Background

Background

Inflammatory Bowel Disease - Overview

The umbrella term “Inflammatory bowel disease” (IBD) includes a spectrum of chronic inflammatory disorders which recurrently affect the gastro-intestinal tract. Ulcerative colitis (UC) and Crohn’s disease (CD) are the two main clinically defined manifestations of IBD, each with distinctive clinical and pathological features (see Table 1) (1).

Table 1: Clinical and pathological features UC and CD
Disease UC CD
Mucosal inflammation non-transmural transmural
Location generally begins in the rectum and extends proximally to the colon entire gastrointestinal tract: from the oral cavity to the rectum
Inflammatory pattern continuous area patchy area
Clinical symptoms bloody diarrhea abdominal pain with weight loss
Co-morbidities musculoskeletal, dermatological, ocular, and hepatobiliary co-morbidities similar to those described in UC
Immune response atypical T helper cell (Th) 2 response mediated by secretion of IL-13 by natural killer T cell Th1 and Th17 cytokine profiles are dominant

 

 From Titz B et al., Int J Mol Sci 2018 19 2775 (1)

Figure 2. Pathomechanisms and selected biomarkers of IBD. The main pathogenesis-associated changes are shown for UC and CD. For both diseases, changes in gut microbiota, disruption of the epithelial barrier function, and chronic immune-activation are observed. Differences have also been reported, such as for immune-regulatory processes and epithelial effects. 

IBD Worldwide Prevalence and Incidence

A systematic review of population-based studies from 1990 to 2016 provides information on the incidence (the number of newly diagnosed cases in a population and given time period) and prevalence (the total number of cases in a population at a given time) of UC and CD around the world (2).

Europe and North America show the highest prevalence values worldwide, e.g., 505 and 286 UC subjects per 100’000 in Norway and USA, respectively and 322 and 319 CD subjects per 100’000 in Germany and Canada, respectively. While the incidence of IBD has stabilized in western countries, IBD has become a global disease with accelerating incidence in newly industrialized countries (2).

IBD Diagnosis 

Endoscopy constitutes the gold standard for the diagnosis and monitoring of IBD (3). The diagnosis is usually confirmed by biopsies on colonoscopy and complemented with the measurement of molecular biomarkers including fecal calprotectin, serum C-reactive protein (CRP), and serum antibody markers including autoantibodies and microbial and peptide antibodies (4,5). However, their low sensitivity and high variability limit the clinical efficacy (Supplementary Table S2. “IBD biomarker products” in Titz et al. (1)). Thus, there is a need to identify novel molecular biomarkers that could be assessed with less invasive methods, and could benefit IBD clinical management and treatment.

IBD and Microbiome

IBD comprises complex genetic disorders, with multiple contributing genes (6). However, not all subjects carrying mutations in those identified genes develop IBD. Indeed other components, such as diet and microbiota, seem to play a role in the etiology of the disease (7,8). The human microbiome composed of various microorganisms colonize different body sites, such as the gut, mouth, genitals, skin, and airways, and vary in compositions. The microbiome is recognized to play a positive role in host supporting the maintenance of homeostasis, by contributing in the metabolism of nutrients, detoxification, helping immunity, preventing the propagation of pathogenic microbes for examples (9,10). A balanced interaction of microbes with the host plays an important part in preserving health. The dynamics and function of the microbiota can be influenced by many host-related and environmental factors, such as age, gender, diet, and drugs. Dysbiosis, a disruption of this balance, is associated with skin and neurological disorders as well as many diseases such as immune-related diseases, metabolic diseases, inflammatory bowel disease (8).

The link between pathogenesis of IBD and the intestinal microbiota has been established in: (i) animal models of colitis showing that germ-free conditions prevent inflammation (11); (ii) human studies, showing that probiotics or surgical diversion of the fecal stream help the management of IBD and improve inflammation (12,13). Evidence also points out that microbiome dysbiosis may cause an inappropriate immune response that results in alteration of the intestinal epithelium barrier integrity. An increase of epithelial permeability allows further infiltration of microbial organisms that, in turn, provoke further immune responses (14).

The characterization of the microbiome relies on 16S or shotgun sequencing of metagenomes from fecal or intestine biopsy samples. Recent cross-sectional and longitudinal studies investigated microbiome changes in CD and/or UC compared to non-IBD using metagenomics sequencing data, and reported differences in composition and abundances between subjects suffering from IBD compared with non-IBD subjects (15-17).

The analysis of raw metagenomics data consists in converting sequence reads by clustering or mapping into relative abundances of operational taxomonic units (OTUs) which can be annotated with taxonomy ranks, pathways, or microbial genes. A plethora of approaches exists to analyze shotgun metagenomic sequencing data for taxonomy and pathway profiling (18). The taxonomic or pathway abundances matrix constitutes the starting point for downstream analyses, visualization, and interpretation (10), or possibly, for machine learning and the identification of discriminative metagenomics features and model predictive of IBD status (Figure 3). Our new sbv IMPROVER Challenge aims to explore this new avenue.

 

 

Modified from Poussin et al., Drug Discovery Today. 2018, 23(9), 1644 (18) 

Figure 3. Schematic view of possible analysis paths and methods used for metagenomics data processing and downstream computational evaluation.

 

 

References 

1. Titz, B., Gadaleta, R. M., Lo Sasso, G., Elamin, A., Ekroos, K., Ivanov, N. V., Peitsch, M. C., and Hoeng, J. (2018) Proteomics and Lipidomics in Inflammatory Bowel Disease Research: From Mechanistic Insights to Biomarker Identification. Int J Mol Sci 19

2. Ng, S. C., Shi, H. Y., Hamidi, N., Underwood, F. E., Tang, W., Benchimol, E. I., Panaccione, R., Ghosh, S., Wu, J. C. Y., Chan, F. K. L., Sung, J. J. Y., and Kaplan, G. G. (2017) Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. The Lancet 390, 2769-2778

3. Bernstein, C. N., Fried, M., Krabshuis, J. H., Cohen, H., Eliakim, R., Fedail, S., Gearry, R., Goh, K. L., Hamid, S., Khan, A. G., LeMair, A. W., Malfertheiner, Ouyang, Q., Rey, J. F., Sood, A., Steinwurz, F., Thomsen, O. O., Thomson, A., and Watermeyer, G. (2010) World Gastroenterology Organization Practice Guidelines for the Diagnosis and Management of IBD in 2010. Inflammatory Bowel Diseases 16, 112-124

4. Mitsuyama, K., Niwa, M., Takedatsu, H., Yamasaki, H., Kuwaki, K., Yoshioka, S., Yamauchi, R., Fukunaga, S., and Torimura, T. (2016) Antibody markers in the diagnosis of inflammatory bowel disease. World J Gastroenterol 22, 1304-1310

5. Takedatsu, H., Mitsuyama, K., Fukunaga, S., Yoshioka, S., Yamauchi, R., Mori, A., Yamasaki, H., Kuwaki, K., Sakisaka, H., Sakisaka, S., and Torimura, T. (2018) Diagnostic and clinical role of serum proteinase 3 antineutrophil cytoplasmic antibodies in inflammatory bowel disease. J Gastroenterol Hepatol

6. Bonen, D. K., and Cho, J. H. (2003) The genetics of inflammatory bowel disease. Gastroenterology 124, 521-536

7. Ananthakrishnan, A. N., Bernstein, C. N., Iliopoulos, D., Macpherson, A., Neurath, M. F., Ali, R. A. R., Vavricka, S. R., and Fiocchi, C. (2018) Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol 15, 39-49

8. Scotti, E., Boué, S., Lo Sasso, G., Zanetti, F., Belcastro, V., Poussin, C., Sierro, N., Battey, J., Gimalac, A., Ivanov, N. V., and Hoeng, J. (2017) Exploring the microbiome in health and disease: implications for toxicology Toxicoloy Research and Application 1

9. Koppel, N., Maini Rekdal, V., and Balskus, E. P. (2017) Chemical transformation of xenobiotics by the human gut microbiota. Science 356

10. Lloyd-Price, J., Abu-Ali, G., and Huttenhower, C. (2016) The healthy human microbiome. Genome medicine 8, 51

11. Powrie, F., and Leach, M. W. (1995) Genetic and spontaneous models of inflammatory bowel disease in rodents: evidence for abnormalities in mucosal immune regulation. Ther Immunol 2, 115-123

12. Ganji-Arjenaki, M., and Rafieian-Kopaei, M. (2018) Probiotics are a good choice in remission of inflammatory bowel diseases: A meta analysis and systematic review. J Cell Physiol 233, 2091-2103

13. Larson, D. W., and Pemberton, J. H. (2004) Current concepts and controversies in surgery for IBD. Gastroenterology 126, 1611-1619

14. Maloy, K. J., and Powrie, F. (2011) Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298-306

15. He, Q., Gao, Y., Jie, Z., Yu, X., Laursen, J. M., Xiao, L., Li, Y., Li, L., Zhang, F., Feng, Q., Li, X., Yu, J., Liu, C., Lan, P., Yan, T., Liu, X., Xu, X., Yang, H., Wang, J., Madsen, L., Brix, S., Wang, J., Kristiansen, K., and Jia, H. (2017) Two distinct metacommunities characterize the gut microbiota in Crohn's disease patients. Gigascience 6, 1-11

16. Santoru, M. L., Piras, C., Murgia, A., Palmas, V., Camboni, T., Liggi, S., Ibba, I., Lai, M. A., Orru, S., Blois, S., Loizedda, A. L., Griffin, J. L., Usai, P., Caboni, P., Atzori, L., and Manzin, A. (2017) Cross sectional evaluation of the gut-microbiome metabolome axis in an Italian cohort of IBD patients. Sci Rep 7, 9523

17. Schirmer, M., Franzosa, E. A., Lloyd-Price, J., McIver, L. J., Schwager, R., Poon, T. W., Ananthakrishnan, A. N., Andrews, E., Barron, G., Lake, K., Prasad, M., Sauk, J., Stevens, B., Wilson, R. G., Braun, J., Denson, L. A., Kugathasan, S., McGovern, D. P. B., Vlamakis, H., Xavier, R. J., and Huttenhower, C. (2018) Dynamics of metatranscription in the inflammatory bowel disease gut microbiome.Nat Microbiol 3, 337-346

18. Poussin, C., Sierro, N., Boue, S., Battey, J., Scotti, E., Belcastro, V., Peitsch, M. C., Ivanov, N. V., and Hoeng, J. (2018) Interrogating the microbiome: experimental and computational considerations in support of study reproducibility. Drug discovery today 23, 1644-1657

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