

gula

tion

ofpr

oin

flam

mat

ory

cyto

kin

essu

chas

IL-6

and

IFN

-γpr

odu

ctio

nin

LPM

C(i

ii)

IL-6

rele

ase

inLP

S-ac

tiva

ted

LI-L

PM

C,R

AW

264.

7,an

du

lcer

ativ

eco

litis

-per

iph

eral

bloo

dm

onon

ucl

ear

cells

(UC

-PB

MC

s)w

asin

hib

ited

byLc

S-de

rive

dpo

lysa

cch

arid

e-pe

ptid

ogly

can

com

plex

(PSP

G)

(iv)

Inlip

opol

ysac

char

ide-

(LP

S-)

stim

ula

ted

LI-

LP

MC

and

RA

W26

4.7

cells

,Lc

Sin

hib

ited

the

prod

uct

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of nuclear receptors and their mechanisms of action isbeyond the scope of this article; however, further discussionof two nuclear receptors (peroxisome-proliferator-activatedreceptor gamma (PPARγ) and vitamin D receptor (VDR))with putative roles in inflammation is warranted.

PPARγ is a member of a class of nuclear receptors thatform obligate heterodimers with the retinoid X receptor(RXR) [129]. The PPAR family has been shown to affectvarious cellular functions including “adipocyte differentia-tion, fatty-acid oxidation, and glucose metabolism” [129].PPARγ is highly expressed in the large intestine [133], and itsactivation has been shown to be protective in animal modelsof colitis [134, 135]. Decreased PPARγ expression in UCpatients has been shown [136], and the anti-inflammatorycompound 5-aminosalicylic acid (5-ASA) commonly uti-lized in IBD therapy was shown to be a PPARγ agonist,thereby establishing a possible mechanism by which it exertsits anti-inflammatory effects [137]. PPARγ also plays a rolein the maintenance of “constitutive epithelial expression of asubset of β defensins in the colon” [122].

6. Vitamin D and Vitamin D Receptor (VDR)

Vitamin D receptor (VDR) is a nuclear receptor that medi-ates most known functions of 1,25-dihydroxyvitamin D(1,25(OH)2D3), the active form of vitamin D [138]. VDRheterodimerizes with RXR once VDR is activated by1,25(OH)2D3. VDR binds to the vitamin D response elementin the target gene promoter to regulate gene transcription[139]. VDR downstream target genes include antimicrobialpeptides such as cathelicidin and β defensin.

VDR is critical in regulating intestinal homeostasis bypreventing pathogenic bacterial invasion, inhibiting inflam-mation, and maintaining cell integrity [140–145]. VitaminD directly modulates the T-cell receptor (TCR) [146], andvitamin D has also been shown to downregulate the expres-sion of proinflammatory cytokines and have regulatoryeffects on autophagy and various immune cells includingT cells, B cells, macrophages, dendritic cells, and epithelialcells [147, 148]. It has been reported that 1,25(OH)2D3suppresses the development of IBD in animal models [149].Deficiency of 1,25(OH)2D3 has been reported in patientswith IBD [150, 151], and, recently, using a novel vitamin Dbioavailability test, vitamin D deficiency or insufficiency wasseen in more than 70% of patients with quiescent CD [152].Given the diverse immune functions of vitamin D, deficientlevels may have important implications for the developmentand maintenance of intestinal homeostasis. A possible roleof vitamin D status and VDR signaling in modulating theeffects of intestinal microflora in other conditions suchas asthma and obesity has been suggested [100]. Whilepresent literature has primarily focused on elucidating theimmunoregulatory effects of vitamin D, there is a paucity ofdata on the status and function of VDR [147]. In addition,probiotic-induced modulation of anti-inflammatory VDRsignaling in colitis remains virtually unexplored.

Recent studies indicate that VDR−/− mice haveincreased bacterial loading in the intestine [145, 153]. Ourmicroarray data found that VDR signaling responds to

pathogenic Salmonella in intestinal colitis in vivo [154]. Datafrom a recent study demonstrate that bacterial stimulation,both commensal and pathogenic, regulates VDR expressionand location and that VDR negatively regulates bacterial-induced intestinal NF-κB activation [153]. In general,probiotic-induced nuclear receptor signaling is not well char-acterized. The probiotic VSL3# was associated with nuclearreceptor signaling in the IL10−/− colitis model [67]. Nuclearreceptors have been shown to negatively regulate bacterial-stimulated NF-κB activity in intestinal epithelium [153, 155].Our recent data show probiotic treatment is able to enhanceVDR expression and activity in the host. An increase inVDR expression and a concomitant increase in cathelicidinmRNA in cultured intestinal epithelial cells when treatedwith Lactobacillus plantarum were seen [156]. We used aprobiotic monoassociated pig model to assess the probioticeffect on VDR expression in vivo and found intestinal VDRincreased significantly after probiotic colonization comparedto the ex-germ-free pig. Furthermore, our unpublished dataindicate that probiotics did not inhibit inflammation in micelacking VDR.

The presence of VDR in various tissues along with itsability to exert diverse actions in differentiation, growth, andanti-inflammation sets the stage for exploitation of VDRligands for the treatment of various inflammatory conditions[157, 158]. Although the potential importance of VDR as atherapeutic target has been appreciated [159], no approachto date has safely and effectively altered VDR’s activity.Hence, understanding VDR’s contribution to probiotic-induced anti-inflammation may provide significant insightin the pathogenesis of inflammatory conditions such as IBD,and thereby, guide the development of novel treatments.Further investigation of the complex interplay of nuclearreceptors, defensins, probiotics, and inflammatory pathwaysmay provide significant insight into the mechanisms ofaction of probiotics in anti-inflammation.

7. Current Problems and Future Directions

The individual diversity of the intestinal microflora under-scores the difficulty of identifying the entire human micro-biota and poses barriers to this field of research. In addition,it is apparent that the actions of probiotics are species andstrain specific [19]. It is also apparent that even a single strainof probiotic may exert its actions via multiple, concomitantpathways. Current investigation into the mechanism ofaction of specific probiotics has focused on probiotic-induced changes in the innate immune functions involvingTLRs and its downstream systems including NF-κB, JAK-STAT, MAPK, and SAPK/JNK pathways. Future research onnovel mechanisms of action for probiotics involving nuclearreceptor signaling, including PPARγ and VDR, is needed.With evolving knowledge, effective probiotic therapy will bepossible in the future.

AbbreviationsAAD: Antibiotic-associated diarrheaAP-1: Activator protein-1CD: Crohn’s disease


CDAD: Clostridium-difficile-associated diseaseCDM: Chemically defined mediaCM: Conditioned mediaCTFR: Cystic fibrosis transmembrane

conductance regulatorECN: E. coli Nissle 1917EGFR: Epidermal growth factor receptorEHEC: E. coli O157:H7EPEC: Enteropathogenic E. coliERK: Extracellular-signal-regulated kinaseGSH: GlutathionehBD: Human beta defensinHSP: Heat shock proteinsIBD: Inflammatory bowel diseaseIBS: Irritable bowel syndromeIEC: Intestinal epithelial cellIFN: InterferonIL: InterleukinIκB: Inhibitor of kappa BJAK/STAT: Janus kinase/signal transducers and

activators of transcriptionLa: Lactobacillus acidophilusLc: Lactobacillus caseiLcS: Lactobacillus casei ShirotaLGG: Lactobacillus rhamnosus GGLI-LPMC: Large intestinal lamina propria

mononuclear cellsLP: Lactobacillus plantarumLPS: LipopolysaccharideLr: Lactobacillus rhamnosusMAPK: Mitogen-activated protein kinaseMCP: Monocyte chemotactic proteinNEC: Necrotizing enterocolitisNF-κB: Nuclear factor kappa BPKC: Protein kinase CPPARγ: Peroxisome-proliferator-activated

receptor gammaROS: Reactive oxygen speciesRXR: Retinoid X receptorSAPK/JNK: Stress-activated protein kinase/c-Jun

NH2-terminal kinaseSb: Saccharomyces boulardiiSOCS: Suppressor of cytokine signalingTCR: T-cell receptorTER: Transepithelial electrical resistanceTJs: Tight junctionsTLR: Toll-like receptorTNF: Tumor necrosis factorUC: Ulcerative colitisUCB: Unconjugated bilirubinVDR: Vitamin D receptorZO: Zonula occludens.

Acknowledgments

This work was supported by the National Institutes of Health(DK075386-0251, R03DK089010-01) and the IDEAL awardfrom the New York State’s Empire State Stem Cell Board(N09G-279) to J. Sun.

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