Both intestinal helminth parasites and certain bacterial microbiota species have been credited with strong immunomodulatory effects. Recent studies reported that the presence of helminth infection alters the composition of the bacterial intestinal microbiota and, conversely, that the presence and composition of the bacterial microbiota affect helminth colonization and persistence within mammalian hosts. This article reviews recent findings on these reciprocal relationships, in both human populations and mouse models, at the level of potential mechanistic pathways and the implications these bear for immunomodulatory effects on allergic and autoimmune disorders. Understanding the multidirectional complex interactions among intestinal microbes, helminth parasites, and the host immune system allows for a more holistic approach when using probiotics, prebiotics, synbiotics, antibiotics, and anthelmintics, as well as when designing treatments for autoimmune and allergic conditions.

The mammalian immune system has evolved to cope with immense microbial presence, including some dangerous, some harmless, and some beneficial microbes (1), as well as in conjunction with macrobionts, such as helminth parasites (2). In each case, host immunity has to make the correct judgment about whether to reject or accept the new species and, if the latter, how to control it. In parallel, incoming organisms have evolved to maximize their chances of acceptance, through immune evasion, mimicry, and induction of host immunoregulatory pathways. Thus, although commensal bacteria and multicellular helminths occupy very different taxonomic space, they have both responded to evolutionary forces by developing similar strategies of modulating host immunity. Moreover, it is apparent that these different kingdoms of life have developed a surprising degree of dialogue with a common agenda of establishing a new homeostasis in the host intestinal tract (3, 4).

The parallel agendas of bacterial microbes and intestinal helminths include dampening or deceiving host immunity to permit their survival, even though bacteria and helminths need to suppress very different Th1/17- and Th2-dominated effector mechanisms, respectively. Common strategies include the induction of suppressive regulatory T cells (Tregs) by a range of bacteria, including Bacteroides fragilis (5), Bifidobacterium infantis (6), Clostridium spp. (79), and Lactobacillus spp. (1013), as well as by intestinal nematode parasites, such as Heligmosomoides polygyrus (14) and Strongyloides ratti (15). Interestingly, activation of Tregs appears to be a widespread feature of both microbiota colonization (16, 17) and helminth parasite infection (18) (Fig. 1).

FIGURE 1.

Parallel immunomodulatory strategies of helminths and bacteria in the intestinal tract: mechanisms of Treg induction. Both helminths and several bacterial microbiota species have been credited with host immunomodulatory capabilities, including the induction of Tregs. Various human and mouse helminth parasites stimulate Treg generation in the intestinal tract (18). In the case of the small intestinal mouse parasite H. polygyrus, de novo Foxp3 expression can be induced by its secretory products (HES), which is dependent on signaling through T cell TGF-βR (14). SCFAs, end products of bacteria-mediated fermentation of dietary fibers, can induce IL-10–producing Tregs in the colonic lamina propria (98100). Particular species of bacteria, such as B. fragilis or select Clostridium spp., can induce Tregs in the colonic lamina propria (5, 7, 8, 107). Treg induction by B. fragilis is dependent on the production of B. fragilis polysaccharide A (PSA) and the expression of T cell TLR2 (5, 107), and Treg induction by Clostridium spp. is though to be due, at least in part, to the stimulation of TGF-β secretion by intestinal epithelial cells (7, 8). Many additional bacterial microbiota species are capable of inducing Treg generation in the intestinal lamina propria (17, 108), and it is likely that a combination of signals from the microbiota and macrobionts, such as helminth parasites, maintains a tolerogenic intestinal environment.

FIGURE 1.

Parallel immunomodulatory strategies of helminths and bacteria in the intestinal tract: mechanisms of Treg induction. Both helminths and several bacterial microbiota species have been credited with host immunomodulatory capabilities, including the induction of Tregs. Various human and mouse helminth parasites stimulate Treg generation in the intestinal tract (18). In the case of the small intestinal mouse parasite H. polygyrus, de novo Foxp3 expression can be induced by its secretory products (HES), which is dependent on signaling through T cell TGF-βR (14). SCFAs, end products of bacteria-mediated fermentation of dietary fibers, can induce IL-10–producing Tregs in the colonic lamina propria (98100). Particular species of bacteria, such as B. fragilis or select Clostridium spp., can induce Tregs in the colonic lamina propria (5, 7, 8, 107). Treg induction by B. fragilis is dependent on the production of B. fragilis polysaccharide A (PSA) and the expression of T cell TLR2 (5, 107), and Treg induction by Clostridium spp. is though to be due, at least in part, to the stimulation of TGF-β secretion by intestinal epithelial cells (7, 8). Many additional bacterial microbiota species are capable of inducing Treg generation in the intestinal lamina propria (17, 108), and it is likely that a combination of signals from the microbiota and macrobionts, such as helminth parasites, maintains a tolerogenic intestinal environment.

Close modal

Expansion of Treg activity may underpin an additional feature shared among many helminths and microbiota species: the systemic muting of the immune response so that reactivity to bystander Ags, such as allergens and autoantigens, is inhibited. The parallels were not immediately articulated and, indeed, separate models emerged of helminth-mediated (19) and microbial-mediated (20) protection against allergy, before more recently coalescing. These similarities are illustrated by the fact that both H. polygyrus (21, 22) and Lactobacillus spp. (12) in the intestinal tract can block the development of allergic reactivity in the airways of mice, whereas heightened susceptibility to allergy development in humans and in animal allergy models can result from either antibiotic or anthelmintic treatment (2325). Likewise, both commensals (26, 27) and helminths (28) can ameliorate autoimmune and colitic disease. It will be interesting to follow these parallels as further systemic effects of intestinal colonization come to light, including changes in metabolism, obesity, and behavior (2931).

Given the relatively unexplored theme of bacterial–parasite interactions within the mammalian host and the emerging therapeutic potential of both bacterial microbiota species (32) and parasitic helminths (33), it is now essential to understand the multilateral interactions between these organisms and the host immune system. In this review, we discuss the experimental evidence regarding these relationships and examine to what extent the reported immunomodulatory effects of helminths can be attributed to a modulation of microbiota composition or function.

Controlled laboratory animal experiments clearly demonstrated that infection with helminth parasites results in substantial shifts in the intestinal microbiota species composition. Chronic H. polygyrus infection in the duodenum of mice results in an increased abundance of Lactobacillaceae and Enterobacteriaceae species in the small intestine (3436). Similarly, a chronic infection with the mouse whipworm Trichuris muris, which colonizes the cecum, leads to a reduced diversity of fecal bacterial species, particularly within the phylum Bacteroidetes, as well as an increase in the abundance of Lactobacillaceae family members (37, 38). Rats infected with the tapeworm Hymenolepis diminuta had an altered community structure compared with uninfected animals that involved ∼20% of their total cecal bacterial microbiota, with a general shift in abundance from class Bacilli to the class Clostridia in helminth-infected rats (39). Microbiota changes following helminth infection correlate with worm burdens (36, 40) but revert to normal following drug clearance of helminths, indicating that the continuing presence of parasites is required for sustained changes to the bacterial microbiota (38). In wild mice (Apodemus flavicollis), around half of animals sampled were simultaneously infected with more than one helminth species, most commonly a combination of H. polygyrus, Syphacia spp. (pinworm), and Hymenolepis spp. (tapeworm) (41). Helminth infections correlated with heightened bacterial microbiota diversity, with the presence of each helminth being associated with specific shifts in microbiota species composition or abundance (41).

Very recent findings indicate that helminth infection can also modify host metabolism, with ensuing implications for immune modulation. Thus, experimental T. muris infection in mice reduced a large number of metabolomic products, as measured in the feces, including vitamin D2/D3 derivatives, many fatty acids and related metabolites, glycerophospholipids, dietary plant-derived carbohydrates, and amino acid synthesis intermediates (38); hamsters infected with the human hookworm Necator americanus similarly showed extensively altered urinary metabolite levels that could be explained by changes in the intestinal microflora (42). Infection of pigs with the related porcine whipworm Trichuris suis, which also alters the composition of the colonic microbiota, is again accompanied by a metabolic shift, with infection resulting in reduced cofactors for carbohydrate metabolism and amino acid biosynthesis (40, 43). Such metabolomic alterations following helminth infection may result from microbiota compositional changes, altered intestinal absorption of dietary products, or direct production of metabolites by helminth parasites (38).

In human populations, studies on the influence of helminth infection on microbiota composition and function have only recently commenced. In a cohort of Zimbabwean children, those positive for Schistosoma hematobium infection were found to have a significantly higher fecal abundance of several operational taxonomic units from within the genus Prevetella (44). In these subjects, praziquantel-induced helminth clearance did not revert the microbiome composition, suggesting that childhood helminth exposure may have long-term effects on microbiota community structure (44). In a Malaysian population, the fecal microbiota of individuals colonized by at least one helminth parasite (Trichuris spp., Ascaris spp., or hookworms) harbored a more diverse community compared with individuals free from helminth infection (45). However, less marked differences emerged from a study of school-age children in Ecuador with similar helminths (46) or from eight human volunteers experimentally infected with N. americanus (47).

It should be noted that populations with a high prevalence of helminth parasites are also very distinct in diet, lifestyle, and host genetics from those in major industrialized societies and appear to carry markedly different sets of intestinal microbes (48). Interpretation of data is likely to be further confounded by variable infection intensities in natural helminth infections. These human studies are also restricted to fecal analyses, which do not accurately reflect local microbiota shifts that may occur, for example, postinfection with small intestine dwelling hookworms (e.g., N. americanus) and roundworm (Ascaris lumbricoides).

A characteristic feature of helminth infection is the elicitation of a type 2 immune response, alongside a regulatory response, especially in the setting of chronic, asymptomatic infection (2). Given the immune system’s role in regulating and containing the intestinal microbiota population (1), it seems likely that disruption and rebalancing of immune homeostasis can result in functional shifts in microbial composition. Interestingly, such changes to the set points can be observed through both innate and adaptive pathways (Fig. 2).

FIGURE 2.

Proposed mechanisms by which intestinal helminths and bacterial microbiota bidirectionally influence persistence in the mammalian host. It has recently become clear that intestinal helminth parasites and members of the bacterial microbiota influence one another’s ability to persist in the mammalian intestinal tract. The mechanisms by which they do so are likely multifactorial and site- and context-dependent, and probably include direct, as well as indirect, effects on each other.

FIGURE 2.

Proposed mechanisms by which intestinal helminths and bacterial microbiota bidirectionally influence persistence in the mammalian host. It has recently become clear that intestinal helminth parasites and members of the bacterial microbiota influence one another’s ability to persist in the mammalian intestinal tract. The mechanisms by which they do so are likely multifactorial and site- and context-dependent, and probably include direct, as well as indirect, effects on each other.

Close modal

A significant effect of helminths on innate interactions with the microbiota may be to alter the production of antimicrobial peptides in the intestinal tract. BALB/c mice, which mount a Th2-polarized immune response following T. muris infection, showed increased expression of the antimicrobial peptide angiogenin 4 in colonic goblet cells after T. muris infection (49). Furthermore, H. polygyrus infection increased expression levels of the antimicrobial C-type lectin RegIIIγ in the cecum of mice (50). Such alterations in antimicrobial peptide secretion leading to microbiota compositional shifts following helminth infection may be evoked by specific products released by helminths (termed excretory/secretory [ES] products) acting on intestinal epithelial cells. Consistent with this is a report that the broad microbiota compositional changes caused by H. polygyrus infection in mice were independent of IL-4Rα signaling and Th2 induction (35).

An altered physical microenvironment elicited by helminth infection, including epithelial barrier disruption and the stimulation of mucus production, may also select for the outgrowth of specific species within the microbiota (43). Changes to the intestinal mucus layer include a switch from Muc2 to Muc5AC following T. muris infection (51) and more subtle changes to the glycosylation patterns of mucins (which impact upon viscosity) following infection of rats with the rodent helminth parasite Nippostrongylus brasiliensis (52). Most significantly, perhaps, the IL-13/IL-22–dependent hyperproliferation of goblet cells and overproduction of mucus following helminth infection (53) are likely to substantially alter the ability of different bacterial species to remain in the intestinal tract.

TLR interactions are central to the maintenance of host–microbiota homeostasis (54), and interference with TLR or other pattern recognition receptor signaling may be a mechanism by which the presence of helminths alters microbiota composition. There is evidence that helminth infection can alter expression levels of TLRs (55, 56) and modulate downstream signaling following TLR stimulation (28, 5759). Within the intestinal setting, infection of rats with H. diminuta increases expression of TLR2 and TLR4 (60), whereas H. polygyrus infection induces TLR4 expression specifically on small intestinal lamina propria T cells (61), which may be stimulated through the increased exposure of host immune cells to microbiota ligands during helminth infection.

As well as altering TLR expression levels, it is well documented that helminth ES products can modulate inflammatory responses from dendritic cells (DCs) and macrophages following stimulation with TLR ligands (62). For example, a fatty acid–binding protein from the human and animal parasitic trematode Fasciola hepatica (Fh12) can suppress IL-12p35, TNF-α, IL-6, and IL-1β production from bone marrow–derived macrophages in response to LPS stimulation (63), and the ES products of H. polygyrus (HES) can suppress IL-12p70 and IL-10 production in response to CpG stimulation of bone marrow–derived DCs (64). Interestingly, ES products from the whipworm T. suis downregulates DC TLR responses but interacts with C-type lectin receptors though specific glycan moieties (65). The functional role of these modulatory responses in the intestinal setting is not clear; however, these pathways may be important in situations where helminth infection promotes host tolerance against specific groups within the bacterial microbiota.

Modulation of microbiota populations through the adaptive, Ag-specific arm of the immune system can also take place. For example, microbiota-specific T cells are generated following epithelial barrier breach induced either by dextran sodium sulfate administration or by acute infection with the protozoan parasite Toxoplasma gondii (66). Intestinal helminths could likewise boost the T cell response to microbial Ags, although in other contexts certain helminth species effectively downregulate the host T cell compartment (67) to establish a more tolerogenic environment.

An additional component aiding in containment of the intestinal microbiota is the production of mucosal IgA by lamina propria plasma cells, which is stimulated by the presence of the microbiota itself (68). Surprisingly, although robust parasite-specific IgA responses are elicited in helminth infections, these Abs have only a limited role in protective antiparasite immunity (69, 70). However, it is possible that helminth infection modulates the generation of microbe-specific IgA responses, as indeed is reported in the suppression of cholera toxin IgA Abs in patients coinfected with helminths and Vibrio cholerae (71).

A fascinating study of the adaptive Th2 response that may modulate both microbial populations and host pathology concerns the treatment of spontaneous idiopathic chronic diarrhea among captive rhesus macaques. The experimental administration of Trichuris trichiura ova improved disease symptoms (measured by an increased fecal consistency and weight gain) in four of five animals, despite the lack of establishment of a chronic infection with T. trichiura (72). In these animals, a higher frequency of IL-4–producing CD4+ T cells was detected in colonic biopsies taken after, compared with before, helminth exposure (72). Additionally, following helminth exposure, the total load of several bacterial taxa detected in colon biopsies was reduced alongside a heightened diversity of bacterial species (72). A local colonic Th2 response induced by T. trichiura exposure may have promoted mucus production and epithelial turnover that were sufficient to reduce the association of bacterial microbiota species with the colonic mucosa, recovering intestinal homeostasis (73).

Independently of these immunological pathways, there are, of course, likely to be direct interactions between helminths and microbes, as suggested by the identification of an antibacterial peptide from the pig roundworm Ascaris suum (74) and the finding that HES contains at least eight lysozyme homologs with potential antimicrobial effects (75). Furthermore, the ES products of T. suis had antibiotic activity in vitro, although the active principle was not identified (76). The extent to which these effects functionally alter the microbial composition in situ remains to be tested.

In addition to impacting the composition and function of the commensal and symbiotic bacterial microbiota species, helminth infection can alter the host response to infection with pathogenic bacterial species. H. polygyrus or N. brasiliensis coinfection in mice impairs the clearance of Salmonella enterica serovar Typhimurium (S. Typhimurium) compared with S. Typhimurium infection alone, resulting in increased mortality, more pronounced edema of intestinal tissue, further epithelial erosions, and increased thickening of the gut wall (50, 77). Similarly, mice infected with H. polygyrus prior to Citrobacter rodentium infection show higher bacterial colonization levels and greater C. rodentium–induced pathology than mice that were singly infected, as measured by increased weight loss, epithelial cell hyperplasia, inflammatory cell infiltration, thickening of the gut wall, and higher incidences of anal prolapse and mortality (78). In this experimental system, the effect of helminth coinfection was shown to be dependent on the type 2 immune response induced by H. polygyrus, because coinfected STAT6-deficient mice did not exhibit exaggerated disease severity (78). This may be due, in part, to a helminth-induced type 2 response repressing effector IFN-γ responses toward C. rodentium (78), although multiple additional parallel mechanisms likely contribute to the exaggerated pathology in helminth-coinfected mice.

The first striking example of how helminth parasites require the presence of the microbiota to successfully colonize mammals came from the observation that T. muris eggs, which hatch in the large intestine of their hosts after ingestion, fail to do so without signals from the bacterial microbiota (79). T. muris likely uses the high density of microbes in the large intestine as an environmental cue to trigger hatching in the correct location for its larvae to emerge. The requirement for the microbiota seems to be common among helminth parasites, because H. polygyrus is less able to form persistent infections in mice lacking a microbiota (germ free) compared with conventionally raised mice (8082). This is particularly striking because germ-free mice are generally more susceptible to infections with bacterial or viral pathogens (83). Unlike T. muris, H. polygyrus eggs hatch in the external environment, and infective larvae are ingested (84); thus, additional mechanisms must underlie how the presence of the host microbiota benefits H. polygyrus survival within the host. It is possible that the failure of H. polygyrus to chronically infect germ-free mice results from morphological abnormalities along the intestinal tract of germ-free animals, such as an altered villous length (83); additionally, recent evidence suggests that, in conventionally raised mice, the composition of species within the microbiota can alter susceptibility to helminths (Fig. 2).

Treating mice with a low-dose antibiotic to modify the composition of their intestinal microbiota without significantly reducing the total load of bacteria is sufficient to alter susceptibility to infection with H. polygyrus (36). The abundance of Lactobacillus spp. in the duodenum was shown to positively correlate with H. polygyrus adult worm numbers 28 d postinfection and, importantly, experimental administration of the single commensal species Lactobacillus taiwanensis was sufficient to prolong the persistence of an H. polygyrus infection (36). That a chronic H. polygyrus infection results in Lactobacillus spp. expansion and that a Lactobacillus species is able to promote H. polygyrus infection points to mutually beneficial relationships between helminths and select bacterial species within the mammalian host (36). Similarly, the administration of live or dead Lactobacillus casei to mice was shown to enhance susceptibility to T. muris (85), and given that the abundance of Lactobacillaceae family members increases following T. muris infection, the possibility is raised that multiple helminth species have evolved to select for the expansion of bacterial species that promote their own persistence (37, 38).

A type 2 immune response is required for expulsion of helminths (84); thus, the presence of certain bacterial species within the microbiota may aid helminth persistence through inhibiting type 2 immunity. L. casei administration inhibited Th2 cytokine production in the mesenteric lymph nodes and Peyer’s patches of T. muris–infected mice (85), and L. taiwanensis administration resulted in an increased frequency of Tregs in mesenteric lymph nodes and Peyer’s patch tissue (36), although whether these are the primary mechanisms by which these Lactobacillus spp. promote susceptibility to helminth infection remains to be determined. The presence of a specific pathogen–free microbiota can stimulate the induction of RORγt+ Tregs in the intestinal lamia propria, and mice generated to specifically lack RORγt+ Tregs showed heightened frequencies of GATA3+ (Foxp3) CD4+ T cells in their small intestinal lamina propria and were rendered more resistant to H. polygyrus infection (86).

If microbiota-specific responses are generated following epithelial barrier breach (66) during helminth infection, it may reduce the capacity of the host immune system to respond to helminth Ags. Additionally, microbiota compositional differences induced by helminths may lead to an altered metabolomic profile within the intestine, which has the potential to modulate the function of immune cells (87), conceivably reducing the capacity of the host to mount an effective parasite-clearing response.

Perhaps the most central mechanism through which the microbiota influence helminth infections is the ubiquitous TLR signaling pathway. Certainly, mice lacking the TLR adaptor protein MyD88 are better able to control H. polygyrus and T. muris infections than are MyD88-sufficient mice (88, 89). In both models, loss of MyD88 signaling resulted in greater Th2 cytokine release following helminth infection (88, 89). MyD88 mediates signaling through TLRs, but it also mediates signaling of IL-1 family members, including IL-1α, IL-1β, and IL-18 (90); thus, it is possible that a lack of helminth chronicity in MyD88-deficient animals is due to a loss of one or a combination of these signals. In the absence of TLR4 specifically, T. muris failed to maintain a chronic infection (89); however, loss of TLR4 alone did not affect H. polygyrus colonization (88), raising the possibility that, during H. polygyrus infection, redundant signaling through other TLRs or MyD88-dependent pathways maintains susceptibility to this parasite.

A further nexus of helminths, bacteria, and TLR signaling emerged from studies of mice treated with an antibiotic mixture during infection with Schistosoma mansoni; although parasites establish in the mesenteric vasculature rather than the intestinal tract itself, they release eggs that traverse the mucosal epithelium to enter the lumen. Antibiotic treatment significantly reduced the consequent granulomatous pathology in the intestinal mucosa, a reaction that was shown previously to require MyD88 signaling (91), but it also reduced egg egress into the feces; hence, optimal transmission by S. mansoni appears to require costimulation by the microbiota in the intestine (92).

Both helminth parasites and the bacterial microbiota are widely credited with immunomodulatory abilities (28, 93), leading to the question of whether the anti-inflammatory effects of helminth infection are due, at least in part, to changes in microbiota composition or function. Many soluble ES products released by helminths are able to ameliorate disease severity in mouse models of inflammation without the presence of active infection (28, 9497); although it seems unlikely that each of these helminth ES products operate solely through modifying the host microbiota, the degree to which they modulate intestinal microbial biology has yet to be explored.

A key pathway contributing to the immunomodulatory abilities of helminth parasites, particularly in the context of suppression of allergic airway diseases, is the generation of Tregs (14, 21). Foxp3 expression in naive CD4+ T cells can be induced by exposure to HES, through a TGF-β–dependent pathway (14). A parallel induction of Tregs was described for many microbiota species (5, 7, 8, 10, 12, 13), including a mixture of several Clostridia spp., which are able to stimulate TGF-β1 production from human and mouse intestinal epithelial cell lines (8). Metabolites generated by the microbiota can also affect T cell differentiation in the intestine; the short-chain fatty acids (SCFAs) acetate, butyrate, and propionate can potentiate Treg generation and IL-10 production from Tregs in the periphery (98100), which is notable because increased circulating SCFA levels are protective in a mouse model of allergic airway disease (101). Interestingly, parasitic helminths are also known to generate acetate (102), opening the possibility of another common pathway shared by microbiota and helminths. Given that helminth infection shifts the bacterial microbiota composition, and both helminths and the bacterial microbiota can exploit host pathways to generate intestinal Tregs (Fig. 1), it will be important to dissect the relative contributions of helminth product–elicited and microbiota-elicited Tregs during the dampening of allergic inflammation during helminth infection.

Microbes and helminths have coevolved within the mammalian host, and examples of their mutualism and the synergistic pathways by which they cause host immunomodulation to promote their own survival are beginning to emerge (Fig. 1). It is interesting to note that the distinction between symbiotic or commensal microbiota species and parasitic or pathogenic organisms plays through to important differences in their life strategies: to a large extent, commensal microbiota species strive to condition their environment with minimal damage to the host, generally remaining at a safe distance, and are self-regulating in population. In contrast, most parasites and pathogenic bacteria need to breach or invade the mucosal barrier, deplete nutrients, and manipulate the host immune system in a more profound manner. Parasites and pathogenic bacteria, therefore, have a more difficult task, and this may explain why hundreds, if not thousands, of commensal and symbiotic bacterial species can colonize the human gastrointestinal tract, but the number of helminth organisms and pathogenic bacteria that can do so is limited. Notably, these few human-infective helminths and pathogenic bacteria each exert a strong effect on host immunity (28, 103), contrasting with the picture from the commensal and symbiotic microbiota population containing a large number of species each with small effects. An emerging field is the study of how pathogenic immunomodulatory agents, including helminths, protozoan parasites, bacteria, and viruses, interact in a coinfection setting within the mammalian host, given that the global regions where these organisms are most prevalent often overlap (104).

Extending beyond the effect on helminth infections, signals from the microbiota have been shown to affect colonization with bacterial, viral, and fungal pathogens (105). Defining the pathways by which these microbiota species manipulate host immunity will likely reveal novel therapeutic targets to aid the combat of infectious diseases. Further, given the ongoing clinical trials using helminths and helminth products (106) and the ability to modulate the microbiota function using probiotics, prebiotics, and synbiotics, it will be important to define the contribution of the microbiota in mediating helminth immunomodulation to allow for synergistic pathways to be targeted during the treatment of immune dysregulation.

B.B.F. was supported by operating grants from the Canadian Institutes of Health Research, including a Canadian Institutes of Health Research Emerging Team Grant in partnership with Genome British Columbia and the AllerGen NCE. R.M.M. is supported by grants from the Rainin Foundation (Grant 12-H4) and the Wellcome Trust (Grant 106122).

Abbreviations used in this article:

DC

dendritic cell

ES

excretory/secretory

HES

ES product of H. polygyrus

SCFA

short-chain fatty acid.

1
Hooper
L. V.
,
Littman
D. R.
,
Macpherson
A. J.
.
2012
.
Interactions between the microbiota and the immune system.
Science
336
:
1268
1273
.
2
Allen
J. E.
,
Maizels
R. M.
.
2011
.
Diversity and dialogue in immunity to helminths.
Nat. Rev. Immunol.
11
:
375
388
.
3
Bancroft
A. J.
,
Hayes
K. S.
,
Grencis
R. K.
.
2012
.
Life on the edge: the balance between macrofauna, microflora and host immunity.
Trends Parasitol.
28
:
93
98
.
4
Glendinning
L.
,
Nausch
N.
,
Free
A.
,
Taylor
D. W.
,
Mutapi
F.
.
2014
.
The microbiota and helminths: sharing the same niche in the human host.
Parasitology
141
:
1255
1271
.
5
Round
J. L.
,
Mazmanian
S. K.
.
2010
.
Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota.
Proc. Natl. Acad. Sci. USA
107
:
12204
12209
.
6
O’Mahony
C.
,
Scully
P.
,
O’Mahony
D.
,
Murphy
S.
,
O’Brien
F.
,
Lyons
A.
,
Sherlock
G.
,
MacSharry
J.
,
Kiely
B.
,
Shanahan
F.
,
O’Mahony
L.
.
2008
.
Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation.
PLoS Pathog.
4
:
e1000112
.
7
Atarashi
K.
,
Tanoue
T.
,
Shima
T.
,
Imaoka
A.
,
Kuwahara
T.
,
Momose
Y.
,
Cheng
G.
,
Yamasaki
S.
,
Saito
T.
,
Ohba
Y.
, et al
.
2011
.
Induction of colonic regulatory T cells by indigenous Clostridium species.
Science
331
:
337
341
.
8
Atarashi
K.
,
Tanoue
T.
,
Oshima
K.
,
Suda
W.
,
Nagano
Y.
,
Nishikawa
H.
,
Fukuda
S.
,
Saito
T.
,
Narushima
S.
,
Hase
K.
, et al
.
2013
.
Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota.
Nature
500
:
232
236
.
9
Narushima
S.
,
Sugiura
Y.
,
Oshima
K.
,
Atarashi
K.
,
Hattori
M.
,
Suematsu
M.
,
Honda
K.
.
2014
.
Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia.
Gut Microbes
5
:
333
339
.
10
Smits
H. H.
,
Engering
A.
,
van der Kleij
D.
,
de Jong
E. C.
,
Schipper
K.
,
van Capel
T. M.
,
Zaat
B. A.
,
Yazdanbakhsh
M.
,
Wierenga
E. A.
,
van Kooyk
Y.
,
Kapsenberg
M. L.
.
2005
.
Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin.
J. Allergy Clin. Immunol.
115
:
1260
1267
.
11
Karimi
K.
,
Inman
M. D.
,
Bienenstock
J.
,
Forsythe
P.
.
2009
.
Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice.
Am. J. Respir. Crit. Care Med.
179
:
186
193
.
12
Jang
S. O.
,
Kim
H. J.
,
Kim
Y. J.
,
Kang
M. J.
,
Kwon
J. W.
,
Seo
J. H.
,
Kim
H. Y.
,
Kim
B. J.
,
Yu
J.
,
Hong
S. J.
.
2012
.
Asthma prevention by Lactobacillus rhamnosus in a mouse model is associated with CD4+CD25+Foxp3+ T cells.
Allergy Asthma Immunol. Res.
4
:
150
156
.
13
Shah
M. M.
,
Saio
M.
,
Yamashita
H.
,
Tanaka
H.
,
Takami
T.
,
Ezaki
T.
,
Inagaki
N.
.
2012
.
Lactobacillus acidophilus strain L-92 induces CD4(+)CD25(+)Foxp3(+) regulatory T cells and suppresses allergic contact dermatitis.
Biol. Pharm. Bull.
35
:
612
616
.
14
Grainger
J. R.
,
Smith
K. A.
,
Hewitson
J. P.
,
McSorley
H. J.
,
Harcus
Y.
,
Filbey
K. J.
,
Finney
C. A.
,
Greenwood
E. J. D.
,
Knox
D. P.
,
Wilson
M. S.
, et al
.
2010
.
Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway.
J. Exp. Med.
207
:
2331
2341
.
15
Blankenhaus
B.
,
Klemm
U.
,
Eschbach
M. L.
,
Sparwasser
T.
,
Huehn
J.
,
Kühl
A. A.
,
Loddenkemper
C.
,
Jacobs
T.
,
Breloer
M.
.
2011
.
Strongyloides ratti infection induces expansion of Foxp3+ regulatory T cells that interfere with immune response and parasite clearance in BALB/c mice.
J. Immunol.
186
:
4295
4305
.
16
Faith
J. J.
,
McNulty
N. P.
,
Rey
F. E.
,
Gordon
J. I.
.
2011
.
Predicting a human gut microbiota’s response to diet in gnotobiotic mice.
Science
333
:
101
104
.
17
Geuking
M. B.
,
Cahenzli
J.
,
Lawson
M. A.
,
Ng
D. C.
,
Slack
E.
,
Hapfelmeier
S.
,
McCoy
K. D.
,
Macpherson
A. J.
.
2011
.
Intestinal bacterial colonization induces mutualistic regulatory T cell responses.
Immunity
34
:
794
806
.
18
Maizels
R. M.
,
Smith
K. A.
.
2011
.
Regulatory T cells in infection.
Adv. Immunol.
112
:
73
136
.
19
Yazdanbakhsh
M.
,
van den Biggelaar
A.
,
Maizels
R. M.
.
2001
.
Th2 responses without atopy: immunoregulation in chronic helminth infections and reduced allergic disease.
Trends Immunol.
22
:
372
377
.
20
Noverr
M. C.
,
Huffnagle
G. B.
.
2005
.
The ‘microflora hypothesis’ of allergic diseases.
Clin. Exp. Allergy
35
:
1511
1520
.
21
Wilson
M. S.
,
Taylor
M. D.
,
Balic
A.
,
Finney
C. A.
,
Lamb
J. R.
,
Maizels
R. M.
.
2005
.
Suppression of allergic airway inflammation by helminth-induced regulatory T cells.
J. Exp. Med.
202
:
1199
1212
.
22
Kitagaki
K.
,
Businga
T. R.
,
Racila
D.
,
Elliott
D. E.
,
Weinstock
J. V.
,
Kline
J. N.
.
2006
.
Intestinal helminths protect in a murine model of asthma.
J. Immunol.
177
:
1628
1635
.
23
Noverr
M. C.
,
Falkowski
N. R.
,
McDonald
R. A.
,
McKenzie
A. N.
,
Huffnagle
G. B.
.
2005
.
Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13.
Infect. Immun.
73
:
30
38
.
24
Endara
P.
,
Vaca
M.
,
Chico
M. E.
,
Erazo
S.
,
Oviedo
G.
,
Quinzo
I.
,
Rodriguez
A.
,
Lovato
R.
,
Moncayo
A. L.
,
Barreto
M. L.
, et al
.
2010
.
Long-term periodic anthelmintic treatments are associated with increased allergen skin reactivity.
Clin. Exp. Allergy
40
:
1669
1677
.
25
Reynolds
L. A.
,
Finlay
B. B.
.
2013
.
A case for antibiotic perturbation of the microbiota leading to allergy development.
Expert Rev. Clin. Immunol.
9
:
1019
1030
.
26
Wen
L.
,
Ley
R. E.
,
Volchkov
P. Y.
,
Stranges
P. B.
,
Avanesyan
L.
,
Stonebraker
A. C.
,
Hu
C.
,
Wong
F. S.
,
Szot
G. L.
,
Bluestone
J. A.
, et al
.
2008
.
Innate immunity and intestinal microbiota in the development of Type 1 diabetes.
Nature
455
:
1109
1113
.
27
Kostic
A. D.
,
Xavier
R. J.
,
Gevers
D.
.
2014
.
The microbiome in inflammatory bowel disease: current status and the future ahead.
Gastroenterology
146
:
1489
1499
.
28
McSorley
H. J.
,
Maizels
R. M.
.
2012
.
Helminth infections and host immune regulation.
Clin. Microbiol. Rev.
25
:
585
608
.
29
Tremaroli
V.
,
Bäckhed
F.
.
2012
.
Functional interactions between the gut microbiota and host metabolism.
Nature
489
:
242
249
.
30
Hsiao
E. Y.
,
McBride
S. W.
,
Hsien
S.
,
Sharon
G.
,
Hyde
E. R.
,
McCue
T.
,
Codelli
J. A.
,
Chow
J.
,
Reisman
S. E.
,
Petrosino
J. F.
, et al
.
2013
.
Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.
Cell
155
:
1451
1463
.
31
Zhao
L.
2013
.
The gut microbiota and obesity: from correlation to causality.
Nat. Rev. Microbiol.
11
:
639
647
.
32
Stefka
A. T.
,
Feehley
T.
,
Tripathi
P.
,
Qiu
J.
,
McCoy
K.
,
Mazmanian
S. K.
,
Tjota
M. Y.
,
Seo
G. Y.
,
Cao
S.
,
Theriault
B. R.
, et al
.
2014
.
Commensal bacteria protect against food allergen sensitization.
Proc. Natl. Acad. Sci. USA
111
:
13145
13150
.
33
Weinstock
J. V.
,
Elliott
D. E.
.
2013
.
Translatability of helminth therapy in inflammatory bowel diseases.
Int. J. Parasitol.
43
:
245
251
.
34
Walk
S. T.
,
Blum
A. M.
,
Ewing
S. A.
,
Weinstock
J. V.
,
Young
V. B.
.
2010
.
Alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus.
Inflamm. Bowel Dis.
16
:
1841
1849
.
35
Rausch
S.
,
Held
J.
,
Fischer
A.
,
Heimesaat
M. M.
,
Kühl
A. A.
,
Bereswill
S.
,
Hartmann
S.
.
2013
.
Small intestinal nematode infection of mice is associated with increased enterobacterial loads alongside the intestinal tract.
PLoS One
8
:
e74026
.
36
Reynolds
L. A.
,
Smith
K. A.
,
Filbey
K. J.
,
Harcus
Y.
,
Hewitson
J. P.
,
Redpath
S. A.
,
Valdez
Y.
,
Yebra
M. J.
,
Finlay
B. B.
,
Maizels
R. M.
.
2014
.
Commensal-pathogen interactions in the intestinal tract: lactobacilli promote infection with, and are promoted by, helminth parasites.
Gut Microbes
5
:
522
532
.
37
Holm
J. B.
,
Sorobetea
D.
,
Kiilerich
P.
,
Ramayo-Caldas
Y.
,
Estellé
J.
,
Ma
T.
,
Madsen
L.
,
Kristiansen
K.
,
Svensson-Frej
M.
.
2015
.
Chronic Trichuris muris Infection Decreases Diversity of the Intestinal Microbiota and Concomitantly Increases the Abundance of Lactobacilli.
PLoS One
10
:
e0125495
.
38
Houlden
A.
,
Hayes
K. S.
,
Bancroft
A. J.
,
Worthington
J. J.
,
Wang
P.
,
Grencis
R. K.
,
Roberts
I. S.
.
2015
.
Chronic Trichuris muris infection in C57BL/6 mice causes significant changes in host microbiota and metabolome: effects reversed by pathogen clearance.
PLoS One
10
:
e0125945
.
39
McKenney
E. A.
,
Williamson
L.
,
Yoder
A. D.
,
Rawls
J. F.
,
Bilbo
S. D.
,
Parker
W.
.
2015
.
Alteration of the rat cecal microbiome during colonization with the helminth Hymenolepis diminuta.
Gut Microbes
6
:
182
193
.
40
Wu
S.
,
Li
R. W.
,
Li
W.
,
Beshah
E.
,
Dawson
H. D.
,
Urban
J. F.
 Jr.
2012
.
Worm burden-dependent disruption of the porcine colon microbiota by Trichuris suis infection.
PLoS One
7
:
e35470
.
41
Kreisinger
J.
,
Bastien
G.
,
Hauffe
H. C.
,
Marchesi
J.
,
Perkins
S. E.
.
2015
.
Interactions between multiple helminths and the gut microbiota in wild rodents.
Philos. Trans. R. Soc. Lond. B Biol. Sci.
370
: (1675).
42
Wang
Y.
,
Xiao
S. H.
,
Xue
J.
,
Singer
B. H.
,
Utzinger
J.
,
Holmes
E.
.
2009
.
Systems metabolic effects of a Necator americanus infection in Syrian hamster.
J. Proteome Res.
8
:
5442
5450
.
43
Li
R. W.
,
Wu
S.
,
Li
W.
,
Navarro
K.
,
Couch
R. D.
,
Hill
D.
,
Urban
J. F.
 Jr.
2012
.
Alterations in the porcine colon microbiota induced by the gastrointestinal nematode Trichuris suis.
Infect. Immun.
80
:
2150
2157
.
44
Kay
G. L.
,
Millard
A.
,
Sergeant
M. J.
,
Midzi
N.
,
Gwisai
R.
,
Mduluza
T.
,
Ivens
A.
,
Nausch
N.
,
Mutapi
F.
,
Pallen
M.
.
2015
.
Differences in the faecal microbiome in Schistosoma haematobium infected children vs. uninfected children.
[Published erratum appears in 2015 PLoS Negl. Trop. Dis. 9: e0003969.]
PLoS Negl. Trop. Dis.
9
:
e0003861
.
45
Lee
S. C.
,
Tang
M. S.
,
Lim
Y. A.
,
Choy
S. H.
,
Kurtz
Z. D.
,
Cox
L. M.
,
Gundra
U. M.
,
Cho
I.
,
Bonneau
R.
,
Blaser
M. J.
, et al
.
2014
.
Helminth colonization is associated with increased diversity of the gut microbiota.
PLoS Negl. Trop. Dis.
8
:
e2880
.
46
Cooper
P.
,
Walker
A. W.
,
Reyes
J.
,
Chico
M.
,
Salter
S. J.
,
Vaca
M.
,
Parkhill
J.
.
2013
.
Patent human infections with the whipworm, Trichuris trichiura, are not associated with alterations in the faecal microbiota.
PLoS One
8
:
e76573
.
47
Cantacessi
C.
,
Giacomin
P.
,
Croese
J.
,
Zakrzewski
M.
,
Sotillo
J.
,
McCann
L.
,
Nolan
M. J.
,
Mitreva
M.
,
Krause
L.
,
Loukas
A.
.
2014
.
Impact of experimental hookworm infection on the human gut microbiota.
J. Infect. Dis.
210
:
1431
1434
.
48
De Filippo
C.
,
Cavalieri
D.
,
Di Paola
M.
,
Ramazzotti
M.
,
Poullet
J. B.
,
Massart
S.
,
Collini
S.
,
Pieraccini
G.
,
Lionetti
P.
.
2010
.
Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.
Proc. Natl. Acad. Sci. USA
107
:
14691
14696
.
49
D’Elia
R.
,
DeSchoolmeester
M. L.
,
Zeef
L. A.
,
Wright
S. H.
,
Pemberton
A. D.
,
Else
K. J.
.
2009
.
Expulsion of Trichuris muris is associated with increased expression of angiogenin 4 in the gut and increased acidity of mucins within the goblet cell.
BMC Genomics
10
:
492
.
50
Su
L.
,
Su
C. W.
,
Qi
Y.
,
Yang
G.
,
Zhang
M.
,
Cherayil
B. J.
,
Zhang
X.
,
Shi
H. N.
.
2014
.
Coinfection with an intestinal helminth impairs host innate immunity against Salmonella enterica serovar Typhimurium and exacerbates intestinal inflammation in mice.
Infect. Immun.
82
:
3855
3866
.
51
Hasnain
S. Z.
,
Evans
C. M.
,
Roy
M.
,
Gallagher
A. L.
,
Kindrachuk
K. N.
,
Barron
L.
,
Dickey
B. F.
,
Wilson
M. S.
,
Wynn
T. A.
,
Grencis
R. K.
,
Thornton
D. J.
.
2011
.
Muc5ac: a critical component mediating the rejection of enteric nematodes.
J. Exp. Med.
208
:
893
900
.
52
Tsubokawa
D.
,
Ishiwata
K.
,
Goso
Y.
,
Yokoyama
T.
,
Kanuka
H.
,
Ishihara
K.
,
Nakamura
T.
,
Tsuji
N.
.
2015
.
Induction of Sd(a)-sialomucin and sulfated H-sulfomucin in mouse small intestinal mucosa by infection with parasitic helminth.
Exp. Parasitol.
153
:
165
173
.
53
Turner
J. E.
,
Stockinger
B.
,
Helmby
H.
.
2013
.
IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection.
PLoS Pathog.
9
:
e1003698
.
54
Rakoff-Nahoum
S.
,
Paglino
J.
,
Eslami-Varzaneh
F.
,
Edberg
S.
,
Medzhitov
R.
.
2004
.
Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.
Cell
118
:
229
241
.
55
Venugopal
P. G.
,
Nutman
T. B.
,
Semnani
R. T.
.
2009
.
Activation and regulation of toll-like receptors (TLRs) by helminth parasites.
Immunol. Res.
43
:
252
263
.
56
Sun
S.
,
Wang
X.
,
Wu
X.
,
Zhao
Y.
,
Wang
F.
,
Liu
X.
,
Song
Y.
,
Wu
Z.
,
Liu
M.
.
2011
.
Toll-like receptor activation by helminths or helminth products to alleviate inflammatory bowel disease.
Parasit. Vectors
4
:
186
.
57
Balic
A.
,
Harcus
Y.
,
Holland
M. J.
,
Maizels
R. M.
.
2004
.
Selective maturation of dendritic cells by Nippostrongylus brasiliensis-secreted proteins drives Th2 immune responses.
Eur. J. Immunol.
34
:
3047
3059
.
58
Kane
C. M.
,
Cervi
L.
,
Sun
J.
,
McKee
A. S.
,
Masek
K. S.
,
Shapira
S.
,
Hunter
C. A.
,
Pearce
E. J.
.
2004
.
Helminth antigens modulate TLR-initiated dendritic cell activation.
J. Immunol.
173
:
7454
7461
.
59
Semnani
R. T.
,
Venugopal
P. G.
,
Leifer
C. A.
,
Mostböck
S.
,
Sabzevari
H.
,
Nutman
T. B.
.
2008
.
Inhibition of TLR3 and TLR4 function and expression in human dendritic cells by helminth parasites.
Blood
112
:
1290
1298
.
60
Kosik-Bogacka
D. I.
,
Wojtkowiak-Giera
A.
,
Kolasa
A.
,
Salamatin
R.
,
Jagodzinski
P. P.
,
Wandurska-Nowak
E.
.
2012
.
Hymenolepis diminuta: analysis of the expression of Toll-like receptor genes (TLR2 and TLR4) in the small and large intestines of rats.
Exp. Parasitol.
130
:
261
266
.
61
Ince
M. N.
,
Elliott
D. E.
,
Setiawan
T.
,
Blum
A.
,
Metwali
A.
,
Wang
Y.
,
Urban
J. F.
 Jr.
,
Weinstock
J. V.
.
2006
.
Heligmosomoides polygyrus induces TLR4 on murine mucosal T cells that produce TGFbeta after lipopolysaccharide stimulation.
J. Immunol.
176
:
726
729
.
62
Ludwig-Portugall
I.
,
Layland
L. E.
.
2012
.
TLRs, Treg, and B cells, an interplay of regulation during helminth infection.
Front. Immunol.
3
:
8
.
63
Martin
I.
,
Cabán-Hernández
K.
,
Figueroa-Santiago
O.
,
Espino
A. M.
.
2015
.
Fasciola hepatica fatty acid binding protein inhibits TLR4 activation and suppresses the inflammatory cytokines induced by lipopolysaccharide in vitro and in vivo.
J. Immunol.
194
:
3924
3936
.
64
Segura
M.
,
Su
Z.
,
Piccirillo
C.
,
Stevenson
M. M.
.
2007
.
Impairment of dendritic cell function by excretory-secretory products: a potential mechanism for nematode-induced immunosuppression.
Eur. J. Immunol.
37
:
1887
1904
.
65
Klaver
E. J.
,
Kuijk
L. M.
,
Laan
L. C.
,
Kringel
H.
,
van Vliet
S. J.
,
Bouma
G.
,
Cummings
R. D.
,
Kraal
G.
,
van Die
I.
.
2013
.
Trichuris suis-induced modulation of human dendritic cell function is glycan-mediated.
Int. J. Parasitol.
43
:
191
200
.
66
Hand
T. W.
,
Dos Santos
L. M.
,
Bouladoux
N.
,
Molloy
M. J.
,
Pagán
A. J.
,
Pepper
M.
,
Maynard
C. L.
,
Elson
C. O.
 III
,
Belkaid
Y.
.
2012
.
Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses.
Science
337
:
1553
1556
.
67
Maizels
R. M.
,
Balic
A.
,
Gomez-Escobar
N.
,
Nair
M.
,
Taylor
M. D.
,
Allen
J. E.
.
2004
.
Helminth parasites--masters of regulation.
Immunol. Rev.
201
:
89
116
.
68
Macpherson
A. J.
,
Geuking
M. B.
,
McCoy
K. D.
.
2012
.
Homeland security: IgA immunity at the frontiers of the body.
Trends Immunol.
33
:
160
167
.
69
Wedrychowicz
H.
,
Maclean
J. M.
,
Holmes
P. H.
.
1984
.
Secretory IgA responses in rats to antigens of various developmental stages of Nippostrongylus brasiliensis.
Parasitology
89
:
145
157
.
70
McCoy
K. D.
,
Stoel
M.
,
Stettler
R.
,
Merky
P.
,
Fink
K.
,
Senn
B. M.
,
Schaer
C.
,
Massacand
J.
,
Odermatt
B.
,
Oettgen
H. C.
, et al
.
2008
.
Polyclonal and specific antibodies mediate protective immunity against enteric helminth infection.
Cell Host Microbe
4
:
362
373
.
71
Harris
J. B.
,
Podolsky
M. J.
,
Bhuiyan
T. R.
,
Chowdhury
F.
,
Khan
A. I.
,
Larocque
R. C.
,
Logvinenko
T.
,
Kendall
J.
,
Faruque
A. S.
,
Nagler
C. R.
, et al
.
2009
.
Immunologic responses to Vibrio cholerae in patients co-infected with intestinal parasites in Bangladesh.
PLoS Negl. Trop. Dis.
3
:
e403
.
72
Broadhurst
M. J.
,
Ardeshir
A.
,
Kanwar
B.
,
Mirpuri
J.
,
Gundra
U. M.
,
Leung
J. M.
,
Wiens
K. E.
,
Vujkovic-Cvijin
I.
,
Kim
C. C.
,
Yarovinsky
F.
, et al
.
2012
.
Therapeutic helminth infection of macaques with idiopathic chronic diarrhea alters the inflammatory signature and mucosal microbiota of the colon.
PLoS Pathog.
8
:
e1003000
.
73
Leung
J. M.
,
Loke
P.
.
2013
.
A role for IL-22 in the relationship between intestinal helminths, gut microbiota and mucosal immunity.
Int. J. Parasitol.
43
:
253
257
.
74
Kato
Y.
,
Komatsu
S.
.
1996
.
ASABF, a novel cysteine-rich antibacterial peptide isolated from the nematode Ascaris suum. Purification, primary structure, and molecular cloning of cDNA.
J. Biol. Chem.
271
:
30493
30498
.
75
Hewitson
J. P.
,
Harcus
Y.
,
Murray
J.
,
van Agtmaal
M.
,
Filbey
K. J.
,
Grainger
J. R.
,
Bridgett
S.
,
Blaxter
M. L.
,
Ashton
P. D.
,
Ashford
D. A.
, et al
.
2011
.
Proteomic analysis of secretory products from the model gastrointestinal nematode Heligmosomoides polygyrus reveals dominance of venom allergen-like (VAL) proteins.
J. Proteomics
74
:
1573
1594
.
76
Abner
S. R.
,
Parthasarathy
G.
,
Hill
D. E.
,
Mansfield
L. S.
.
2001
.
Trichuris suis: detection of antibacterial activity in excretory-secretory products from adults.
Exp. Parasitol.
99
:
26
36
.
77
Bobat
S.
,
Darby
M.
,
Mrdjen
D.
,
Cook
C.
,
Logan
E.
,
Auret
J.
,
Jones
E.
,
Schnoeller
C.
,
Flores-Langarica
A.
,
Ross
E. A.
, et al
.
2014
.
Natural and vaccine-mediated immunity to Salmonella Typhimurium is impaired by the helminth Nippostrongylus brasiliensis.
PLoS Negl. Trop. Dis.
8
:
e3341
.
78
Chen
C. C.
,
Louie
S.
,
McCormick
B.
,
Walker
W. A.
,
Shi
H. N.
.
2005
.
Concurrent infection with an intestinal helminth parasite impairs host resistance to enteric Citrobacter rodentium and enhances Citrobacter-induced colitis in mice.
Infect. Immun.
73
:
5468
5481
.
79
Hayes
K. S.
,
Bancroft
A. J.
,
Goldrick
M.
,
Portsmouth
C.
,
Roberts
I. S.
,
Grencis
R. K.
.
2010
.
Exploitation of the intestinal microflora by the parasitic nematode Trichuris muris.
Science
328
:
1391
1394
.
80
Wescott
R. B.
1968
.
Experimental Nematospiroides dubius infection in germfree and conventional mice.
Exp. Parasitol.
22
:
245
249
.
81
Weinstein
P. P.
,
Newton
W. L.
,
Sawyer
T. K.
,
Sommerville
R. I.
.
1969
.
Nematospiroides dubius: development and passage in the germfree mouse, and a comparative study of the free-living stages in germfree feces and conventional cultures.
Trans. Am. Microsc. Soc.
88
:
95
117
.
82
Chang
J.
,
Wescott
R. B.
.
1972
.
Infectivity, fecundity, and survival of Nematospiroides dubius in gnotobiotic mice.
Exp. Parasitol.
32
:
327
334
.
83
Smith
K.
,
McCoy
K. D.
,
Macpherson
A. J.
.
2007
.
Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota.
Semin. Immunol.
19
:
59
69
.
84
Reynolds
L. A.
,
Filbey
K. J.
,
Maizels
R. M.
.
2012
.
Immunity to the model intestinal helminth parasite Heligmosomoides polygyrus.
Semin. Immunopathol.
34
:
829
846
.
85
Dea-Ayuela
M. A.
,
Rama-Iñiguez
S.
,
Bolás-Fernandez
F.
.
2008
.
Enhanced susceptibility to Trichuris muris infection of B10Br mice treated with the probiotic Lactobacillus casei.
Int. Immunopharmacol.
8
:
28
35
.
86
Ohnmacht
C.
,
Park
J. H.
,
Cording
S.
,
Wing
J. B.
,
Atarashi
K.
,
Obata
Y.
,
Gaboriau-Routhiau
V.
,
Marques
R.
,
Dulauroy
S.
,
Fedoseeva
M.
, et al
.
2015
.
The microbiota regulates type 2 immunity through RORγt+ T cells.
Science
349: 989–993.
87
Brestoff
J. R.
,
Artis
D.
.
2013
.
Commensal bacteria at the interface of host metabolism and the immune system.
Nat. Immunol.
14
:
676
684
.
88
Reynolds
L. A.
,
Harcus
Y.
,
Smith
K. A.
,
Webb
L. M.
,
Hewitson
J. P.
,
Ross
E. A.
,
Brown
S.
,
Uematsu
S.
,
Akira
S.
,
Gray
D.
, et al
.
2014
.
MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite Heligmosomoides polygyrus.
J. Immunol.
193
:
2984
2993
.
89
Helmby
H.
,
Grencis
R. K.
.
2003
.
Essential role for TLR4 and MyD88 in the development of chronic intestinal nematode infection.
Eur. J. Immunol.
33
:
2974
2979
.
90
Adachi
O.
,
Kawai
T.
,
Takeda
K.
,
Matsumoto
M.
,
Tsutsui
H.
,
Sakagami
M.
,
Nakanishi
K.
,
Akira
S.
.
1998
.
Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.
Immunity
9
:
143
150
.
91
Layland
L. E.
,
Wagner
H.
,
da Costa
C. U.
.
2005
.
Lack of antigen-specific Th1 response alters granuloma formation and composition in Schistosoma mansoni-infected MyD88-/- mice.
Eur. J. Immunol.
35
:
3248
3257
.
92
Holzscheiter
M.
,
Layland
L. E.
,
Loffredo-Verde
E.
,
Mair
K.
,
Vogelmann
R.
,
Langer
R.
,
Wagner
H.
,
Prazeres da Costa
C.
.
2014
.
Lack of host gut microbiota alters immune responses and intestinal granuloma formation during schistosomiasis.
Clin. Exp. Immunol.
175
:
246
257
.
93
Belkaid
Y.
,
Hand
T. W.
.
2014
.
Role of the microbiota in immunity and inflammation.
Cell
157
:
121
141
.
94
Trujillo-Vargas
C. M.
,
Werner-Klein
M.
,
Wohlleben
G.
,
Polte
T.
,
Hansen
G.
,
Ehlers
S.
,
Erb
K. J.
.
2007
.
Helminth-derived products inhibit the development of allergic responses in mice.
Am. J. Respir. Crit. Care Med.
175
:
336
344
.
95
Ferreira
I.
,
Smyth
D.
,
Gaze
S.
,
Aziz
A.
,
Giacomin
P.
,
Ruyssers
N.
,
Artis
D.
,
Laha
T.
,
Navarro
S.
,
Loukas
A.
,
McSorley
H. J.
.
2013
.
Hookworm excretory/secretory products induce interleukin-4 (IL-4)+ IL-10+ CD4+ T cell responses and suppress pathology in a mouse model of colitis.
Infect. Immun.
81
:
2104
2111
.
96
Ruyssers
N. E.
,
De Winter
B. Y.
,
De Man
J. G.
,
Loukas
A.
,
Pearson
M. S.
,
Weinstock
J. V.
,
Van den Bossche
R. M.
,
Martinet
W.
,
Pelckmans
P. A.
,
Moreels
T. G.
.
2009
.
Therapeutic potential of helminth soluble proteins in TNBS-induced colitis in mice.
Inflamm. Bowel Dis.
15
:
491
500
.
97
Cançado
G. G.
,
Fiuza
J. A.
,
de Paiva
N. C.
,
Lemos
Lde. C.
,
Ricci
N. D.
,
Gazzinelli-Guimarães
P. H.
,
Martins
V. G.
,
Bartholomeu
D. C.
,
Negrão-Corrêa
D. A.
,
Carneiro
C. M.
,
Fujiwara
R. T.
.
2011
.
Hookworm products ameliorate dextran sodium sulfate-induced colitis in BALB/c mice.
Inflamm. Bowel Dis.
17
:
2275
2286
.
98
Arpaia
N.
,
Campbell
C.
,
Fan
X.
,
Dikiy
S.
,
van der Veeken
J.
,
deRoos
P.
,
Liu
H.
,
Cross
J. R.
,
Pfeffer
K.
,
Coffer
P. J.
,
Rudensky
A. Y.
.
2013
.
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.
Nature
504
:
451
455
.
99
Smith
P. M.
,
Howitt
M. R.
,
Panikov
N.
,
Michaud
M.
,
Gallini
C. A.
,
Bohlooly-Y
M.
,
Glickman
J. N.
,
Garrett
W. S.
.
2013
.
The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.
Science
341
:
569
573
.
100
Furusawa
Y.
,
Obata
Y.
,
Fukuda
S.
,
Endo
T. A.
,
Nakato
G.
,
Takahashi
D.
,
Nakanishi
Y.
,
Uetake
C.
,
Kato
K.
,
Kato
T.
, et al
.
2013
.
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.
Nature
504
:
446
450
.
101
Trompette
A.
,
Gollwitzer
E. S.
,
Yadava
K.
,
Sichelstiel
A. K.
,
Sprenger
N.
,
Ngom-Bru
C.
,
Blanchard
C.
,
Junt
T.
,
Nicod
L. P.
,
Harris
N. L.
,
Marsland
B. J.
.
2014
.
Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis.
Nat. Med.
20
:
159
166
.
102
Tielens
A. G.
,
van Grinsven
K. W.
,
Henze
K.
,
van Hellemond
J. J.
,
Martin
W.
.
2010
.
Acetate formation in the energy metabolism of parasitic helminths and protists.
Int. J. Parasitol.
40
:
387
397
.
103
Finlay
B. B.
,
McFadden
G.
.
2006
.
Anti-immunology: evasion of the host immune system by bacterial and viral pathogens.
Cell
124
:
767
782
.
104
Salgame
P.
,
Yap
G. S.
,
Gause
W. C.
.
2013
.
Effect of helminth-induced immunity on infections with microbial pathogens.
Nat. Immunol.
14
:
1118
1126
.
105
Kamada
N.
,
Seo
S. U.
,
Chen
G. Y.
,
Núñez
G.
.
2013
.
Role of the gut microbiota in immunity and inflammatory disease.
Nat. Rev. Immunol.
13
:
321
335
.
106
Fleming
J. O.
,
Weinstock
J. V.
.
2015
.
Clinical trials of helminth therapy in autoimmune diseases: rationale and findings.
Parasite Immunol.
37
:
277
292
.
107
Round
J. L.
,
Lee
S. M.
,
Li
J.
,
Tran
G.
,
Jabri
B.
,
Chatila
T. A.
,
Mazmanian
S. K.
.
2011
.
The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota.
Science
332
:
974
977
.
108
Faith
J. J.
,
Ahern
P. P.
,
Ridaura
V. K.
,
Cheng
J.
,
Gordon
J. I.
.
2014
.
Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice.
Sci. Transl. Med.
6
:
220ra11
.

The authors have no financial conflicts of interest.