Microbiota and innate immunity in intestinal inflammation... : Current Opinion in Gastroenterology (original) (raw)
INTRODUCTION
Mucosal homeostasis in the healthy intestine depends on a protective balance between immunostimulation and immunosuppression through appropriately timed and limited immune responses to luminal antigens [1,2]. Innate immunity represents the first line of host defense against any form of physiological stress. Tight control of innate immunity is critical for maintaining tissue integrity and homeostasis within the intestinal mucosa, yet many mucosal insults in the intestine may disrupt this finely tuned system. When innate immune cells detect tissue irritation, injury, or infection, inflammation is triggered.
Chronic inflammation is one of the hallmarks of cancer [3▪▪]. Patients with inflammatory bowel diseases (IBD), particularly ulcerative colitis, are at increased risk of developing colon cancer, and the risk correlates directly with the activity and extent of inflammation [4]. Inflammation disturbs the normal wound healing process, resulting in a vicious interplay between excessive mucosal injury and tissue remodeling through sustained innate immune cell recruitment, proliferation, and migration. It may directly damage cells and promote malignant transformation by inducing chromosomal and microsatellite instability, CpG island methylation, epigenetic alterations, and posttranslational modifications. Thus, chronic inflammation can be critically involved in all phases of colonic carcinogenesis: tumor initiation, perpetuation, and progression. Increased inflammation can be found within premalignant colonic adenomas [5]. Chronic inflammatory responses create a tumor supporting microenvironment through activated innate immune cells that secrete multiple mediators, which may influence neoplastic development, invasion, metastasis, and angiogenesis. The transcriptional factors NF-κB and signal transducer and activator of transcription 3 (STAT3) [6] play key roles in promoting inflammation-associated tumorigenesis via processes such as cell type-specific suppression of apoptosis and acceleration of the cell cycle. Soluble mediators produced by cancer cells may impair antitumor responses mounted by the innate immune system, which would then further stimulate tumor growth and survival.
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Within the healthy intestine, the normal commensal microbiota and cells of the intestinal mucosa usually co-exist in a mutually beneficial relationship [7,8]. Although commensals shape both mucosal and systemic immune homeostasis in the host, cells of the intestinal mucosa modulate the commensal habitat and maintain a commensal composition that avoids excessive antigen signaling. Regulatory defects in the physiological interaction between the microbiota and the host innate immune system may lead to inflammation and cancer. Studies over the past year provide novel mechanistic insights into the molecular events that may link intestinal microbiota and innate immunity in chronic inflammation and neoplasia.
ALTERATIONS IN THE ENVIRONMENT: MICROBES AND BEYOND
The commensal microbiome is part of the host environment (together with viruses, eukaryotes dietary antigens and metabolites), and constantly interacts with the host immune system in a multidimensional and multidirectional network [9]. Growing evidence suggests that alterations in the complex host environment (e.g., dysbiosis and overgrowth of select commensal species, certain dietary factors, copresence of facultative pathogenic viruses or fungi, and changes in mucus components) may contribute to the development of intestinal inflammation and associated cancer.
Dysbiosis allows rare commensal species to colonize and expand. These indigenous microorganisms may produce DNA-damaging superoxide radicals and genotoxins, and induce innate immune mediated procarcinogenic pathways. Recently, colon cancer was associated with sporadic, but not consistent, shifts in the adherent intestinal microbiota [10,11]. Such changes in commensal composition could subvert mucosal immune responses to a predominantly proinflammatory and proliferative phenotype, but clear functional evidence to support this notion is lacking. Two independent studies identified a high prevalence of the gram-negative, obligate anaerobic Fusobacterium nucleatum in human colorectal carcinoma [12▪,13▪]. However, interpretation of this correlation presents a ‘chicken-and-egg’ dilemma. Is this observation of overpresentation incidental or causal? Does F. nucleatum primarily promote colon tumor formation, or do (pre) neoplastic lesions and surrounding proinflammatory conditions secondarily manipulate the commensal composition and select for this potentially pathogenic microorganism? Although invasive F. nucleatum induces MUC2 secretion and elicits proinflammatory responses in intestinal epithelial cells (IEC) _in vitro_[14], it is possible that F. nucleatum just ‘follows’ the proinflammatory stimulus of the tumor microenvironment. The presence of F. nucleatum does not appear to be specific for mucinous or any other type of sporadic adenocarcinoma of the colon, as it has also been linked to other gastrointestinal disorders [15]. Furthermore, there may be significant differences in virulence between F. nucleatum strains [15]. Enterotoxigenic Bacteroides fragilis (ETBF) is also associated with IBD and colon cancer [16]. ETBF induces the polyamine catabolic enzyme spermine oxidase (SMO) in IEC, leading to SMO-dependent reactive oxygen species generation, DNA damage, and uncontrolled cellular proliferation [17▪]. It is noteworthy that inhibition of polyamine catabolism via SMO reduces ETBF-mediated chronic inflammation and tumorigenesis in ApcMin/+ mice (a mouse model of familial adenomatous polyposis). Future functional studies will need to demonstrate whether and how commensal species, such as F. nucleatum or ETBF, may directly affect disease development in the gastrointestinal tract in vivo. SMO could represent an interesting target for cancer prevention and treatment. However, it must now be determined whether SMO is specifically activated in the in-vivo setting of human colon cancer, and whether other intestinal bacterial species associated with human colon cancer also induce SMO.
So far most studies have provided relatively small ‘snapshot’ analyses of the microbiota composition in the gut, focusing on a handful of specific species in a few individuals with different diseases. However, dramatic advances in large-scale sequencing technology, high-performance computing, and systems biology approaches have allowed the Metagenomics of the Human Intestinal Tract (MetaHIT) and the Human Microbiome Project (HMP) Consortia to aim for a more comprehensive characterization of the human microbes within their communities, and of baseline diversity. Last year, MetaHIT researchers [18▪▪] identified three dominant enterotypes of well balanced commensal species clusters that exist across healthy individuals worldwide, independent of varying nutritional and environmental conditions or genetic influences. It remains to be shown how potential sub-enterotypes modulate host immune function, and whether any changes may specifically correlate with disease phenotypes, for example, IBD and colon cancer. In addition, recent results from the HMP research groups (simultaneously published in more than a dozen articles [19▪▪–21▪▪]) provided the first glimpses of the longitudinal variation in both diversity and composition of the microbial communities between different body sites and different individuals. The findings of these studies, which are also just at the initial stages, imply that microbial diversity varies substantially, albeit stably, between healthy individuals, although commensal functionality appears to be conserved. The next hugely complex and challenging steps are to decipher what is causing the variability. For example, how is the human microbiome influenced by key environmental factors, metabolic, neurological and postnatal/developmental processes, genotypes, and immune system alterations? How does the human microbiome change intraindividually and interindividually in health and disease states, such as intestinal inflammation and colon cancer?
Apart from diet [22] and other environmental factors, it is possible that variations in the virome may also shape the complex dynamics of the gut microbiome and initiate the onset of disease. Viruses and their particles can infect bacteria, potentially modulating host-bacterial interactions. Conversely, microbial communities may regulate the gut virome. Two recent studies [23▪,24▪] show that commensal microbiota can promote viral propagation and transmission in host target cells. Viruses (e.g., MMTV and poliovirus) may bind to the TLR4 ligand, LPS, expressed by commensal bacteria, and suppress antiviral host responses by inducing the production of anti-inflammatory interleukin 10 (IL-10; [23▪]) and enhance viral attachment [24▪]. Depletion of the gut microbiota by antibiotics impairs viral dissemination [24▪]. These exciting findings may open new ways to improve vaccine efficacy and to treat viral infections in the intestine by targeting the microbiome. Although profiling of the human gut virome has just begun, findings already demonstrate viral hypervariability between individuals and under conditions of diet-induced fluctuations [25▪,26]. It is likely that novel enteric viruses will soon emerge as potential obligate or facultative pathogens (with or without bacterial cofactors) in intestinal disorders, including IBD and colon cancer.
The gut microbiome is tightly intertwined with the preepithelial mucus layer, and each regulates the other. The mucus layer in the healthy gut consists of mucins, trefoil peptides, and antimicrobial peptides (produced by goblet and paneth cells), as well as secretory IgA (transcytosed by enterocytes). Innate immunity regulates the integrity of the mucus layer by controlling terminal goblet cell differentiation (via TLR2 through TFF3 [27]) and paneth cell function (via MyD88 through RegIIIγ [28▪] or via NOD2 through defensins [29]). The protective inner mucus, which mostly consists of mucins, provides a spatial separation between the microbiota and colonic IEC [30]. By contrast, the mucus layer in the small intestine is less dense, and the antibacterial protein, RegIIIγ, limits contact between the IEC and bacteria [28▪]. Patients with IBD and/or colon cancer may have a severely compromised colonic mucus layer. Apart from mucolytic bacteria, genetic defects and/or aberrant immune-mediated modulation of innate immune sensors and associated effector pathways may impair the protective mucus layer, diminishing antimicrobial activity and disturbing bacterial clearance, which could lead to a colitogenic and/or cancerogenic commensal composition. It will be important to consider mucus characteristics in future microbiome studies. Dysfunction of the inner colon mucus layer may allow luminal bacteria to reach the intestinal epithelium and drive inflammatory and proliferative responses. For instance, mice deficient in mucin-type O-linked oligosaccharides (a central component of intestinal mucins) show impaired mucus barrier integrity and develop commensal-induced colitis [31▪], but it remains unclear whether neoplastic features are also induced in this model.
ALTERATIONS IN THE HOST INNATE IMMUNE SYSTEM
Progress has been made in defining the mechanistic functions by which the gastrointestinal innate immune surveillance system shapes its commensal interactions via cell surface or cytosolic pattern recognition receptor (PRR) families and their interconnected signaling platforms. Toll-like receptors (TLR) and NOD-like receptors (NLR) play important roles in the recognition of commensal microbiota, induction of host defense effector pathways against pathogenic and nonpathogenic dangers, and control of adaptive immune responses [32]. Both PRR families are widely expressed by various cell types of the gastrointestinal mucosa. PRR expression is not limited to innate immune cells, but can also be found in cancer cells and nearby stromal cells. In nonhematopoietic cells (such as IECs), aberrant PRR signaling may induce hyperproliferative and antiapoptotic responses. In hematopoietic cells, aberrant PRR signaling may drive and maintain the chronically inflamed environment in the lamina propria [33]. Thus, innate immune malfunction may trigger inflammation-associated mucosal barrier rearrangement and neoplastic growth.
Host genetic variations may affect innate immune function and signaling, as well as commensal composition. Mutations in specific innate immune sensors and related pathways may modulate cell priming of the intestinal mucosa and handling of the intestinal microbiota, driving inflammation, and carcinogenesis. Inflammasomes represent cytoplasmic multiprotein complexes composed of several members of the NLR family, procaspase-1, and the adaptor protein ASC [34,35]. Upon activation, caspase-1 cleaves IL-1β and IL-18, resulting in secretion of their mature forms. Mice lacking MyD88, the common adaptor for TLR/IL-1R/IL-18R signal transduction, are highly susceptible to developing colitis-associated tumors in the murine azoxymethane (AOM)/dextran sodium sulfate (DSS) model, possibly due to their inability to signal through the IL-18R [36]. Mice deficient in different inflammasome components (NLRP3, NLRP6, NLRP12, NLRC4, Casp-1, ASC, or IL-18R [36–42,43▪–45▪]) show a similar phenotype, with impaired mucosal regeneration and barrier permeability, altered IEC proliferation and antiapoptosis, and increased inflammation and tumor load. Notably, deficiency in NLRP6 predisposes mice to a communicable colitogenic microbiota (dominated by the presence of Prevototellaceae and candidate phylum TM7), that is, the increased susceptibility to chemically induced colitis observed in NLRP6−/− could be passed on to other mice housed in the same cage [43▪]. Future studies will need to delineate whether the altered microbial community composition may contain functional cancer-specific features. It is possible that perturbations in the inflammasome pathway may affect metabolic processes that trigger cancerogenesis. Collectively, these data imply that the inflammasome-IL-18R/MyD88 axis may function as an important tumor suppressor in this particular colitis/cancer model, potentially in part through IL-18-mediated IFN-γ stimulation and STAT1 activation [38]; however, the exact mechanisms remain to be elucidated. By contrast, MyD88 drives intestinal tumorigenesis in ApcMin/± [46,47] and AOM/oxazolone-colitis [48▪] mouse models. Here, the pro-tumorigenic role of MyD88 was attributed to the induction of the IL-6/STAT3-pathway. The role of TLRs is even less clear. Although activation of TLR4 promotes colitis-associated tumor growth, presumably through Cox-2/PGE2 [49,50], TLR2 signaling seems to protect against colonic cancer in the AOM/DSS model [51].
Various reported effects of innate immune signaling in the development of inflammation-associated colon cancer underscore the complexity and variability of experimental models, each depending on different net effects of immune cells, and the genetic and environmental/commensal context [32]. When interpreting the ambiguous results, one must also consider that none of these mouse models of intestinal tumorigenesis fully reflect the human pathology of colitis-associated colonic carcinogenesis. Although these models provide useful settings in which to explore certain aspects of inflammation-associated colon cancer pathogenesis, one important disadvantage of all of the models is the lack of invasion and metastasis. Moreover, because the mice receive the detergent DSS along with the mutagen, it is difficult to dissect whether neoplasia primarily develops as a result of mutagen-induced cell damage and/or aberrant inflammatory reactions. In addition, ApcMin/+ mice develop benign adenomas in the small intestine but not in the colon, and mostly in the absence of inflammatory responses.
More studies on the impact of genetic defects in innate immune signaling in inflammation and neoplasia in human tissues are now warranted. We recently identified the human variant, TLR4-D299G, as an aberrant innate immune mediator that may create an autoinflammatory environment, favoring excessive IEC remodeling, which drives tumor progression. Two missense mutations, A896G (D299G) and C1196T (T399I) were identified with frequencies up to 10–18% in humans, depending on the population. TLR4-D299G and TLR4-T399I are associated with increased disease risk for _Helicobacter pylori_-mediated noncardia gastric carcinoma [52] and IBD [53]. The TLR4-D299G polymorphism seems to compromise recruitment of the signaling adaptors MyD88 and TRIF, thereby impairing downstream activation of NF-κB target genes [54]. Instead, activation of STAT3 is likely the principal target of TLR4-D299G, thereby promoting malignant tumor progression in human IECs [55▪]. We showed that TLR4-D299G in IECs induces significant changes in expression levels of proinflammatory and protumorigenic genes, which correlate with morphological changes of epithelial-mesenchymal transition and STAT3-dependent cellular invasion. TLR4-D299G IECs constitutively secrete large amounts of proinflammatory mediators (acute phase response, coagulation, and complement); thus, the TLR4-D299G variant represents a ‘gain-of-function’ mutation, which enhances the host inflammatory response. These alterations are not present in human IECs expressing wild-type TLR4. Furthermore, primary human sporadic adenocarcinomas from patients carrying TLR4-D299G are more frequently associated with an advanced tumor stage and metastasis at the time of diagnosis than those carrying wild-type TLR4. This observation correlates with enhanced STAT3 activation in primary human colon cancer expressing TLR4-D299G compared with TLR4-WT. Thus, the TLR4-D299G mutation may link aberrant innate immunity with inflammation-associated colonic carcinogenesis through STAT3 in the human intestinal epithelium [55▪]. Future studies (with larger cohorts) will need to determine whether TLR4-D299G represents a valid biomarker for risk stratification in colon cancer patients to develop a more aggressive disease phenotype, and whether STAT3 may serve as a therapeutic target in this subgroup. Studies will also need to elucidate whether TLR4-D299G and other IBD/cancer associated genotypes correlate with alterations in the host microbiome.
CONCLUSION
Commensal microbiota, host innate immunity, and genetics form a multidimensional network that controls homeostasis of the intestinal mucosal barrier (Fig. 1). An imbalance in the relationships within this triad may promote chronic intestinal inflammatory processes and cancer. Recent analyses of the human gut microbiota and its interactions with the host innate immune system have yielded several important findings linking inflammation and tumorigenesis in the gut, but they also have raised more questions than answers. The large-scale sequencing projects, MetaHIT and HMP, have begun to catalog the healthy human microbiome, and it has become apparent that (so far) we have only explored the tip of the iceberg. At this point, it is unclear whether inflammation and neoplasia in the gut may be associated with dominant shifts between individual species or, rather, entire commensal communities, and whether such changes are indeed causal or rather correlative. The next steps will be to focus on the microbial composition in well defined diseased states (and known genotypes), and to elucidate mucosal immune functions. It is evident that the net outcome of the interactions between the commensal microbiota and the host innate immune system is entirely context-dependent and cell-type/tissue-type specific. Both the commensal microbiota and the host immune system are modulated by multiple cofactors and metabolites; yet the totality of environmental influences and contributions (‘environmentome’) remains to be understood. The field will be facing enormous challenges to provide integrated mechanistic insights that can hopefully unite the numerous and complex interactions between the ‘microbiome-virome-environmentome’ and host innate (and adaptive) immunity and genetics in order to clarify disease pathogenesis, explain subphenotypes, predict prognosis, and select adequate therapies. It will be essential to merge multiple patient-based datasets with the results from experimental animal models (e.g., strategized in [56]) into interdisciplinary approaches. Future studies need to show whether the targeted manipulation of intestinal microbiota and its ecosystem may prove valuable [57] in host immunomodulation to prevent and treat inflammation and associated colon cancer. Given the pace of discovery, the advances made over the last few years, the number of new hypotheses introduced, and the number of questions that remain unanswered, the future looks bright for this exciting field of research.
Commensal microbiota, host innate immunity, and genetics form a multidimensional network that controls homeostasis of the intestinal mucosal barrier.
Acknowledgements
Supported by grants from the Deutsche Forschungsgemeinschaft (CA226/8-1; CA226/9-1; CA226/4-3) and the Crohn's and Colitis Foundation of America (RFP 3191).
Conflicts of interest
None declared.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 103–105).
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Keywords:
carcinogenesis; colitis; inflammatory bowel diseases; intestinal epithelium; STAT3
© 2013 Lippincott Williams & Wilkins, Inc.