Spandana Amarthaluru, Cheryl Joseph, Daniela Kovasevic, Kimberly Ng, Maxwell Tran, Mark Zasowski
Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
Publication date: September 18, 2015
Abstract: Celiac disease (CD) is an autoimmune disorder, triggered by gluten ingestion, which is characterized by villous atrophy and crypt hyperplasia in the small intestine. The development of CD is dependent on numerous factors such as genetic predisposition and environmental triggers. For patients with confirmed CD, the current gold-standard treatment is a gluten-free diet (GFD), although due to the expense and limited availability of gluten-free foods, alternative therapies are needed. The gut microbiota has been implicated in both worsening and potentially alleviating intestinal damage. Generally, the over-colonization of Gram-negative bacteria in the gastrointestinal (GI) tract has been correlated with the exacerbation of CD symptoms through the upregulation of proinflammatory cytokines, increased gut permeability, and upregulation of matrix metalloproteinases, which cause intestinal remodelling. Conversely, many Gram-positive bacteria have been used in probiotic treatments which have been shown to upregulate anti-inflammatory cytokines, prevent the production of proinflammatory cytokines, decrease paracellular permeability, and hydrolyze potentially immunogenic gliadin peptides. As such, this review aims to explore the diverse mechanisms by which the gut microbiota can aggravate and improve CD symptoms.
Introduction: Celiac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten in genetically susceptible individuals1. As of 2012, the prevalence of CD in the United States was 0.71% (0.58-0.86%; 95% confidence interval)2. CD is characterized by villous atrophy and crypt hyperplasia in the small intestine, which can result in digestive symptoms (e.g. diarrhea, nausea, vomiting), extraintestinal symptoms (e.g. neurological effects3, osteoporosis4, iron deficiency), and stunted growth due to poor nutrient absorption1. The symptoms manifest at different ages, with development and intestinal symptoms occurring more frequently in children and extraintestinal symptoms occurring more in adults and the elderly5. The current gold-standard treatment is a gluten-free diet (GFD), which, although proven to be safe and effective, has a high rate of dietary transgressions6. Gluten-free foods are expensive and not widely available, indicating a need for alternative therapies besides GFDs.
The bacteria inhabiting the human gastrointestinal (GI) tract have become a major research interest recently as they are implicated in the pathogenesis of numerous diseases7. Commensal bacteria live in symbiosis with the host, providing many functional benefits that include improved digestion and increased immune function8. However, pathogenic bacteria typically cause infection and damage to the GI tract. An imbalance of commensal and pathogenic bacteria can result in dysbiosis of the gut microbiota, which can worsen the symptoms associated with CD9. This review will address the role of the gut microbiota in the exacerbation of CD symptoms as well as the potential of probiotics as a treatment option.
Genetic Predisposition to CD: The majority of CD incidences occur in genetically predisposed individuals who carry certain isoforms of the human leukocyte antigen (HLA) gene10. These genes code for HLA complexes found on antigen presenting cells (APCs), which activate naïve T cells11. Approximately 90-95% of CD patients in the American population carry the HLA-DQ2 isoform. The remaining 5-10% of CD patients mostly carry the HLA-DQ8 isoform10. Recently, other isoforms such as HLA-DQ2.5 have been associated with CD as well12.
While the majority of CD patients are genetically predisposed to the condition, only marginal populations of HLA-DQ2/8+ individuals exhibit clinical CD symptoms13. Thus, there has recently been much interest regarding the role of the gut microbiota dysbiosis in the manifestation of CD symptoms.
CD Pathogenesis: Certain environmental triggers, such as gluten consumption, are known to stimulate autoimmune responses in genetically predisposed individuals14. In the healthy gut, gluten consumption occurs without immunogenic consequences. However, in CD patients, gluten catabolism causes the activation of specific immune pathways, which lead to autoimmunity and CD-associated symptoms15.
Gluten is a protein found in wheat, barley, and rye, consisting of two main classes of proteins: gliadins and glutenins16. Gliadin proteins are extremely high in proline and glutamine content, making them fairly resistant to proteolysis by GI enzymes due to the structures of these amino acids14. Consequently, large, undigested peptides accumulate in the gut lumen following gluten consumption. In healthy individuals, these peptides are simply excreted, as the protein zonulin only allows certain macromolecules through the tight junctions (TJ) between enterocytes17. However, in CD patients, zonulin is overexpressed, facilitating the movement of gliadin peptides into the lamina propria18. This contributes to the activation of autoimmunity by inciting various immune pathways in the underlying tissues15.
Following passage into the lamina propria, the gliadin peptides interact with the enzyme tissue transglutaminase 2 (TG2)14. TG2 bears a high avidity for gliadin peptides and catalyzes the deamidation of neutral glutamine residues into negatively charged glutamates19. Since HLA-DQ2 and HLA-DQ8 complexes have a high affinity for negatively charged ligands, the deamidation increases gliadin-HLA-DQ2/8 binding and the efficiency of antigen presentation to T cells19. In this way, TG2 is pivotal in the pathogenesis of CD as it largely accounts for the immunogenic properties of gliadin peptides.
In the process of gliadin deamidation by TG2, APCs may uptake some of the TG2-gliadin complexes15. This causes the production of anti-gliadin antibodies as well as anti-TG2 autoantibodies by plasma cells15. While the role of these autoantibodies have yet to be verified, there are many postulates as to how they may further CD pathogenesis.
Firstly, using intestinal epithelial Caco-2 cell lines, Paolella et al. (2013) demonstrated that anti-TG2 autoantibodies interact with cell-surface TG2 enzymes to modify actin fibres20. These fibres are attached to TJ structural proteins and are polymerized in the zonulin pathway17. The activation of zonulin by gliadin peptides increases intestinal paracellular permeability, which is characteristic of CD17. Gliadin peptides in the gut lumen bind to the chemokine receptor CXCR3 on intestinal epithelial cells, contributing to the increased spacing between epithelial cells17. Anti-TG2 autoantibodies, through their alteration of actin fibres, compromise intestinal permeability even further20. Anti-TG2 autoantibodies may also contribute to the activation of TG220. In order for TG2 to function, the presence of calcium ions is required20. Paolella et al. (2013) also observed the autoantibodies recruiting calcium ions from the endoplasmic reticulum and mitochondria of the cell, allowing for increased TG2 activation20. Furthermore, anti-TG2 autoantibodies may significantly alter gut vasculature due to their tendency to deposit around mucosal blood vessels21. This inhibits angiogenesis, which may result in the characteristic disorganization of mucosal vasculature presented in CD21. These autoantibodies also promote increased blood vessel permeability to macromolecules and lymphocytes in vitro, allowing for immune cells to more readily reach the small intestine to stimulate an amplified immune response21. Lastly, anti-TG2 autoantibodies may act as APCs and present deamidated gliadin peptides to gliadin-specific T cells, greatly increasing the CD4+T cell response to gliadin15.
The gliadin/HLA-DQ2/8 complexes that are not taken up by plasma cells present gliadin molecules to naive CD4+ T cells by binding to their T cell receptors22. The activation of T cells initiates the production of cytokines leading to CD-associated symptoms15,22. For example, upregulation of interferon (IFN)-γ following T helper type 1 (Th1) cell activation results in low-grade inflammation and tissue damage, ultimately leading to villous atrophy23.
In addition to villous atrophy, mucosal inflammation is one of the most common characteristics associated with CD. Sjöberg et al. (2013) proposed that inflammation begins when there is a challenge at the mucosal lining by gliadin peptides24. The production of proinflammatory cytotoxic interleukin 17-A (IL-17A) results as IFN-γ activates intraepithelial IL-17-secreting CD8+ T (Tc17) cells. IFN-γ acts upon these Tc17 cells in an autocrine manner, prompting further differentiation into hyperactivated cytotoxic CD8+ T cells that are no longer antigen-specific24-26. IFN-γ produced by Th1 cells also acts in a paracrine manner on CD4+ Th17 cells to produce IL-17A24,27. Regulatory T (Treg) cells secrete the anti-inflammatory cytokine IL-10, which downregulates the effects of Th17 and Th1 cells. However, Sjöberg et al. (2013) further postulated that Tc17 and Tc1 cells are not susceptible to modulation by Treg cells24. IFN-γ production by Tc17 and Tc1 cells continues as well as IL-17A production by Tc17 cells, causing inflammation to persist24 (Figure 1). As mucosal inflammation is extremely prevalent in CD patients, the cytokines associated with inflammation have become promising therapeutic targets.
Figure 1: Proposed mechanism of mucosal inflammation.IFN-y activates IL-17 secreting Tc17 cells. Activation causes transformation into hyperactivated CD8+ lymphocytes and loss of antigen specificity. IFN-y produced by Th1 cells also stimulates production of the proinflammatory cytokine IL-17A. IL-10 production by Treg cells downregulates the effects of Th1 and Th17 cells but not those of Tc1 or Tc17, resulting in persistent mucosal inflammation.
The pathogenesis of CD results in self-amplifying loops that further intensify the symptoms of CD13, 23. Firstly, as TG2 is typically released in response to tissue damage, the intestinal degradation caused by IFN-γ stimulates an increased release of TG213. This results in increased gliadin deamidation and Th1 cell activation10. Secondly, it has been shown that IFN-γ upregulates the expression of HLA complexes28. Consequently, the cytokines released in the pathogenesis of CD cause further expression of the antigen-presenting complexes which contribute to autoimmune responses14,28. IFN-γ has also been associated with increased intestinal permeability, which complicates matters further as more gliadin peptides seep through the TJs29. Thus, increased IFN-γ secretion greatly amplifies gliadin-induced autoimmunity in CD patients13.
Gut Microbiota: Microbiota refers to the population of microorganisms that inhabit the human body. The microbiome has co-evolved with the human host over millennia and continues to do so. Commensal bacteria provide many benefits to the host. These benefits include, though are not limited to, aid in proper digestion, the production of nutrients, protection against pathogens, and regulation of immune function30. Pathogenic bacteria cause damage to the host, as their infectious nature can kill healthy cells and cause inflammation of healthy tissues, which impairs their function. The gut microbiome exists in a fine balance of eliminating pathogenic bacteria and conserving tolerance to healthy host tissues30. This homeostatic balance can be disrupted, which is referred to as dysbiosis. Dysbiosis leads to many complications that can manifest into clinical symptoms; for instance, pathogenic bacteria can facilitate the pathogenesis of autoimmune disorders, such as CD.
The GI tract is the most heavily colonized system in the body, acting as a host to over 35,000 different bacterial species31. The composition of bacteria varies between individuals, due to various factors, such as environment and diet32. Interestingly, it has been discovered that colonisation patterns are determined as early as birth. Individuals delivered through natural birth as opposed to caesarean sections have been shown to have significant variation in the composition of the gut flora. Typically, individuals delivered naturally tend to have a more diverse microbiome resembling that of their mother’s vaginal tract, compared to individuals delivered by caesarean section33.
The majority of these species are strict anaerobes. Two phyla of bacteria dominate in a healthy GI tract: Bacteroidetes and Firmicutes, although Proteobacteria, Verrucomicrobia, Actinobacteria, Fusobacteria, and Cyanobacteria are present in minor amounts30. The density and diversity of bacteria also varies within a host over the length of the GI tract; the colon is the most heavily colonized, while the proximal segments host significantly smaller bacterial populations31.
Bacteria can be classified by their structure into two domains: Gram-positive and Gram-negative bacteria. One criterion by which they are classified is by the component of the bacterial cell wall that acts as a ligand for toll-like receptors (TLR) on host immune cells. TLRs are pattern recognition receptors that recognize pathogen-associated molecular patterns. This is part of the innate immune system used to distinguish between commensal and pathogenic bacteria34. In Gram-positive bacteria, lipoteichoic acid binds to TLR-2 while in Gram-negative bacteria, lipopolysaccharide (LPS) binds to TLR-435. This is a significant distinction, as specific TLRs activate unique immune responses. In general, Gram-positive bacteria are regarded as commensal bacteria, while Gram-negative tend to be considered pathogenic. It is important to note that this is only a trend, with numerous exceptions. In CD, many strains of Gram-negative bacteria have been shown to cause an increase in the release of proinflammatory cytokines36.
Gut Microbiota and CD: A large body of research has focused on the role of the gut microbiota in a number of pathologies, including CD. This disease is prevalent in both children and adults, and studies characterizing the microbiota of both populations have been conducted. The sampling of an individual’s gut microbiota is achieved most commonly through the analysis of either fecal samples37,38 or biopsies of the small intestine39,40. By comparing bacterial samples collected from CD patients to those from healthy controls, Nadal et al. (2007) found that the ratio of Gram-negative to Gram-positive bacteria is significantly increased (p<0.05) in CD patients40. Bacterial colonies were analyzed using fluorescent in situ hybridization coupled with flow cytometry. The Gram-negative, bacterial genera found in abundance in CD were predominantly Bacteroides and Prevotella40. Gram-positive commensal bacteria, such as Bifidobacterium and Lactobacillus, were relatively less prominent in CD patients40. Most of these Gram-negative bacteria increase both inflammation and the permeability of the gut lining. Furthermore, with a long-term GFD treatment approach, the bacterial dysbiosis seen in CD patients normalized, primarily through a decrease in the number of Gram-negative bacteria41.
The epidemiological evidence suggesting the concomitance between intestinal microbiota dysbiosis and the occurrence of CD has prompted further research into the role of these bacteria in CD pathogenesis. The mucosal lining of the GI tract prevents direct contact between the intestinal epithelial cells and enteric microbes, and the lining creates sites for the adhesion of commensal bacteria36. Using intestinal biopsies and lectin immunochemistry, Forsberg et al. (2007) reported differences in the composition of the mucosal lining/glycocalyx in CD patients relative to healthy controls42. Ulex europaeus agglutinin I (UEAI) lectin binding caused intense mucus secretion from goblet cells and glycocalyx staining in CD patients, but not in controls. Increased UEAI indicates an increase in fucosylation as the lectin binds to glycoproteins and glycolipids containing alpha-linked fucose42. Another lectin, peanut agglutinin (PNA), showed staining of glycocalyx in controls, but not in CD patients. Decreased PNA indicates a decrease in galactosylation as PNA binds galactosyl (β-1,3) N-acetylgalactosamine42. In explaining these observations, one hypothesis is that CD pathogenesis is more likely to occur with a particular glycosylation pattern present in genetically predisposed individuals. Alternatively, it has also been suggested that alterations in the microbiota, characteristic of CD, lead to modifications in the glycosylation patterns and impair the role of the mucosal lining against CD42. This is hypothesized to be the cause of the Gram-negative bacterial dominance observed in CD patients. As a result, the proinflammatory effects of these bacteria become problematic due to inefficient regulation by Gram-positive bacteria in the gut, which would not cause harm to the host with a healthy microbiome.
The stimulation of TLR-4 on APCs by LPS ligands causes the release of proinflammatory cytokines characteristic of CD. This stimulation leads to the initiation of a signalling cascade, which will result in the activation of NF-κB transcription factor43. NF-κB, through MyD88 dependent and independent pathways, upregulates the expression of proinflammatory cytokines and type I interferons43. This is the method by which the Gram-negative enteric dominance observed in CD patients causes the release of specific proinflammatory cytokines. IL-1β, IL-6, IL-18 and TNF-α, are some which are responsible for the exacerbation of CD symptoms40.
Gram-negative bacteria have also been shown to significantly increase gut permeability, facilitating increased movement of immunogenic gliadin peptides into the gut lumen, amplifying the effects of CD pathogenesis. Specifically, with the presence of increased Gram-negative E. coli CBL2 and Shigella CBD8 strains, reduced levels of structural proteins in the TJ system contribute to additional entry of gliadin peptides into the lamina propria36.
In addition to their role in the zonulin pathway, Gram-negative bacteria have also been observed to affect cytokine secretion. In the presence of E. coli CBL2 and gliadin peptides, the production of monocyte chemoattractant protein-1 (MCP-1) and tissue inhibitor of metalloproteinase (TIMP-1) was reduced36. This was seen in contrast to the effect of Bifidobacterium bifidum IATA-ES2, which induced MCP-1 and TIMP-1 cytokine production. Both MCP-1 and TIMP-1 play a role in tissue protection; MCP-1 regulates the migration of monocytes and TIMP-1 specifically inhibits the effects of metalloproteinases induced by IFN-γ. MMP-12 and MMP-13 are metalloproteinases secreted by macrophages in the presence of IFN-γ which absorb and remodel the extracellular matrix of intestinal epithelial cells, resulting in villous atrophy and crypt hyperplasia44. With the inhibition of TIMP-1 and MCP-1, tissue damage in CD is induced36. Studies have confirmed that Gram-negative bacteria elicit increased production and activation of proinflammatory cytokines and increased intestinal permeability. Hence, research to date has established that Gram-negative bacteria interact with both immune and homeostatic mechanisms in the body at various points along the pathogenesis of CD to exacerbate CD symptoms such as inflammation.
Probiotics in the Treatment of CD: As previously discussed, small intestinal biopsies from CD patients demonstrate a higher proportion of Gram-negative to Gram-positive bacteria compared to healthy controls43. The gut microbiota dysbiosis observed in CD suggests a possible therapeutic role for probiotics. Probiotic treatment involves the introduction of commensal bacteria, which compete with pathogenic bacteria for adhesion sites and nutrients45. Moreover, probiotic bacteria produce antimicrobial compounds and enhance the host immune response by stimulating production of IgA and defensins45.
Bifidobacterium is one example of a Gram-positive bacterial genus that is found in reduced numbers in CD patients46. One particular strain, Bifidobacterium infantis 35624, was shown to improve symptoms of irritable bowel syndrome (IBS) such as cramping, abdominal pain, and diarrhea. Consequently, B. infantis was suggested to contribute to immune regulation due to the restored balance of proinflammatory and anti-inflammatory cytokines in IBS. As IBS and CD are both disorders of the gut, B. infantis was suggested to be a potential probiotic treatment for CD46. Furthermore, Smecuol et al. (2012) conducted a double-blind randomized study comparing B. infantis probiotic treatment to placebo in 22 CD patients, who consumed gluten-containing foods throughout the duration of the study47. Following three weeks of treatment, the probiotic group demonstrated reduced CD symptoms such as indigestion, constipation, and gastroesophageal reflux, in addition to reduced serum antibody levels (anti-TG2 IgA). While the differences between the probiotic and control groups were not statistically significant and the exact mechanism of action is not understood, B. infantis remains a promising candidate strain for the development of a CD probiotic treatment47.
Laparra and Sanz (2010) conducted an experiment that models gluten digestion and subsequent interaction with resident gut microbiota in the small intestine48. Commercial extracts of gliadin were subjected to in vitro GI digestion: pepsin at pH 3, pancreatin-bile at pH 6. The gluten digestions were inoculated with different strains of bacteria, including Bifidobacterium IATA-ES2. Afterwards, enzyme-linked immunosorbent assay (ELISA) was used to measure levels of proinflammatory markers, including NF-κB, TNF-ɑ, and IL-1β. As hypothesized, when the gluten digestions were exposed to B. bifidum IATA-ES2, production of proinflammatory markers was greatly decreased. Additionally, decreased permeability of the intestinal walls was also observed. Based on these observations, the authors hypothesized that the presence of Bifidobacterium modifies gluten peptide sequences in vitro to become less toxic48.
De Sousa Moraes et al. (2014) demonstrated that Bifidobacterium longum CECT 7347 achieves the same outcome as B. bifidum IATA-ES2 through a different mechanism that involves an increased anti-inflammatory response, as opposed to a decreased proinflammatory response49. Using a gliadin-induced enteropathy animal model (sensitized to IFN-γ and fed gliadin), administration of B. longum CECT 7347 decreased levels of TNF-ɑ and increased the induction of anti-inflammatory IL-10. Notably, post-administration, B. longum CECT 7347 improved gut barrier function by increasing villi width and enterocyte height49.
Another example of a bacterial strain that may alleviate intestinal damage in CD is Lactobacillus jensenii TL2937. Villena and Kitazawa (2014) studied porcine epithelial lymphocyte (PIE) cell lines and found that upon LPS challenge, PIE cells produced high amounts of proinflammatory cytokines such as IL-6, IL-8 and MCP-150. In contrast, PIE cells treated with L. jensenii TL2937 produced less IL-6 and IL-8. The authors hypothesized a mechanism of action whereby L. jensenii TL2937 activates TLR-2 on intestinal epithelial cells, which, in turn, upregulates negative TLR regulators in the TLR-4 pathway, specifically A20 protein, B-cell lymphoma 3-encoded protein (Bcl-3), and mitogen-activated protein kinase phosphatase-1 (MKP-1). TLR regulators determine whether TLR activation results in homeostatic or inflammatory responses. When the negative TLR regulators are increased, NF-κB and MAPK signalling is inhibited. A20 limits TNF-ɑ or LPS-induced NF-κB responses by interacting with the nucleotide-binding oligomerization domain-containing protein 2 (NOD-2) receptor, which recognizes peptidoglycan in Gram-positive and Gram-negative bacteria and initiates a subsequent immune reaction. Bcl-3 maintains NF-κB homodimers in a DNA-bound state, preventing the binding of active dimers to DNA and limiting the transcriptional upregulation of proinflammatory cytokines. Lastly, MKP-1 desensitizes cells to TLR ligands by inactivating the p38 signalling pathway in enterocytes. This inhibits proinflammatory mRNA expression. Overall, the inhibition of the NF-κB and MAPK signalling pathways decreases intestinal inflammation in CD50.
An emerging idea in the realm of probiotic treatments for CD is probiotic combinations. One example is VSL#3, a combination of 8 Gram-positive bacterial strains, including Bifidobacterium and Lactobacillus genera17. Typically, CD patients exhibit increased gut permeability through the zonulin pathway, whereby TJs are pulled apart. VSL#3 can directly hydrolyze gliadin peptides. While a single bacterial strain cannot contain all of the peptidases and other enzymes required for gluten digestion, various bacteria in combination are capable of cross-feeding, or hydrolyzing each other’s metabolites. Since VSL#3 reduces the number of gliadin peptides in the gut lumen, the production of zonulin decreases, thereby limiting the movement of TJs and decreasing gut permeability17. Considering that microbiota are able to modulate many factors such as mucosal inflammation, TJ permeability, and immunogenicity of gliadin peptides (Figure 2), they warrant continued research as a means of understanding and treating CD.
Figure 2: Role of the gut microbiota in CD pathogenesis and potential probiotic intervention. (1) TG2 causes deamidation of gliadin allowing for better HLA-DQ2/8 binding (2) APCs present gliadin to plasma cells, which produce anti-gliadin antibodies. (3) Plasma cells also produce anti-TG2 antibodies, which, along with binding of gliadin peptides to CXCR3, modulate tight junctions (TJs) via activation of zonulin, allowing gliadin to enter the lamina propria. (4) Gliadin is presented on HLA-DQ2 or HLA-DQ8 to CD4+T cells, which differentiate into Th1 cells to produce IFN-γ. (5) IFN-γ stimulates the production of IL-17A in Th17 and Tc1 cells, which cause mucosal inflammation. (6) T regulatory CD4+ cells produce anti-inflammatory IL-10 which reduces inflammatory cytokine secretion of Th1 and Th17. (7) IFN-γ causes mucosal inflammation, TJ modulation, and increased TG2 release. (8) IFN-γ also upregulates expression of HLA complexes. (9) Gram-negative bacteria lipopolysaccharide (LPS) binding to TLR-4 receptors on APCs causes the release of IL-1β, IL-6, IL-18 and TNF-α inflammatory cytokines. (10) Gram-negative bacteria (LPS) binding to TLR-4 receptors activate intestinal epithelial cells (IELs) to produce inflammatory cytokines IL-6 and IL-8, causing mucosal inflammation. (11) IFN-γ stimulates macrophages to produce metalloproteinases (MMP) which remodel the extracellular matrix, potentially leading to apoptosis. Gram-negative bacteria inhibit TIMP-1 whose role is to reduce MMP activity. Probiotic arrows (green) indicate potential points of intervention.
Conclusion: CD is an autoimmune enteropathy that is triggered upon gluten ingestion. It has been well-established that the specific outcomes of CD pathogenesis such as inflammation, crypt hyperplasia, and intestinal remodelling, are subject to modulation by specific gut bacteria. Probiotic strains have also demonstrated their ability to target various factors that contribute to CD pathogenesis such as membrane permeability, production of proinflammatory cytokines, and adherence to enteric lumen. To date, research has shown that the composition of the gut microbiome heavily impacts the ongoing cellular processes in the GI tract of CD patients, due to the characteristics of the bacterial species present. Therefore, gut microbiota dysbiosis is a significant driver in CD. However, it also presents an opportunity for treatment in the form of probiotics and probiotic combinations. Moving forward, additional research is needed to further understand and consolidate the relationship between the gut microbiome and CD.
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