Life on the edge: the balance betweenmacrofauna, microflora and hostimmunityAllison J. Bancroft, Kelly S. Hayes and Richard K. Grencis

Manchester Immunology Group, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK

Opinion

Mammals, microflora and gut-dwelling macrofaunahave co-evolved over many millions of years until rela-tively recently when the geographical prevalence ofmacrofauna in humans has become restricted to thedeveloping world. Immune homeostasis relies on a bal-ance in the composition of intestinal microflora; long-lived macrofauna have also been shown to regulateimmune function, and their absence in Western lifestylesis suggested to be a factor for the increasing frequency ofallergy and autoimmunity. The intestinal nematode Tri-churis muris was recently demonstrated to utilise mi-croflora to initiate its life cycle. The interdependence onone another of all three factors is such that when thebalance is perturbed it must be realigned or the con-sequences may be detrimental to the mammalian host.

Location, locationStudies of human tropical diseases show that many para-sites exist as co-infections and polyparasitism is the normrather than the exception. It was shown in 1977 [1] thattissue-dwelling lymphatic filarial parasites possessed en-dosymbiotic parasites which in 1995 were identified asWolbachia [2]. The host immune response to filariae couldnot be considered in isolation without considering theresponse to the endosymbiont of the parasite (reviewedin [3]). Furthermore, it has been demonstrated that theprotozoan parasite Leishmania guyanensis has an RNAvirus, Leishmania RNA virus-1 (LRV-1), and that thisaffects the host immune response to infection, promotingparasite persistence [4].

Interestingly, it has recently been revealed that entericviruses can bind lipopolysaccharide (LPS), thus using thehost microbiota to facilitate their transmission [5,6]. Thesestudies demonstrate that it is impossible to view an infec-tious organism without considering the context and habi-tat within which it survives. Parasites which inhabit thelarge intestine of many animals are unique in coexistingalongside essentially a large ecosystem, the billions of hostcommensals; maintenance of this balance is of benefit tothe host, the parasite and the gut microbiota. A wealth ofliterature has emerged over recent years concerning the co-evolution of the intestinal microbiota, the immune systemand the importance of maintaining this mutualistic

Corresponding author: Bancroft, A.J. (allison.j.bancroft@manchester.ac.uk).

1471-4922/$ – see front matter � 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2011.12

relationship [7,8]. It is also the case that our immunesystem has co-evolved with larger gut-dwelling macro-fauna, i.e. intestinal parasites [9]. It is now pertinentand timely to consider the three major players together.

It was recently demonstrated that a nematode worm,Trichuris muris, exploits the intestinal microflora and thata structural component of bacteria is necessary for thehatching of the T. muris ova (Figure 1) [10]. This isparticularly important when considering that the humanmicroflora is continually being modified via extensive an-tibiotic treatment, probiotic and prebiotic usage [11,12],and emerging treatments to modulate aberrant healthconditions using parasites are being undertaken (e.g. [13]).

There is a worm at the bottom of the intestineTrichuris as a genus must be considered as one of the mostsuccessful groups of gastrointestinal dwelling nematodeparasites because the 50 to 60 known Trichuris species arerecognised to infect numerous mammalian species. Thehuman infective species Trichuris trichiura is estimated toinfect up to a billion people [14] and is responsible forconsiderable morbidity, particularly in a group of the mostvulnerable people on the planet, the children of developingcountries. All Trichuris species have a similar life cycle andinhabit the same niche, the caecum and proximal colon.Infection is initiated with the ingestion of embryonatedeggs. It is perhaps not surprising, therefore, that theseparasites are some of the most uniquely adapted to not onlyexisting alongside the commensal flora of the large intes-tine but actually utilising this ecosystem for their ownpropagation. From prevalence data in humans and ani-mals throughout the ages it is plausible to suggest thatthese metazoan parasites of the large intestine have beeninstrumental in shaping our immune systems, and indeedhelminths have been shown to drive the selection of inter-leukin (IL) genes and their polymorphisms [15]. Earlylarval stages of Trichuris species burrow into the intestinalmucosa, allowing access of the microflora directly to theepithelium, breaching the mucus barrier and thus the hostimmune system. This implies that to avoid pathologicalconsequences the host needs to respond in a regulated way.T. muris plays an important role in this regulation, follow-ing infection of the mouse [10]; e.g. chronic T. murisis associated with changes in microflora in the caecum(A. Houlden, I. Roberts and R. Grencis, unpublished).Moreover, the presence of intestinal microflora clearly

.001 Trends in Parasitology, March 2012, Vol. 28, No. 3 93

(a) (b)

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Figure 1. Microflora and macrofauna interaction. Consolidated sequential z stack images of eggs allow visualisation of attached microflora. Microflora initiates hatching of

Trichuris muris ova (a) by attaching to the polar plugs, resulting in the removal of the plug, thus allowing the larvae to exit (b).

Opinion Trends in Parasitology March 2012, Vol. 28, No. 3

alters the immunoregulatory mechanisms operatingagainst T. muris.

Helminth infection alters intestinal microfloraIntestinal dwelling nematodes constantly excrete and se-crete proteins, and in addition to stimulating the hostimmune system, it is reasonable to suggest that thesemolecules may change the environment for the intestinalmicroflora. Indeed, alterations in gut microbiota wereobserved following Heligmosomoides polygyrus bakeri in-fection in mice [16]. This study showed that infection ofmice with H. polygyrus bakeri, which inhabits the duode-num, dramatically shifted the numbers and also the com-position of the bacteria in the ileum (the terminal smallintestine) but not in the colon. The majority of bacteriawithin the infected ileum were Lactobacillae sp. (Figure 2).Interestingly, H. polygyrus bakeri has previously beenshown to significantly reduce inflammation in a mousemodel of colitis [17] and more recently affect alterationsin epithelial barrier function in the colon [18].

Alterations in microflora change the Th17–T regulatorycell balanceA clear consequence of changes in the microflora will bealteration of intestinal homeostasis, particularly regardingthe immune system via populations of CD4 T cells (Box 1[19–29]). Changes in the symbiotic microbiota play a role inthe balance between inflammatory Th17 cells and regula-tory Foxp3+ cells operating in the intestine. In addition tobeing involved in inflammation, Th17 cells produce IL-22,which stimulates the production of antimicrobial peptidessuch as defensins and regulins, and plays a role in protec-tion against infectious agents such as Citrobacter roden-tium and Candida albicans (reviewed in [30]). RegIIIg, anantibacterial lectin, has been shown to regulate the spatialrelationship between the microbiota and the host; RegIIIgknockout mice demonstrated an increased bacterial colo-nization of the intestinal epithelium and enhanced activa-tion of the intestinal adaptive immune response [31]. In

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addition, the colonic lamina propria also has Foxp3 regu-latory T (Treg) cells at higher frequencies than in otherorgans [32].

Recently, particular groups of microflora have beenshown to influence the balance of inflammatory Th17and Tregs in the intestine. The sigmentous filamentousbacteria (SFB) which adhere tightly to the epithelium ofthe terminal ileum were shown to be responsible for driv-ing Th17 responses and secretion of IL-17 and IL-22, whichresulted in enhanced resistance to the intestinal pathogenC. rodentium [33]. Conversely, it was recently shown thatClostridium species are responsible for the induction of IL-10+FoxP3+ regulatory cells in the colon. These species ofGram positive, spore-forming bacteria are indigenous tothe mouse gastrointestinal tract and were able to protectagainst dextran sodium sulphate (DSS) and oxazalone-induced colitis [34].

Epithelial cells which express IL-22R are thought to beparticularly important in the microflora/immune axis. Themajority of intestinal IL-22 was recently shown to beproduced by RORgt+ innate lymphoid cells (ILCs) suchas lymphoid tissue inducer cells (LTi) and NKp46+ cells[35]. Moreover, the production of IL-22 by RORgt+ ILCswas shown to be repressed by the symbiotic microbiota,which stimulated IL-25 production by the epithelial cells.

IL-23 production by monocytes has been shown to be acritical cytokine in driving the Th17 cell phenotype, whichplays an important role in both mouse models of colitis andin human studies of inflammatory bowel disease (IBD) andulcerative colitis (UC). It was recently demonstrated thata population of CD3�ve ILCs respond to IL-23 by theproduction of IL-17 and interferon g (IFN-g) in a mousemodel of intestinal inflammation [36]. A separate studyshowed a CD4+ LTi population of ILCs which were impor-tant in innate immunity in the gut; again, these cellsresponded to IL-23 and produced IL-22, demonstratinga complex network of cells which are ready to respond tomucosal pathogens [37]. CD3� ILCs were also shown to bea feature of T cell mediated colitis and again expressed the

SFB + HES driveFox P3+ Treg cells andincreased numbers of

Lactobacillae sp. ?

Infection with Heligmosomoides polygyrusbakeri infection in the duodenum causes

secretion of HES

SFB drive Th17responses

FoxP3

SFB

Villi and crypt of the terminal ileum

FoxP3FoxP3

FoxP3

Th17

Th17

Th17

Th17

Infection with T. muris

Clostridium sp drivesFoxP3+ Treg cells in thecolonic lamina propria

Chronic T. muris infection drives aTh1 response with also some FoxP3+

Treg cells and a possibleTh17and Th22 response

Crypts of the large intestine

Th17FoxP3

FoxP3

FoxP3

FoxP3

FoxP3Th1

Th1

Th22

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(a)

(b)

Figure 2. Possible microflora and macrofauna induced changes on host immune responses in the small and large intestine. (a) Section of terminal ileum showing villi and a

crypt with a complex variety of microflora and sigmentous filamentous bacteria (SFB) which drive Th17 responses. After infection with Heligmosomoides polygyrus bakeri,

the excretory secretory products (HES) drives the induction of FoxP3+ Treg cells, and there is an increasing prevalence of Lactobacillae spp. (shown as blue rods). (b) Section

of the large intestine showing crypts of the large intestine where indigenous Clostridium spp. drive FoxP3+ T regulatory (Treg) cells. Chronic Trichuris muris infection drives

expression of Th1, FoxP3+ Treg and possiblyTh17 and Th22 cells. Coloured circles and rods represent various gut microflora species.

Opinion Trends in Parasitology March 2012, Vol. 28, No. 3

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Box 2. The intestinal niche

The mammalian intestine forms the largest organ of the immune

system, and as stated previously, not only comes into contact with

the commensal microflora but also has almost continual stimulation

from dietary antigens and less frequent stimulation with enteric

pathogens. As such, it must possess a wide variety of tightly

regulated mechanisms to prevent a breakdown of tolerance to food

and harmless microbes but also have a robust array of innate and

adaptive mechanisms for preventing infection.

The intestinal epithelium is a physical and immunological barrier

with the primary role of protecting the host. The lining of the

intestinal epithelium is continually self-renewing and is mainly

composed of intraepithelial cells (IECs) interspersed with intrae-

pithelial lymphocytes (IELs), Goblet cells, Paneth cells and M cells.

The IECs are arranged into crypts in the large intestine and a villus

and crypt structure in the small intestine to maximise the surface

area available for absorption of nutrients and to provide defence

against infection. These cells are linked by tight junctions to prevent

paracellular permeability into the immune system.

Underlying the IECs is the lamina propria which is composed of

both innate and adaptive immune cells. There are populations of

dendritic cells (DCs), macrophages, IgA-secreting plasma cells,

natural killer (NK) cells, T cells and mast cells all specifically adapted

to the environment within which they are residing. Moreover, there

is a high proportion of g d T cells in the intestine which recognise

antigen in a manner different to conventional a b T cells and have

the potential to rapidly interact with intestinal microflora [41].

Overlaying the outer intestinal epithelium is a layer of mucus

which is produced by specialised goblet cells. Mucus is produced at

all epithelial surfaces and is composed of two layers, a thinner, more

stable sterile layer and a thicker less sterile and more motile outer

layer. It is composed of mucins, which are glycoproteins and

antimicrobial peptides [42].

As a whole, these cells possess a variety of cell surface and

intracellular molecules to detect danger and damage and respond

by secreting a variety of cytokines and antimicrobial factors to

restore a level of balance to a continually challenged environment.

Box 1. Intestinal microflora

The microflora of the mammalian intestine mainly comprise the

phyla Bacteroides and Firmicutes. Their sheer number (in the order

of 1014) [19] is almost inconceivable and is approximately 10 times

more than the number of cells which make up the human body; as a

whole, these organisms contain approximately 100 times more

genes than the human genome. The collective microbial genome

known as the microbiome has been suggested to be considered as

our second genome, such is our intimate and dependent relation-

ship with it [20]. The colonisation of the intestinal tract takes place

after birth and plays an important role in the generation and

development of the immune system. It also forms a buffer between

the host immune system and potentially harmful food antigens such

as gluten and peanut allergen and pathogens such as Escherichia

coli and Cryptosporidium parvum and is in general well-tolerated by

the host.

Recognition of commensal microflora by innate Toll-like receptors

(TLRs) has been shown to be important in intestinal homeostasis

[21]. A recent study highlights this by showing that the common gut

commensal Bacteroides fragilis enables host–microbial symbiosis

through activation of TLR2 [22]. Interestingly, mice deficient in

innate recognition pathways were shown to produce higher serum

antibodies to their commensal microbiota. These antibodies were

shown to be essential in maintaining the host–microbiota mutual-

ism [23]. Moreover, the microflora affect host nutritional uptake, [24]

although recent studies have shown using defined diets and

gnotobiotic mice repopulated with specific populations of micro-

flora that the composition of the diet can be used to predict the

make-up of the microflora [25].

Intestinal diseases such as Crohn’s disease (CD) and ulcerative

colitis (UC) are thought to be driven by an altered immune response

to the intestinal microflora (reviewed in [26]) and separate studies

have shown the microbiota to be responsible for playing a role in

the generation of type I diabetes [27], modulating brain develop-

ment and behaviour [28] and regulating the immune defence

against respiratory tract influenza A virus infection [29].

Opinion Trends in Parasitology March 2012, Vol. 28, No. 3

transcription factor RORgt [38]. Furthermore, IL-23 re-sponsive ILCs were shown to be increased in inflammatorybowel disease in humans [39].

It is thus reasonable to suggest that disruption of themicroflora will alter homeostatic immune mechanismsfrom operating. Indeed, we have shown that broad spec-trum antibiotic treatment of mice subsequently infectedwith T. muris can significantly downregulate the levels ofIL-17 produced and can also alter the broader host immuneresponse to T. muris. These data build up a scenario inwhich distinct components of the microflora differentiallystimulate multiple cell populations that are involved in themaintenance of the intestinal mucosal barrier.

Although not the focus of this review, it is important tomention that there have been many recently describedpopulations of Th2 driving ILCs which in the majority ofanimal models of nematode infection are associated withexpulsion of the gut-dwelling macrofauna from the intes-tine [40].

Alterations in the TH17–Foxp3 balance promoteparasite survivalAlthough avoidance of pathology that may be induced byparasite invasion of the mucosa is an important componentof the host–parasite relationship, it is also desirable formost species of gastrointestinal dwelling nematodes tosurvive for extended periods to maximise egg output,thereby facilitating transmission (Box 2 [41,42]). Oneway in which regulation may be driven by the parasite

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is by the generation of induced Tregs (iTregs), and recentwork suggests that Foxp3+ Tregs could protect the hostfrom intestinal pathology associated with T. muris infec-tion [43]. There is also expansion and activation ofCD4+CD25+ in H. polygyrus bakeri infection [44,45]. Inter-estingly, transfer of CD4 effector cells from H. polygyrusbakeri-infected mice conferred protection in naıve micesubsequently infected with the same parasite, whereastransfer of CD4 T regulatory cells had no effect on wormburdens when they too were transferred into mice whichwere then infected [46]. Remarkably, H. polygyrus bakerihas been shown to directly induce Foxp3+ cells by secretionof a transforming growth factor b (TGF-b) mimic whichcould ligate the TGF-b receptor and induce downstreamsignalling by phosphorylation of SMAD2/3 (Figure 2) [47].Furthermore, Th17 cells were shown to be redirected toand controlled in the small intestine where they can beeliminated or acquire a regulatory phenotype, rTh17 [48].

Although there are unlikely to be universal mechanismsfor modulating immunity for all gastrointestinal nema-todes, it does highlight the long-held view that such para-sites are potent in this regard. This fact has been exploitedin the clinical setting over recent years with species such asNecator americanus [49,50] and Trichuris suis [13]. Thelatter nematode has been used to treat UC in humans with43.3% of patients showing an improvement after T. suistreatment compared with 16.7% given a placebo. In aseparate study, a patient suffering from UC self cured

Helminth infectionalters intestinal

microflora

Intestinal microfloraaffect the Th17/Treg

balance

The Th17/Tregbalance affectsparasite survival

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Figure 3. The relationship between the microflora, macrofauna and host immune

system. The interdependence of the mammalian host, the microflora and the gut-

dwelling macrofauna on each other are shown. Although the text describes a one

way system, the arrows are double-ended, suggesting that all three players can

influence each other and as such should be viewed as an integrated system.

Box 3. Outstanding questions

� How does the gut-dwelling macrofauna change the composition

of the intestinal microflora in humans and animals during

helminth infection in the field?

� Does intestinal helminth infection influence immunity to other

pathogens indirectly through effects on the intestinal microflora?

Opinion Trends in Parasitology March 2012, Vol. 28, No. 3

his symptoms when he infected himself with Trichuristrichiura. In this case, a population of IL-22+ CD4+ T cellswere shown to be associated with both remission of colitisand parasite exposure, whereas a population of Th17 cellswere associated with active colitis [51]. It is noteworthythat the diseases initially targeted for therapy have beenthe IBDs where altered immune responses to microfloraare central to their aetiology. Nevertheless, it is clear thathelminth infections can affect sites away from their habi-tat, and this is not surprising given the fact that chronicinfections must present a considerable antigenic stimula-tion to the host and are known to induce regulatory cir-cuits. As detailed above, H. polygyrus bakeri, which residesin the small intestine, had considerable effects on theepithelial cell permeability of the colon. This was shownto be dependent on both T cells and STAT6. Furthermore, arecent study [52] showed that chronic T. muris infectionexacerbated pathology in an experimental murine strokemodel whereby stroke was induced in mice following tran-sient middle cerebral artery occlusion (MCAo) T. murisexclusively resides in the epithelium of the large intestinebut significantly enhanced stroke-induced inflammatorychanges in the striatum and the hippocampus of the brain.

This review has focussed on chronic infection and onTh1, FoxP3 regulatory cells and Th17 cells. Nematodeparasites often elicit strong Th2 responses in animal mod-els which commonly lead to parasite expulsion. A strongTh2 response would potentially drive lower numbers of allthree of the above cell populations [40].

Concluding remarksThe co-evolution of gut-dwelling macrofauna, intestinalmicroflora and the host immune system in humans havecome under new selection pressures over recent years,where owing to increased hygiene, the prevalence of thegut-dwelling macrofauna is restricted to subtropical en-demic areas, although this still presents a considerableglobal burden. It is timely considering the volume of liter-ature on immunomodulation by parasitic helminths andthe recognition of the importance of microflora on ourimmune system to now start to view them as an integrated

system (Figure 3). When this balance is disrupted, it isimportant to consider the effects on not just one aspect buton all three of these factors as this will both enhance ourknowledge of host infection interactions and also provideinsight into new therapeutic targets for intervention andcandidate vaccine strategies.

Future areas for research should not only definechanges in populations of intestinal microflora duringchronic helminth infection but also explore the metabo-lome of these populations and their relationship with hostimmunoregulatory mechanisms (Box 3).

AcknowledgementsThe Bioimaging Facility microscope used in Figure 1 was purchased withgrants from the Biotechnology and Biological Sciences Research Council(BBSRC), Wellcome and the University of Manchester Strategic Fund.Special thanks go to Jane Kott and Robert Fernandez for their help withthe microscopy. A.B. and K.H. are supported by the Wellcome Trust(083620Z).

References1 Kozek, W.J. (1977) Transovarially-transmitted intracellular

microorganisms in adult and larval stages of Brugia malayi. J.Parasitol. 63, 992–1000

2 Sironi, M. et al. (1995) Molecular evidence for a close relative of thearthropod endosymbiont Wolbachia in a filarial worm. Mol. Biochem.Parasitol. 74, 223–227

3 Taylor, M.J. et al. (2010) Lymphatic filariasis and onchocerciasis.Lancet 376, 1175–1185

4 Ives, A. et al. (2011) Leishmania RNA virus controls the severity ofmucocutaneous leishmaniasis. Science 331, 775–778

5 Kane, M. et al. (2011) Successful transmission of a retrovirus dependson the commensal microbiota. Science 334, 245–249

6 Kuss, S.K. (2001) Intestinal microbiota promote enteric virusreplication and systemic pathogenesis. Science 334, 249–252

7 Shibolet, O. and Podolsky, D.K. (2007) TLRs in the gut IV. Negativeregulation of Toll-like receptors and intestinal homeostasis: additionby subtraction. Am. J. Physiol. Gastrointest. Liver Physiol. 292, 1469–

14738 Abraham, C. and Medzhitov, R. (2011) Interactions between the host

innate immune system and microbes in inflammatory bowel disease.Gastroenterology 140, 1729–1737

9 Jackson, J.A. et al. (2008) Review series on helminths, immunemodulation and the hygiene hypothesis: immunity againsthelminths and immunological phenomenon in modern humanpopulations: coevolutionary legacies? Immunology 126, 18–27

10 Hayes, K.S. et al. (2010) Exploitation of the intestinal microflora by theparasitic nematode Trichuris muris. Science 328, 1391–1394

11 Hill, D.A. et al. (2009) Metagenomic analyses reveal antibiotic-inducedtemporal and spatial changes in intestinal microbiota with associatedalterations in immune cell homeostasis. Mucosal Immunol. 3, 148–

15812 Gourbeyre, P. et al. (2011) Probiotics, prebiotics, and synbiotics: impact

on the gut immune system and allergic reactions. J. Leukoc. Biol. 89,685–695

13 Summers, R.W. et al. (2005) Trichuris suis therapy for active ulcerativecolitis: a randomized controlled trial. Gastroenterology 128, 825–832

14 Mascie-Taylor, C.G.N. and Karim, E. (2003) The burden of chronicdisease. Science 302, 1921–1922

15 Fumagalli, M. et al. (2009) Parasites represent a major selective forcefor interleukin genes and shape the genetic predisposition tointerleukin genes. J. Exp. Med. 206, 1395–1408

97

Opinion Trends in Parasitology March 2012, Vol. 28, No. 3

16 Walk, S.T. et al. (2010) Alteration of the murine gut microbiota duringinfection with the parasitic helminth Heligmosomoides polygyrus.Inflamm. Bowel Dis. 16, 1841–1849

17 Elliott, D.E. et al. (2004) Heligmosomoides polygyrus inhibitsestablished colitis in IL-10-deficient mice. Eur. J. Immunol. 34,2690–2698

18 Su, C.W. et al. (2011) Duodenal helminth infection alters barrierfunction of the colonic epithelium via adaptive immune activation.Infect. Immun. 79, 2285–2294

19 Backhed, F. et al. (2005) Host-bacterial mutualism in the humanintestine. Science 307, 1915–1920

20 Qin, J. et al. (2010) A human gut microbial gene catalogue establishedby metagenomic sequencing. Nature 464, 59–65

21 Rakoff-Nahoum, S. et al. (2004) Recognition of commensal microfloraby toll-like receptors is required for intestinal homeostasis. Cell 118,229–241

22 Round, J.L. et al. (2011) The Toll-like receptor 2 pathway establishescolonization by a commensal of the human microbiota. Science 332,974–977

23 Slack, E. et al. (2009) Innate and adaptive immunity cooperateflexibly to maintain host microbiota mutualism. Science 325,617–620

24 Turnbaugh, P.J. et al. (2008) Diet-induced obesity is linked to markedbut reversible alterations in the mouse distal gut microbiome. Cell HostMicrobe 3, 213–223

25 Faith, J.J. et al. (2011) Predicting a human gut microbiota’s response todiet in gnotobiotic mice. Science 333, 101–104

26 Saleh, M. and Elson, C.O. (2011) Experimental inflammatory boweldisease: insights into the host-microbiota dialog. Immunity 34, 293–

30227 Wen, L. et al. (2008) Innate immunity and intestinal microbiota in the

development of type 1 diabetes. Nature 455, 1109–111328 Heijtz, R.D. et al. (2011) Normal gut microbiota modulates brain

development and behaviour. Proc. Natl. Acad. Sci. U.S.A. 108,3047–3052

29 Ichinohe, T. et al. (2011) Microbiota regulates immune defense againstrespiratory tract influenza A virus infection. Proc. Natl. Acad. Sci.U.S.A. 108, 5354–5359

30 Sonnenberg, G.F. et al. (2011) Border patrol: regulation of immunity,inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat.Immunol. 12, 383–390

31 Vaishnava, S. et al. (2011) The antibacterial lectin RegIIIgammapromotes the spatial segregation of microbiota and host in theintestine. Science 334, 255–258

32 Hill, J.A. et al. (2008) Retinoic acid enhances Foxp3 induction indirectlyby relieving inhibition from CD4+CD44hi Cells. Immunity 29, 758–770

33 Ivanov, I.I. et al. (2009) Induction of intestinal Th17 cells by segmentedfilamentous bacteria. Cell 139, 485–498

98

34 Atarashi, K. et al. (2011) Induction of colonic regulatory T cells byindigenous Clostridium species. Science 331, 337–341

35 Sawa, S. et al. (2011) RORgt+ innate lymphoid cells regulate intestinalhomeostasis by integrating negative signals from the symbioticmicrobiota. Nat. Immunol. 12, 320–326

36 Buonocore, S. et al. (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375

37 Sonnenberg, G.F. et al. (2011) CD4+ lymphoid tissue-inducer cellspromote innate immunity in the gut. Immunity 34, 1–13

38 Ahern, P.P. et al. (2010) Interleukin-23 drives intestinal inflammationthrough direct activity on T cells. Immunity 33, 279–288

39 Geremia, A. et al. (2011) IL-23-responsive innate lymphoid cells areincreased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133

40 Neill, D.R. and Mckenzie, A.N. (2011) Nuocytes and beyond: newinsights into helminth expulsion. Trends Parasitol. 27, 214–221

41 Strid, J. et al. (2011) The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy. Science 334, 1293–

129742 McGuckin, M.A. et al. (2011) Mucin dynamics and enteric pathogens.

Nat. Rev. Microbiol. 9, 265–27843 D’Elia, R. et al. (2009) Regulatory T cells: a role in the control of

helminth-driven intestinal pathology and worm survival. J.Immunol. 182, 2340–2348

44 Finney, C.A. et al. (2007) Expansion and activation of CD4(+)CD25(+)regulatory T cells in Heligmosomoides polygyrus infection. Eur. J.Immunol. 37, 1874–1886

45 Maizels, R.M. et al. Immune modulation and modulators inHeligmosomoides polygyrus infection. Exp. Parasitol. doi:10.1016/j.exppara.2011.08.011

46 Rausch, S. et al. (2008) Functional analysis of effector and regulatory Tcells in a parasitic nematode infection. Infect. Immun. 76, 1908–1919

47 Grainger, J.R. et al. (2010) Helminth secretions induce de novo T cellFoxp3 expression and regulatory function through the TGF-b pathway.J. Exp. Med. 207, 2331–2341

48 Esplugues, E. et al. (2011) Control of TH17 cells occurs in the smallintestine. Nature 475, 514–518

49 Daveson, A.J. et al. (2011) Effect of hookworm infection on wheatchallenge in celiac disease – a randomised double-blinded placebocontrolled trial. PLoS ONE 6, e17366

50 McSorley, H.J. et al. (2011) Suppression of inflammatory immuneresponses in celiac disease by experimental hookworm infection.PLoS ONE 6, e24092

51 Broadhurst, M.J. et al. (2010) IL-22+ T cells are associated withtherapeutic Trichuris trichiura infection in an ulcerative colitispatient. Sci. Transl. Med. 2, 1–10

52 Denes, A. et al. (2011) Experimental stroke-induced changes in thebone marrow reveal complex regulation of leukocyte responses. J.Cereb. Blood Flow Metab. 31, 1036–1050