nihms-316581.pdf

Pathobionts of the Gastrointestinal Microbiota and Inflammatory

Disease

Janet Chow

Haiqing Tang

, and

Sarkis K. Mazmanian

1,*

Division of Biology, California Institute of Technology, Pasadena, California, 91125

Abstract

Our immune system is charged with the vital mission of identifying invading pathogens and

mounting proper inflammatory responses. During the process of clearing infections, the immune

system often causes considerable tissue damage. Conversely, if the target of immunity is a

member of the resident microbiota, uncontrolled inflammation may lead to host pathology in the

absence of infectious agents. Recent evidence suggests that several inflammatory disorders may be

caused by specific bacterial species found in most healthy hosts. Although the mechanisms that

mediate pathology remain largely unclear, it appears that genetic defects and/or environmental

factors may predispose mammals to immune-mediated diseases triggered by potentially

pathogenic symbionts of the microbiota. We have termed this class of microbes `pathobionts', to

distinguish them from acquired infectious agents. Herein, we explore burgeoning hypotheses that

the combination of an immunocompromised state with colonization by pathobionts together

comprise a risk factor for certain inflammatory disorders and gastrointestinal cancer.

Introduction

Microbes dominate as the most abundant life form on Earth, occupying almost every

terrestrial, aquatic, and biological ecosystem on our planet. Humans are no exception.

Throughout our lives, we continuously encounter microorganisms that range from those

essential for health to those causing disease [1]. The human body is permanently colonized

by microbial organisms on virtually all environmentally exposed surfaces. The vast majority

of these microbes are harbored in the gastrointestinal (GI) tract where commensal bacteria

can outnumber host cells by 10-fold (thus, we are all 90% bacteria on a cellular level). Many

vital host functions are provided by the microbiota, including the synthesis of vitamins,

digestion of complex polysaccharides, maintenance of the intestinal epithelial barrier, and

resistance to pathogen colonization [2]. Millions of years of co-evolution have

interdependently linked the health of mammals to their microbiotas [3]. The Human

Microbiome Project is currently underway to sequence the microbiota of various populations

of people, with a goal of identifying microbial species implicated in health and disease [4].

What is already clear is that microbes have flourished inside us since time immemorial, and

have diverged to take on many functional roles that are now being uncovered at the genetic

and mechanistic levels. Several descriptions of an intimate link between the microbiota and

To whom correspondence should be addressed. sarkis@caltech.edu.

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Conflicts of Interest

The authors declare no conflict of interest.

NIH Public Access

Author Manuscript

Curr Opin Immunol

. Author manuscript; available in PMC 2012 August 23.

Published in final edited form as:

Curr Opin Immunol

. 2011 August ; 23(4): 473–480. doi:10.1016/j.coi.2011.07.010.

NIH-PA Author Manuscript

the immune system have recently emerged [5–8]. However, not all host-microbiota

interactions promote health, and particular species of resident bacteria appear to activate the

immune system resulting in inflammatory diseases. Thus, our association with the microbial

world is precarious.

It is now appreciated that some symbiotic microorganisms in the GI tract induce pathology

under certain conditions, usually involving environmental and/or genetic alterations. The

term `pathobionts' has been suggested to describe resident microbes with pathogenic

potential [9]. Organisms proposed as pathobionts are associated with chronic inflammatory

conditions, unlike opportunistic pathogens which often cause acute infections and are

typically acquired from the environment or other parts of the body. In addition, pathobionts

are innocuous to the host under normal conditions, distinct from traditional pathogens which

may cause disease even in healthy hosts. In this review, we highlight experimental evidence

mostly from animal models that support the classification of specific microbes as

pathobionts (see Table 1). Furthermore, we explore the role of bacterial pathobionts on

intestinal health and their resulting impact on inflammatory bowel disease (IBD) and

gastrointestinal cancers.

Segmented Filamentous Bacteria

Segmented filamentous bacteria (SFB) comprise a group of Gram-positive

Clostridia

-related

bacteria that closely adhere to Peyer's patches in the mammalian small intestine and have

been shown to potently stimulate immune responses including IgA induction and B cell

activation [10]. Recently, much attention has been focused on SFB due to their ability to

induce T-helper 17 (Th17) cells in the gut [7, 11]. Th17 cells, characterized by IL-17A,

IL-17F, and IL-22 cytokine production, are an important contributor to adaptive immunity,

conferring protection against enteric infection with extracellular pathogens. Specific-

pathogen free (SPF) mice colonized with these non-culturable bacteria showed greater

numbers of Th17 cells in the gut and heightened protection against

Citrobacter rodentium

infection compared to mice without SFB [7]. Germ-free (GF) mice, which have very few

Th17 cells in the gut [12–14], exhibited no appreciable change in Th17 levels when

reconstituted with a microbiota lacking SFB. Surprisingly, reconstitution with SFB alone

was able to significantly increase the number of intestinal Th17 cells [7]. Considering the

microbiota harbors a complex bacterial consortium of hundreds of species, these remarkable

findings indicate the ability to induce Th17 cells in the gut may be uniquely possessed by

only a small subset of the microbiota. Therefore, SFB colonization of healthy animals

appears to play an important role in priming the adaptive immune system and potentially

enhancing immunity against enteric pathogens.

However, the heightened immunity conferred by SFB colonization may also come at a cost

to the host when inflammation is inappropriately triggered. Studies have demonstrated a

pathogenic role for SFB in the gut. SCID (severe combined immunodeficiency) mice

reconstituted with CD4+CD45Rb

high

T cells and colonized with SFB developed severe

colitis and intestinal inflammation [15]. In this particular animal model of colitis, SFB may

synergize with the surrounding microbiota to exert its immunomodulatory effects, as mice

mono-colonized with SFB did not develop intestinal pathology. Furthermore, the impact of

SFB colonization on the host immune system appears to extend beyond the gut, as SFB

mono-colonization in GF mice has been shown to increase the susceptibility of disease in

animal models of rheumatoid arthritis and multiple sclerosis [16–17]. GF or antibiotic

treated animals display reduced Th17 cells outside the gut and do not develop disease; this

suggests that SFB alone can substitute for a complex microbiota in terms of driving

pathology through Th17 cells induction. The observation that gut bacteria affect extra-

intestinal compartments highlights the profound impact of the microbiota in modulating the

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overall health of the host. Although the microbial molecules that drive immunity are

unknown, these results illustrate that in the context of an autoimmune environment, SFB are

pathobionts that promote diseases not observed in healthy hosts.

Helicobacter hepaticus

belongs to the enterohepatic

Helicobacter

species (EHS), a diverse

group of spiral bacteria that thrive on mucosal surfaces of the intestinal tract and/or the liver

of humans and other animals [18].

H. hepaticus

is a well-studied member of EHS and is

prevalent in mice from commercial and academic institutions all around the world [19].

Pioneering work by Fox and co-workers led to the discovery of

H. hepaticus

and its role in

hepatitis, hepatocellular carcinoma, typhlitis and colitis in several strains of

immunodeficient mice [20–22]. Further studies provided evidence suggesting the

involvement of

H. hepaticus

in the development of pathogenic inflammation and

carcinogenesis in certain immunocompromised rodent models. Experimental infection with

H. hepaticus

induces IBD-like lesions in SCID mice reconstituted with naïve

CD4

CD45RB

high

T cells, as well as in C57Bl/6

IL-10

−/− mice [23–24]. Colonization with

H. hepaticus

also initiates rapid development of colitis and large bowel carcinoma in 129/

SvEv

Rag2

−/− mice [25]. However, in immunocompetent wild-type (WT) mice,

hepaticus

fails to induce significant disease, irrespective of the mouse strains [24–25].

Therefore,

H. hepaticus

acts as a pathobiont that is able to promote colitis and in some cases

colon cancer only in mouse strains with disrupted immune function.

Further questions arise from the pathobiont definition. For example, how does

H. hepaticus

interact with the host immune system to maintain a balanced relationship? Why do certain

susceptible mouse strains with compromised immune systems develop inflammatory

responses after

H. hepaticus

colonization, whereas WT mice do not?

H. hepaticus

infection

induces Th1 and Th17 associated intestinal inflammation in

IL-10

−/− mice [26–27]. In

lymphocyte-deficient

Rag

−/− mice, experimental infection with

H. hepaticus

induces colitis

and colorectal cancer through proinflammatory cytokines TNF-

, IL-17, and IL-23 [25, 28–

29].

Rag

−/− mice lacking MyD88 in the hematopoietic compartment are resistant to

hepaticus

-induced colitis, indicating an essential role for toll-like receptor (TLR) signaling

H. hepaticus

-induced innate inflammation [30]. Therefore,

H. hepaticus

is capable of

causing both T cell-dependent and -independent inflammatory responses.

H. hepaticus

induces intestinal inflammation in

IL-10

−/− mice but not WT mice, whose

mesenteric lymph node (MLN) cells produce IL-10 in response to soluble

H. hepaticus

antigen (SHelAg), indicating a crucial role for IL-10 in balancing the

H. hepaticus

-induced

inflammatory responses [26–27]. Furthermore, anti-IL-10R treated MLN cells derived from

H. hepaticus

-infected mice produce higher levels of IL-17 and IFN-

compared with WT

MLNs following response to SHelAg [31]. Transferring

H. hepaticus

-induced

CD4

CD45RB

low

regulatory T cells suppresses

H. hepaticus

-induced colitis in

Rag

−/− mice

[32]. Also, CD4

CD25

regulatory T cells isolated from

Helicobacter

-free 129SvEv mice

prevent both T cell-dependent and -independent intestinal inflammation in an IL-10-

dependent manner [33]. Moreover, an intact NF-

B signaling pathway is required for IL-10-

mediated inhibition of

H. hepaticus

-induced colitis [34]. Therefore, it appears that

hepaticus

colonization induces a tolerogenic IL-10-secreting regulatory T cell response,

which may be important for maintaining immunologic `balance' with the host. In addition,

H. hepaticus

was found to suppress TLR4 and TLR5-mediated immune responses in

intestinal epithelial cells [35]. Our results also showed that

H. hepaticus

suppressed the

expression of TLR4 in the intestinal epithelial cell line MODE-K [36], suggesting another

possible regulatory strategy in epithelial cells mediated by TLR signaling. We propose that

H. hepaticus

maintains symbiotic crosstalk with the host by directing both inflammatory and

tolerogenic responses in the innate and adaptive immune system during long-term

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colonization. However, in genetically susceptible hosts with defects in tolerogenic immune

function and/or regulatory mechanisms,

H. hepaticus

may trigger an imbalanced immune

response leading to pathologic inflammation.

Most studies have focused on the host immune response to

H. hepaticus

colonization and

genetic alterations in mice that lead to disease. Little is known about the bacterial

components produced by

H. hepaticus

that mediate these outcomes. Our recent discovery

revealed that

H. hepaticus

utilizes a type VI secretion system (T6SS) to balance host

colonization and intestinal inflammation [36]. T6SS are multi-protein complexes assembled

on the bacterial surface that function as a biological needle and syringe, injecting microbial

molecules into eukaryotic cells. Deletion of the T6SS apparatus resulted in higher

colonization levels of

H. hepaticus

during experimental colitis. Moreover, a

H. hepaticus

T6SS mutant elicited elevated inflammatory responses in the intestine of

Rag1

−/− mice

reconstituted with CD4+CD45RB

high

T cells compared to WT bacteria. Meanwhile, T6SS

directed an anti-inflammatory response in an intestinal epithelial cell line, characterized by

suppressed expression of TLR4, NF-

B and IL-17R. However, whether T6SS mediated

suppression of innate inflammatory signaling correlates with its regulatory roles is still

unknown. Identification of T6SS substrates of

H. hepaticus

may define the molecular

mechanisms by which this pathobiont `communicates' with its host to establish symbiosis.

Disruption of this communication, through genetic polymorphisms or mutations in the host,

may form the basis for why

H. hepaticus

causes disease in compromised animals.

Helicobacter pylori

In 2005, Barry Marshall and Robin Warren won the Nobel Prize in Medicine for

demonstrating that

Helicobacter pylori

, a bacterium that intimately colonizes the mucosal

lining of the stomach, could directly cause peptic ulcer disease and gastritis. Classified as a

class I carcinogen,

H. pylori

has been shown to lead to gastric adenocarcinoma in 1% of

infected individuals. While 50% of the human population is thought to be colonized with

pylori

, only a small percentage actually develop gastric disorders [37]. Colonization of

humans with

H. pylori

is believed to have occurred since humans migrated out of Africa

58,000 years ago. The bacteria are thought to colonize during early childhood and can thrive

in the stomach for a lifetime. In countries with higher socio-economic standards (involving

increased antibiotic use and hygiene), colonization appears to be less prevalent compared in

developing countries.

The mechanistic details of how

H. pylori

promotes inflammation have been investigated.

Using a Type IV secretion system (T4SS),

H. pylori

translocates the bacterial protein CagA

into gastric epithelial cells. CagA subsequently interacts with host signal transduction

pathways involved in inflammation and oncogenesis [38]. The presence of CagA, along with

other virulence factors such as a pathogenicity island and additional secreted toxins,

correlate well with increased virulence in strains of

H. pylori

[39]. However, even virulent

strains of

H. pylori

are found in asymptomatic individuals suggesting there are other factors

contributing to the induction of disease. Genetic polymorphisms in the

IL1

gene, which

encodes for a pro-inflammatory cytokine important for enhancing the inflammatory

response to

H. pylori

infection, have been shown to be associated with increased risk of

gastric cancer [40].

Adding another layer of complexity is the observation that colonization with

H. pylori

inversely correlates with esophageal adenocarcinoma and childhood asthma [41–42].

Furthermore, individuals colonized with CagA deficient strains of

H. pylori

are at increased

risk for disease [43]. Although

H. pylori

-mediated protection against these pathologies still

remains to be convincingly demonstrated, these results suggest the intriguing concept that

pylori

may have evolved to protect its host against disease in order to promote a healthier

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environment for its long-term survival [44]. Finally, sequencing efforts have revealed highly

diverse panmictic populations of

H. pylori

between geographically separated groups [45].

The extensive diversification of the

H. pylori

genome may have proven advantageous in

surviving the changing immunological and environmental pressures of the stomach.

Implications for Inflammatory Bowel Disease and GI Cancers

Inflammatory bowel diseases (including Crohn's disease (CD) and Ulcerative colitis (UC)),

afflict approximately 1.5 million people in the United States. Currently there is no cure for

IBD, although immunosuppressive therapies and probiotics alleviate symptoms in some

cases. The causes of IBD appear to be multifactorial, integrating the microbiota, host

genetics, and the immune system as factors determining predisposition to disease.

Shifts in the intestinal microenvironment (due to diet, antibiotics, hygiene, etc) may lead to

changes in the microbiota known as dysbiosis. Dysbiosis may increase susceptibility to

intestinal inflammation [46–47]. In support of this hypothesis,

T-bet

−/−

Rag2

−/− (TRUC)

mice spontaneously develop dysbiosis and colitis, which can eventually progress into

colorectal cancer [48]; remarkably, microbiota transfer from these donors into wild-type

mice can confer disease [5]. Subsequent studies identified two proteobacteria over-

represented in TRUC mice,

Proteus mirabilis

and

Klebsiella pneumonia

, as the colitogenic

microbes [49]. However, full induction of disease required the presence of a diverse

microbiota, indicating that interactions with other microbes may define whether a pathobiont

will display a pathogenic profile. Culture-independent 16S rDNA sequence analysis of the

microbiotas of individuals with Crohn's disease revealed lower diversity and greater

temporal instability compared to controls [50]. In patients with IBD, the number of

commensals belonging to the phyla

Firmicutes

and

Bacteroidetes

were found to be

decreased, while concomitant increases in

Actinobacteria

and

Proteobacteria

were observed

[51]. These findings highlight an important link between changes to the composition of the

microbiota and intestinal health in animal models and humans.

Evidence over several decades suggests that the gut microbiota is a key factor in the

pathogenesis of IBD. Studies have shown increased antibody titers against gut bacteria in

IBD patients compared to healthy individuals [52]. Furthermore, treatment with antibiotics

can help alleviate symptoms [53]. It is well documented that in certain mouse models of

experimental colitis, rederivation under germ-free conditions abolishes disease [54].

However, host genetics and their impact on the resulting immunological environment

significantly determine the type of response (or lack thereof) to the microbiota. Numerous

genetic variants have been identified in individuals with IBD and correlate strongly with an

increased risk of disease. Many of these genes are involved in bacterial recognition (

NOD2,

TLR

genes,

IRGM, ATG16L1

) and innate and adaptive immunity (

IL-23R

IL-10

) [55].

Balanced immune responses to the microbiota are critical for intestinal homeostasis, as the

microbiota itself has been shown to coordinate intestinal immunity. Illustrating this concept,

mice expressing the human defensin DEFA5 showed a reduction in SFB colonization and a

corresponding decrease in lamina propria Th17 cells [56]. In addition, perturbations in the

mouse NLRP6 inflammasome pathway led to overgrowth of intestinal

Prevotellaceae

and

TM7 bacteria, resulting in increased susceptibility to chemically-induced colitis [57]. Thus,

although certain symbionts are prominent species in the gut and typically non-pathogenic,

specific host defects can trigger IBD as a result of inflammation directed to pathobionts.

Although our understanding of the role of pathobionts on human health is still in its infancy,

a few studies have highlighted the dangers of disrupting the human gut microbial

community. Pseudomembranous colitis which results in severe diarrhea, fever and

abdominal pain, is caused by overgrowth of

Clostridium difficile

following long-term

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antibiotic treatment [58]. Broad-spectrum antibiotics can also enhance vancomycin-resistant

Enterococcus

(VRE) survival and proliferation in the GI tract, which may subsequently lead

to infection of the bloodstream [59–60]. As the source of

C. difficile

and

Enterococcal

infections is the microbiota, environmental factors may predispose patients to diseases

caused by indigenous pathobionts. We predict that both genetic host alterations and/or

environmental perturbations (such as antibiotic use) may lead to intestinal inflammation

triggered by pathobionts (Figure 1).

Recent studies have suggested that chronic inflammatory conditions can contribute to the

development of some cancers by promoting cell proliferation, cell survival, and/or

angiogenesis [61]. Individuals with IBD (in particular ulcerative colitis) have an increased

risk of developing colorectal cancer [62]. In an experimental animal model of colitis-

associated cancer,

IL-10

−/− mice treated with the chemical carcinogen azoxymethane, were

devoid of tumors when raised under germ-free conditions, indicating the presence of

intestinal bacteria is required for carcinogenesis [63]. Similar results were found in other

animal models of spontaneous colon cancer. Germ-free rederivation of

TCR

−/−

p53

−/−

mice and

TGF

−/− mice eliminated the formation of intestinal tumors [64–65]. In addition,

clinical studies have identified a higher incidence of adherent and invasive

Escherichia coli

(AIEC) in biopsies from carcinoma patients compared to controls [66–67]. Colorectal cancer

is the second most common cause of malignant tumors in the United States [68], and often

has life-threatening consequences. Moreover, epidemiologic and clinical data show that the

incidence of colon cancer is dramatically increasing in Western countries. A genetic basis

for cancer is well established; however it is being increasingly appreciated that non-genetic

(environmental) factors are also crucial to the disease process. Whether there is a causal

relationship between the microbiota, intestinal inflammation, and colon carcinogenesis will

require further investigation.

Concluding Remarks

Recent ground-breaking studies of the interactions between humans and beneficial bacteria

have marked a revolution in microbiology and immunology [3]. The human gastrointestinal

tract harbors astounding multitudes of symbiotic bacterial species living in homeostasis with

the immune system. However, some of these permanent residents appear to take on

pathogenic properties during colonization of hosts with genetic and/or environmental

alterations. Based on this rationale, we have speculated a category of indigenous gut bacteria

termed pathobionts which cause disease only in susceptible hosts. This designation is based

on recent data from animal models, with limited but growing support from clinical studies.

The combination of a compromised host with colonization by pathobionts may be a risk

factor in IBD, colon cancer and perhaps for diseases outside of the intestinal compartment.

Identifying the molecular interactions between pathobionts and the mammalian immune

system may be critical to understanding the etiology of certain diseases with a non-

infectious microbial component. Finally, the design of drugs that inhibit the processes by

which pathobionts promote inflammation may represent novel therapies for chronic human

diseases.

Acknowledgments

J.C. is supported by a pre-doctoral training grant (NIH GM007616). S.K.M. is a Searle Scholar. Work in the

authors' laboratory is supported by funding from the National Institutes of Health (DK078938, DK083633 &

AI088626), Emerald Foundation, Damon Runyon Cancer Research Foundation and the Crohn's and Colitis

Foundation of America to S.K.M.

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Highlights

•

Research now shows that some members of the normal gut microbiota may

promote disease

•

We term these microbes “Pathobionts” to distinguish them from acquired

infections

•

Pathobionts appear to cause chronic inflammatory diseases

•

Understanding how Pathobionts induce disease may lead to anti-microbial

therapies for IBD and colon cancer

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Figure 1. Genetic and environmental alterations may synergize with pathobionts to cause

intestinal inflammation and disease

In addition to acquired pathogens which can cause gastroenteritis, resident gut bacteria

trigger intestinal inflammation. However, unlike acute pathogens, pathobionts appear to

require additional factors to cause disease. Based predominantly on animal models, certain

symbionts of the microbiota can initiation gut inflammation and pathology when colonizing

a genetically susceptible host (e.g.,

H. hepaticus

, SFB,

P. mirabilis

K. pneumonia,

Prevotellaceae

and TM7). In other cases, specific resident gut bacteria can expand following

antibiotic use which clears competing symbionts to promote gastrointestinal disease (VRE,

C. difficile

). The associated genetic defects or antibiotics are denoted in parenthesis.

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Table 1

PATHOBIONTS OF THE GASTROINTESTINAL TRACT

Bacterial strain

Conditions Promoting Pathogenesis

Refs

Segmented Filamentous Bacteria

• leads to colitis in SCID mice reconstituted with CD4

CD45Rb

high

T cells

• promotes disease in experimental models of rheumatoid arthritis and multiple sclerosis in

mono-associated gnotobiotic mice

16,17

Helicobacter hepaticus

• induces colitis in C57BI/6

IL-10

−/− mice

• initiates colitis and large bowel carcinoma in 129/SvEv

Rag2

−/− mice

Helicobacter pylori

• genetic polymorphisms of

IL1B

associated with increased risk of gastric cancer

Proteus mirabilis Klebsiella pneumonia

• responsible for inducing colitis and colorectal cancer in

T-bet

−/−

Rag2

−/− (TRUC) mice

Prevotellaceae

TM7

• responsible for inducing colitis in mice with mutations in the inflammasome pathway

Clostridium difficile

• can lead to pseudomembranous colitis in humans, following long-term antibiotic treatment

Vancomycin-resistant

Enterococcus

• capable of invading the bloodstream in humans treated with broad-spectrum antibiotics

59,60

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. Author manuscript; available in PMC 2012 August 23.