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• W4288077652 abstract "PREFACE My interest in the field of gastrointestinal microbiology started early in my medical career with a study of bacterial gastroenteritis that is included in this dissertation. Over time I have steadily become more involved in the search for new areas where microbiology and gastroenterology may be linked. During my PhD research in the exciting field of Helicobacter pylori infection, I realized that novelty can often be found in the areas lying between fixed sets of thought. No one believed the Australian doctors Warren and Marshall when they claimed that a gastric infection was the cause of gastroduodenal ulcers, but in the end their innovation and persistence managed to convince even the most doubtful scientist. It has certainly underscored that specific or consortia of microorganisms may very well cause, or at least play a central role in, many other chronic diseases such as inflammatory bowel diseases (IBD). Today it is not controversial to perform research trying to improve the dysbiosis linked to IBD using fecal microbiota transplantation (FMT), just as FMT has treated the dysbiosis linked to C. difficile infection. All of these areas are at the core of this dissertation. Hopefully, our research has been one small additional step in the journey leading to new and microbiome-based treatments of IBD, a disease in which we today can’t always find a medical cure, but instead must perform surgical removal of parts of the intestine. Finally, I would like to express my profound gratitude to my main collaborators: Professor Karen A. Krogfelt, Post Doc Hengameh Chloé Mirsepasi-Lauridsen and Post Doc Sofie Ingdam Halkjær with their manifold talents in networking, lab research and project managing. This gratitude is also directed to all my co-authors and all my colleagues in all professions who have helped and supported me along the way, and to my wonderful and adventurous family, Joe and Nicoline. Inflammatory bowel disease (IBD) is the umbrella term for chronic inflammatory diseases of the intestine often affecting children and young adults [1]. Diagnosis of IBD is based on a combination of history, physical and laboratory examination, esophagogastroduodenoscopy and ileocolonoscopy with histology, imaging of the small bowel and, importantly, absence of enteric infections [2]. Currently, IBD is divided into ulcerative colitis (UC) and Crohn's disease (CD) based on intestinal dissemination of the inflammation, in addition to macroscopic and histological features; UC affects the colon, starting from the anus extending in varying degrees into the colon, in some cases resulting in inflammation of the entire colon, defined as pan-colitis [3]. UC generally affects the superficial layers of the epithelium inducing crypt abscesses and subepithelial gathering of inflammatory cells [4]. In contrast, CD can affect any part of the intestine; however, in the majority of cases, inflammation will be found in the terminal ileum, the colon or both of these [5]. CD is associated with deeper penetrating inflammation, occasionally resulting in fistulizing disease and abscess formation [6]. Both UC and CD can, if medical therapy fail, lead to the need for surgery; among patients with CD, intestinal surgery is required for as many as 80%, and a permanent stoma is required in more than 10%. In patients with UC, the lesions usually remain superficial and extend proximally; colectomy is however still required for 10%–30% of patients [7]. It has been suggested that earlier introduction of immunosuppressants and biologics may be associated with a lower risk for surgery, even though data also suggest that a decrease in surgery rates had been achieved even before introduction of biologics [8-10]. Furthermore, the need for surgery has also increased in some cohorts even after introduction of anti-TNF and other biological treatments in IBD [11]. This implies that the introduction of new types of medical treatments, such as biologics, has not changed the need to search for new fundamentally different treatment options for IBD patients. Diagnosis of CD and UC do overlap. Sometimes the diagnosis will shift from UC to CD or from colonic CD to UC over time, and for some patients, the colonic inflammation will remain indeterminate [12]. The anticipation is, however, that IBD in the future will be categorized into additional subtypes taking into account the genetic, the immunological and the intestinal microbiome profile of the individual patient [13]. The pathogenic mechanisms of IBD have been researched intensely and in general, it is believed that genetic, immunological and environmental factors are involved simultaneously. It is, however, remarkable that the intestinal inflammation in IBD has a close macroscopic and microscopic resemblance to infectious diseases of the gut, such as intestinal tuberculosis (TB), cytomegalovirus (CMV) enteritis, Clostridioides difficile infection, campylobacteriosis and many more, and the differential diagnosis can sometimes be difficult [14]. What is even more intriguing is the fact that IBD often has a variation in manifestation in the individual patient over time, with shorter or longer periods with quiescent disease and other periods with a full flare occasionally resulting in the need for surgery [15]. Based on these observations it is of utmost importance also to investigate the causes of IBD flares. One likely event is the occurrence of a gastrointestinal (GI) infection triggering the onset of disease flares. In this respect, it is interesting that the debut of IBD is probably not associated with the most common GI infections such as Salmonella and Campylobacter infections [16]. Over time, many different bacteria (e.g., Mycobacterium avium subspecies paratuberculosis and Escherichia coli pathotypes), viruses (e.g., measles and CMV) and other microorganisms have been suspected to be the pathogenic cause of IBD, or at least to contribute to IBD flares [17]. It is by now well established that luminal factors in the intestine are involved in the inflammatory process of CD and UC. One often referred example is that the diversion of the continuity of the intestines results in healing of the resting gut, whereas the inflammation will return when continuity is reestablished [18]. Furthermore, animal IBD models have documented the importance of the presence of bacteria in the inflammatory process [19]. Numerous experiments involving animal colitis models, such as IL-10 knock-out mice, have shown that these mice will develop fulminant colitis living under normal conditions, whereas they will be disease-free living in germ-free surroundings [20]. Moreover, it has been demonstrated that probiotics will reduce the inflammatory damage of the intestine in, e.g., IL-10 knock-out mice [21, 22]. But without convincing discoveries of the involvement of specific microorganisms in IBD, and acknowledging the fact that immune regulatory medications often have the ability to cure flares of these diseases, CD and UC have for a long time been perceived as immunological diseases with elements of autoimmunity [23]. In this context it is important to underline that the most frequently used medications in IBD are immunomodulators; the medications used to induce remission include 5-aminosalicylic acid products, steroids and tumor necrosis factor (TNF), α4β7 integrin or JAK kinase inhibitors and medications used to maintain remission include 5-aminosalicylic acid products, immunomodulators (Azathioprine, 6-mercaptopurine, methotrexate) and TNF-, α4β7 integrin or JAK kinase inhibitors [24, 25]. Genetic studies have, however, revealed that the mutations associated with IBD (currently 163 IBD-specific loci) are frequently linked to the intestinal immunogenic defense against microorganisms [26]. This has caused the pendulum to swing back from the assumption of IBD as mainly autoimmune diseases towards a greater appreciation of a contribution from the intestinal microbiome [27]. Many of the IBD-associated genetic mutations result in inefficient innate immune responses, e.g., malfunctioning defensins, and defective phagocytic processing of bacteria [27]. Importantly, the early finding of a defect in the caspase recruitment domain family, member 15 (NOD2/CARD15) gene among CD patients, has reawakened the search for specific involved pathogens [28]. NOD2/CARD15 is involved in the innate immune system including the production of defensins; therefore, defects in this gene could imply that the host is more susceptible to gastrointestinal infections [29]. It has, furthermore, been shown that the number of viable internalized Salmonella typhimurium in Caco-2 cells was higher when the Caco-2 cells were transfected with a variant CARD15/NOD2 expression plasmid associated with Crohn's disease [30]. Even though genetic mutations affecting the immune system do not seem to account for all IBD cases, these interesting results created a bridge upon which the immunological and the microbiological believers could meet, regarding the major contributing factors to the pathogenicity of IBD. Therefore, current theories describe IBD as a result of an unfortunate interplay between immunity (based on possible faults in the immunological maturation and in genetics) and specific perturbations in the composition of the intestinal microbiome, the so-called intestinal dysbiosis [31]. This will in the near future, probably lead to new definitions of IBD, with subtypes being primarily based on genetics, subtypes based primarily on immunological dysfunctions, and the possibility that certain subtypes will be explained to a large degree by imbalances in the intestinal microbiome, as illustrated in Figure 1. Diagnostically it is occasionally difficult to separate acute infectious gastroenteritis (AG) from a debut or a flare of IBD [32]. An initial flare of IBD will often be misdiagnosed as a case of AG, and a more prolonged episode of AG could easily be mistaken for IBD [14]. The core symptoms are similar; frequent stools, occasionally blood in stools, abdominal pain, fever, weight loss and sometimes extraintestinal complications such as reactive/inflammatory arthritis. Even endoscopic appearances are sometimes indistinguishable, with hyperemia, edema, submucosal bleeding and ulcers. Some gastrointestinal infections, such as C. difficile infection, intestinal tuberculosis, Giardia, CMV colitis, can furthermore be chronic, or the symptomatology can be prolonged by post-infectious irritable bowel syndrome after an episode of AG [33]. C. difficile has, furthermore, frequently been found in stools of patients with IBD even during quiescent disease [34]. In some countries, e.g., India, intestinal tuberculosis is a very relevant alternative diagnosis to IBD in patients with intestinal inflammation and chronic intestinal ulcers [35]. Therefore, stool sampling and intestinal biopsies with culture/PCR diagnostics for enteropathogens will often be necessary during both initial diagnosis and continuous follow-up of IBD patients. Based on an increase in the number of zoonotic Salmonella infections in Denmark in the 1990s, from a previous level of 500–1000 cases a year to more than 4000 cases a year, we reviewed, retrospectively, the outcome and the symptomatology in patients admitted with more common bacterial gastrointestinal infections such a Salmonellosis, Campylobacteriosis and Yersiniosis, Paper I. Overall Salmonella infection was associated with the highest rate of admission of patients (44%) compared with the other bacterial causes of gastroenteritis, suggesting a more severe disease course during infection with Salmonella spp. However, blood in stools was most frequent in patients infected with Campylobacter, Table 1, Paper I. In general, both Campylobacter and Salmonella infections have been linked to IBD. A search on ‘Salmonella’ and ‘Inflammatory Bowel Disease’ resulted in 406 articles, and a search on ‘Campylobacter’ and ‘Inflammatory Bowel Disease’ resulted in 283 articles, date 17-08-2020. Increased risk of IBD has been described after clinical gastroenteritis especially caused by Salmonella species, Campylobacter species and Clostridioides difficile without any particular difference in odds ratio (OR) for IBD between these microorganisms [36, 37]. However, it has been found in an epidemiological study that also a negative stool sample for enteropathogens was associated with a subsequent diagnosis of IBD. This indicates that a patient with IBD with a concomitant Salmonella, Campylobacter or C. difficile infection probably has a higher risk of a positive stool sample simply because of more frequent submission of stool samples from IBD patients compared to patients with acute gastroenteritis alone [16]. Historically, it seemed necessary to make at least three stool cultures to secure a bacteriologic diagnosis based on the culture of fecal samples in patients with longer disease duration, Paper I. This could presumably have affected the ability to associate IBD with gastrointestinal microorganisms. Currently, diagnosis of GI infection has in many clinical microbiology departments shifted to PCR-based methods with new possibilities for the diagnosis of GI infections, with higher sensitivity and specificity. These diagnostic changes might again affect the frequencies of how often a link will be found between acute GI infections and flares of IBD. Another link between AG and IBD is reactive arthritis linked to AG and inflammatory arthropathy linked to IBD. Reactive arthritis occurred in 4.8% of our cohort of patients with AG, Paper I, compared with a frequency of up to 30% of patients with IBD having some form of inflammatory arthropathy [38]. However, the frequencies in IBD are naturally reported for a much longer disease period compared to patients with AG. It is possible that a common pathogenetic mechanism exists in reactive arthritis and inflammatory arthropathy giving rise to further difficulties when trying to separate AG and IBD diagnostically. Gastrointestinal infections, other than Salmonella, Campylobacter or Yersinia, are, however, even more likely to be a possible differential diagnosis to IBD or to complicate the course of IBD. In many parts of the world where tuberculosis is common, it will be crucial to exclude that a suspected case of IBD is not in fact a case of intestinal tuberculosis. To exclude tuberculosis among IBD patients has now become increasingly important in all parts of the world, since treatment of IBD with TNF-α inhibitors will increase the risk of reactivating a concomitant tuberculosis infection [39]. IBD and intestinal tuberculosis are very similar in symptoms and findings such as weight loss, malabsorption, diarrhea, blood in stools, abdominal pain and even in macroscopic appearance during endoscopy, with CD and intestinal tuberculosis both causing chronic intestinal inflammation with the risk of stenotic behavior and deep ulcerations in the intestinal wall [35]. Furthermore, C. difficile infection can complicate IBD and raise doubts about the right treatment approach; should gastroenterologists in these cases choose metronidazole, vancomycin and/or increased doses of anti-inflammatory medications [40]? In clinical practice, a case of C. difficile infection during a flare of IBD will often result in both antibiotic and anti-inflammatory treatment. Especially diagnostically difficult are cases of CMV colitis, which are often directly caused by the immunosuppressive treatment given to IBD patients [41]. This makes it important to look for and treat a possible CMV infection when initial beneficial treatment of IBD such as high-dose prednisolone suddenly fails. An additional problem is emerging infections; e.g., Shiga toxin-producing E. coli infection (STEC) can cause hemorrhagic colitis, which has been confused with flares of IBD [42]. Bacterial gastroenteritis requiring hospitalization affects mainly children < 5 years [43]; likewise IBD affecting young children has been associated with a more severe disease course [44]. So even without evidence for a direct link between intestinal dysbiosis or specific enteropathogens in IBD pathogenesis, intestinal infectious complications to IBD are an ever-present consideration for clinicians. So, thorough initial microbiological examinations are diagnostically important, as are frequent re-evaluations during IBD treatment courses. This all rests on the diagnostic approach in the clinical and supporting para-clinical departments, and the following question must always be considered when anti-inflammatory treatments fail: Is the current anti-inflammatory treatment failing, requiring treatment replacement with other more intensive anti-inflammatory treatments or surgical intervention, or is a more intensive search for complicating gastrointestinal infectious diseases necessary? The intestinal microbiome, which refers to the microorganisms (gut microbiota), their genomes and the local environment in the human intestine, contains approximately 100 times as many genes as the human genome [45]. Even though an imbalance in the intestinal microbial communities, also referred to as intestinal dysbiosis, is associated with flares of IBD, the exact nature of the involvement of the dysbiotic microbiome in IBD pathogenesis is not fully understood. Furthermore, the IBD-associated intestinal dysbiosis could be driven by the disease through a substrate effect of an inflamed and possibly bleeding mucosa or through effects of IBD medications on the microbiome. In a recent systematic review, a notable impact was found of non-antibiotic prescription drugs on the overall architecture of the intestinal microbiome, e.g., Proton Pump Inhibitors, metformin, NSAIDs, opioids and antipsychotics were associated with increases in members of Proteobacteria (including E. coli) or members of Enterococcaceae [46]. In addition, it has been shown that nitrate generated by the intestinal inflammatory response conferred a growth advantage to E. coli possibly contributing to the dysbiosis associated with IBD [47]. It has, however, also been demonstrated that introduction of IBD dysbiotic communities can stimulate intestinal inflammation in mouse models, even though, it is still not verified whether a healthy intestinal microbiome can be sufficient to prevent the induction of IBD flares [48]. A direct effect of the IBD-associated microbiome on IBD pathogenesis could be due to one of the three following mechanisms: (1) the diseased intestine with epithelial damages and ulcers will be a natural transmission zone for the intestinal microbiome at random, resulting in possible bacteremia, and micro or macroabscess formation; (2) a dysbiotic microbiome could represent microorganisms, which are involved in epithelial destruction (through induction of barrier defects in mucus and/or epithelial cells) and damages to the immune system in the genetically susceptible individual; (3) or, specific emerging pathogens such as e. g. Mycobacteria avium subspecies paratuberculosis and E. coli pathotypes could be the underlying cause of IBD, even in non-genetically susceptible individuals, Table 2. That microorganisms could be involved in IBD pathogenesis, is supported by several meta-analyses of the effect of antibiotics in IBD, which all concluded that there was a positive effect of antibiotic treatment during flares of IBD [49-51]. It has been documented that IBD and flares of IBD are linked to reproducible changes in the gut microbiome based on gut bacteria classification studies [52]. The IBD-associated dysbiosis (not unlike changes found in other diseases such as C. difficile infection, irritable bowel syndrome (IBS), cancer, liver diseases and metabolic syndrome) is characterized by a low diversity microbiome with reduced presence of anaerobes, often found in high numbers in healthy individuals, and an increase in facultative anaerobes [53]. These data provide evidence of a shift in the balance between the bacterial phylae, including depletion of Firmicutes subtypes (such as Faecalibacterium pranusnitzii) and Bacteroidetes [54-56]. Furthermore, the increased presence of Proteobacteria (including the family Enterobacteriaceae) has frequently been described [56-58]. In addition, specific changes in bacteria, viruses and parasites at the species level have been documented, which further have added evidence to the assumption that IBD is linked to a changed/dysbiotic intestinal microbiome. Among the many studied microorganisms, a decrease in the bacterial populations Clostridium leptum group (IV), Roseburia hominis and F. prausnitzii [59, 60] and Lachnospiraceae [61] have been described in IBD patients compared with controls, illustrating the many microbiological studies that are available, Table 3. These shifts in microbial communities, e.g., lower levels of Roseburia hominis and F. prausnitzii, have also been associated with low levels of the short-chain fatty acid (SCFA) butyrate, which is mainly produced from complex sugars by anaerobic bacteria in the colon. Butyrate is an important energy source for the maintenance of a normal colonic epithelium [63], and butyrate has more direct anti-inflammatory properties [64]. Both consequences of the shortage of butyrate could be central in IBD pathogenesis. In addition, the consumption of butyrate by colonic epithelial cells provides a hypoxic environment in the colon [65], which is related to a disadvantage of colonization with facultative anaerobic bacteria such as Salmonella [66]. Interestingly, the sustained response of pediatric CD patients to TNF-α inhibitors was associated with abundance of SCFA-producing bacteria [67]. As another example of dysbiosis-related consequences for the intestinal inflammation seen in IBD, Akkermansia has been found to be decreased in UC, and this could be especially interesting due to an anti-inflammatory effect of Akkermansia-derived vesicles [68]. Parts of the phyla Actinobacteria have been found to convert bile acids, related to a reduced inflammatory response in the colon [69]. This may also play a role in IBD, since these strains have also been found to be decreased in IBD compared with controls [70]. Many of the studies of changes in microbiome structure have so far focused largely on bacterial species; however, microbiome changes in IBD do include other enteric microorganisms. Findings from our own study regarding the presence of the intestinal parasites Blastocystis hominis and Dientamoeba fragilis, likewise, found a change of presence, in this case, a decrease of these microorganisms among patients with IBD compared with controls, Paper II, Table 4. In addition, a significant difference in D. fragilis colonization was found between inactive and active UC, 33% and 5%, respectively, (p < 0.05). Likewise, Blastocystis was found primarily in inactive UC, (p < 0.01), Table 4, Paper II. Similar results have been found in a study from 2010, where Blastocystis was detected in 33% (2/6) of IBD patients compared with 76% (16/21) of IBS patients [71]. These findings could be in accordance with the hygiene theory, which proposes that the microbial challenges to the intestinal immune system are limited in the western parts of the world, and that a continuous microbial challenge is necessary to remain healthy [72]. In this context, it has been speculated that the increased prevalence of IBD could be associated with the decreased prevalence of intestinal helminths, when the distribution of these diseases is compared on a global scale [73]. Furthermore, ingestion of helminths, such as Trichuris suis ova, has been evaluated as treatment against flares of IBD, although no final conclusion can be made regarding the efficiency of this treatment [74, 75]. These data underline the extremely complex nature of the human intestinal microbiome and the possible links to health and disease of a general intestinal low diversity dysbiosis. An obvious strategy is to demonstrate that restoring a healthy high diversity microbiome can prevent the induction of or cure intestinal disorders such as IBD. As demonstrated in our recently published study, Paper III, it is not evident that simply restoring a reduced diversity microbiome with a high diversity microbiome will cure all intestinal dysbiosis-related illnesses. In our placebo-controlled study of fecal microbiota transplant (FMT) treatment of patients with IBS, we found that FMT capsules based on a mixture of fecal donor material from 4 healthy donors increased the diversity of the gut microbiome significantly in IBS patients treated with FMT compared to IBS patients treated with placebo, Figure 2. Furthermore, it was shown that bacteria originating from the donors were established in the recipients for at least six months. But surprisingly, patients in the placebo group experienced greater symptom relief compared with the FMT group after 3 months. In this context, it is interesting that low-grade inflammation is described both in IBS and in quiescent IBD [76], and that paracellular permeability was significantly increased in both quiescent IBD with IBS-like symptoms and IBS compared with quiescent IBD without IBS-like symptoms [77]. Proteobacteria and Bacteroides have been shown to be increased in patients with IBS compared with controls, whereas uncultured Clostridiales, Faecalibacterium prausnitzii and Bifidobacterium were decreased in patients with IBS [78]. Similar microbiome changes are also seen when comparing IBD patients to healthy controls as already described. It is, however, important to note that FMT has shown promise as a possible treatment of active UC. In a meta-analysis by Costello et al. [79] including 4 placebo-controlled trials of FMT for UC, it was reported that clinical remission was achieved in 39 of 140 (28%) patients in the FMT groups compared with 13 of 137 (9%) patients in the placebo groups. In FMT-treated UC patients, microbial diversity increased with and persisted after FMT [80], similarly to what we have shown in FMT-treated IBS patients, Paper III. Interestingly, stool of donors with a high bacterial richness and a high relative abundance of Akkermansia muciniphila, unclassified Ruminococcaceae and Ruminococcus spp. have been found to be more likely to induce remission in UC [81]. Importantly, it is evident that in the future the use of more advanced sequencing techniques will provide further knowledge regarding the involvement and function of the intestinal microbiome in IBD pathogenesis. 16 S rRNA sequencing mainly provides us with knowledge of involved bacteria. Unquestionably more data on metagenomic, metabolomic and proteomic profiles of IBD patients (with and without flares) and controls will be able to further elucidate IBD pathogenesis, both regarding the involvement of other microorganisms than bacteria and the immunological regulation performed by the IBD-related dysbiosis, but these data are limited [62]. In this light, it does seem reasonable that individual microorganisms with a possible pathogenic potential have been subject to an increased number of studies within the field of IBD research. Specifically, the low diversity dysbiosis linked to IBD includes an expansion of facultative anaerobes of the Enterobacteriaceae family (Proteobacteria) [82], increased Proteobacteria abundance has been found associated with both UC patients with an ileal-pouch anal anastomosis after a colectomy and a history of pouchitis, Paper IV, Figure 3 and Crohn's disease patients with an aggressive disease course, [83]. Increased abundance of Proteobacteria was in our study not associated with acute pouch inflammation in patients with a history of pouchitis, Paper IV, whereas the abundance of Fusobacteria was. In a recent paper, fecal metagenomics showed an increased abundance of Proteobacteria and Fusobacteria to be linked to future relapse in patients with IBD [84]. Escherichia coli has been found in increased numbers in fecal and mucosal samples in patients with both UC and CD suggesting a possible involvement of E. coli in both diseases [85]. In a recent review of gut microbiome differences between IBD patients and controls, Proteobacteria was, at the phylum level, highlighted as possibly associated with both UC and CD. Interestingly, of all potentially harmful bacteria associated with IBD, increased E. coli was found to be the most consistent finding [86]. IBD patients had compared with controls enrichment of bacterial virulence factors linked to E. coli [87] and the treatment naïve microbiome in newly onset IBD is especially enriched in E. coli [88]. A recent paper using metagenomics and studies of co-abundance of species, again confirmed the association of a high level of E. coli with IBD [89]. Most studies do not examine the microbiome differences at the strain level, so there is still a lack of studies thoroughly determining if the increased presence of E. coli in IBD patients is due to colonization with especially virulent or commensal strains. These factors highlight that the search for a possible link between emerging enteropathogenic Escherichia coli (pathobionts) and IBD, as described in the following, is of major importance. Even though E. coli does not constitute the major part of the intestinal microbiome, E. coli has the capacity to be both a peaceful commensal and a pathogen with links to a wide range of human infectious diseases. All depend on the virulence genes associated with the colonizing E. coli strain. E. coli is part of the intestinal microbiome in over 90% of humans, and even though E. coli strains are outnumbered by anaerobic bacteria, they do constitute the predominant aerobic microorganism in the human intestine. Furthermore, E. coli strains are some of the earliest colonizers of a child's intestine just after birth [90]. Most frequently these E. coli are commensal, harmless symbionts [91], natural inhabitants" @default.
• W4288077652 created "2022-07-28" @default.
• W4288077652 creator A5036519887 @default.
• W4288077652 date "2022-07-27" @default.
• W4288077652 modified "2023-09-27" @default.
• W4288077652 title "Gastrointestinal dysbiosis and <i>Escherichia coli</i> pathobionts in inflammatory bowel diseases" @default.
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