Annotated Bibliography

1932-1950            

Crohn, B.B., Ginzburg, L., Oppenheimer, G.D., 1932. Regional Ileitis: A Pathological and Clinical Entity. JAMA 99, 1323–1329. https://doi.org/10.1001/jama.1932.02740680019005

  • The first paper describing Crohn’s disease (CD) refers to the condition as regional ileitis and differentiates it from ulcerative colitis and other bowel diseases. The authors describe the clinical manifestations of this disease, anatomical/physical differences in affected colons, the clinical progression of the disease, and possible treatment, which is only “palliative and supportive” at this stage (Crohn, Ginzburg, and Oppenheimer, 1932).

Hadfield, G., 1939. The Primary Histological Lesion of Regional Ileitis. The Lancet 234, Issue 6058, 773–776. https://doi.org/10.1016/S0140-6736(00)62866-0

  • Hadfield’s paper is perhaps the second most impactful paper after Crohns’ original report. In this article, he describes in great detail the histological features of the colon inflicted by Crohn’s disease and compares the appearances with other inflammatory diseases, like Boeck’s scarcoidosis. He reports the thickening of submucosa, the development of ulcers and lesions, the impact of the disease on lymphoid tissue, and the absence of acid-fast bacilli, which is notable because a potential cause of CD was thought to be tuberculosis (Hadfield, 1939).

Warren, S., Sommers, S.C., 1948. Cicatrizing Enteritis (Regional Ileitis) as a Pathologic Entity. Am J Pathol 24, 475–501. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942793/

  • Warren and Sommers describe the pathological and histological features of cicatrizing enteritis, i.e. regional ileitis/Crohn’s disease, and explain the three phases of the disease: acute, subacute, and chronic. They explain how differentiating between cicatrizing enteritis and other diseases, particularly intestinal tuberculosis, can be quite difficult because the differences often lie at the cellular level, which is not easily seen by the naked eye. The cause of this disease remains unknown at this point, although bacterial infection or involvement is suspected (Warren and Sommers, 1948).

1951-1970

Lockhart-Mummery, H.E., Morson, B.C., 1960. Crohn’s Disease (Regional Enteritis) of the Large Intestine and its Distinction from Ulcerative Colitis. Gut 1, 87–105. https://www.ncbi.nlm.nih.gov/pubmed/?term=PMC1413217  

  • As is the case with early papers of Crohn’s disease, Lockhart-Mummery and Morson describe the pathology of the condition using an analysis of 25 cases.  They examine the differences between Crohn’s disease and chronic ulcerative colitis, which include continuity of mucosal abnormalities, depth of inflammation, cause of submucosal thickening, and presence of giant-cells granuloma (in Crohn’s disease only). Their findings were notable due to the attempt at distinguishing between CD and ulcerative colitis, which are quite similar but rarely present simultaneously in the same patient, and their meticulous and comprehensive description (Lockhart-Mummery and Morson, 1960).

Williams, W.J., 1964. Histology of Crohn’s syndrome. Gut 5, 510–516. https://doi.org/10.1136/gut.5.6.510

  • Besides describing the histological characteristics of colons inflicted by Crohn’s disease, which can be grouped into three categories of inflammation (non-specific – present in all cases, diffuse granulomatous, and focal granulomatous inflammation), Williams draws a distinction between the use of ‘Crohn’s syndrome’ (preferred) and ‘Crohn’s disease’ because the cause is still unclear (Williams, 1964).

Schmidt, G.T., Lennard-Jones, J.E., Morson, B.C., Young, A.C., 1968. Crohn’s disease of the colon and its distinction from diverticulitis. Gut 9, 7–16.
http://dx.doi.org/10.1136/gut.9.1.7 h  

  • It can often be difficult to distinguish between Crohn’s disease and other conditions of the gastrointestinal tract. This paper highlighted several differences between simple diverticulitis and diverticulitis with Crohn’s disease; patients with Crohn’s have a higher incidence of bleeding, anal lesions, and abnormal sigmoidoscopies. As has been the case with many articles, granulomatous tissue is a diagnostic factor of CD (Schmidt et al., 1968).

Mitchell, D.N., Rees, R.J., 1970. Agent transmissible from Crohn’s disease tissue. Lancet 2, 168–171.
https://doi.org/10.1016/S0140-6736(70)92532-8

  • Mitchell and Reese were among the first to conduct a scientific experiment investigating the etiology of Crohn’s disease. Homogenates isolated from patients with Crohn’s disease were inoculated into the footpads of normal and immune-deficient mice. Compared to the control group, mice in both groups exposed to Crohn’s disease tissue developed similar histological characteristics (giant-cell granulomas) as is present in humans affected by the disease, suggesting that the agent(s) that contribute to the onset of Crohn’s is/are transmissible (Mitchell and Rees, 1970).

1971-1990

Shorter, R.G., Huizenga, K.A., Spencer, R.J., 1972. A working hypothesis for the etiology and pathogenesis of nonspecific inflammatory bowel disease. Am J Dig Dis 17, 1024–1032.
https://doi.org/10.1007/BF02239143

  • Shorter, Huizenga, and Spencer formulate a hypothesis of the etiology of nonspecific inflammatory bowel diseases (IBDs), including Crohn’s disease, that rests on the idea that the body becomes hypersensitive to antigens present in bacteria that normally inhabit the GI tract, which produces an inappropriate immune response. They propose several factors that may influence the chronicity of nonspecific IBDs, including the repeated immune stimulation from normal bacterial antigens. This was among the first papers to formally connect immune function and IBDs (Shorter, Huizenga, and Spencer, 1972).   

Greenstein, A.J., Janowitz, H.D., Sachar, D.B., 1976. The extra-intestinal complications of Crohn’s disease and ulcerative colitis: a study of 700 patients. Medicine (Baltimore) 55, 401–412. https://www.ncbi.nlm.nih.gov/pubmed/957999 

  • This study groups complications of Crohn’s into 3 groups: A, associated with active inflammation, B, associated with disruptions in small bowel function, and C, non-specific issues like osteoporosis and liver disease. Incidence of complications were compared to respective incidences in patients with ulcerative colitis, furthering the distinction between the two IBDs (Greenstein, Janowitz, and Sachar, 1976).

Chiodini, R.J., Van Kruiningen, H.J., Merkal, R.S., Thayer, W.R., Coutu, J.A., 1984. Characteristics of an unclassified Mycobacterium species isolated from patients with Crohn’s disease. J Clin Microbiol 20, 966–971. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC271485/

  • Chiodini, et.al identified and characterized mycobacteria in isolates of patients with Crohn’s disease, a species of bacteria that was previously thought not to impact the onset of Crohn’s because it was never found in isolates. The authors later conducted studies showing that granulomas form in goats when inoculated with the Mycobacterium species, suggesting a causative role in at least some cases of CD (Chiodini et al., 1984).

Küster, W., Pascoe, L., Purrmann, J., Funk, S., Majewski, F., Opitz, J.M., Reynolds, J.F., 1989. The genetics of Crohn disease: Complex segregation analysis of a family study with 265 patients with Crohn disease and 5,387 relatives. American Journal of Medical Genetics 32, 105–108. https://doi.org/10.1002/ajmg.1320320122

  • The results of this genetic study show that a recessive gene increases susceptibility of Crohn’s disease, furthering understanding of the underlying causes of CD (Küster et al., 1989).

1991-2000

Gilberts, E.C., Greenstein, A.J., Katsel, P., Harpaz, N., Greenstein, R.J., 1994. Molecular evidence for two forms of Crohn disease. Proc. Natl. Acad. Sci. U.S.A. 91, 12721–12724. https://doi.org/10.1073/pnas.91.26.12721

  • Researchers analyzed mRNA levels of several cytokines, including IL-1β and TNF- α, in tissue samples of patients with perforating or non-perforating Crohn’s disease. Compared to the control group, expression of several cytokines were distinct between the two forms, suggesting that the form, and therefore severity, of Crohn’s is influenced by the host immune response (Gilberts et al., 1994).

Satsangi, J., Farrant, J.M., Jewell, D.P., Bell, J.I., Welsh, K.I., Bunce, M., Julier, C., 1996. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. The Lancet 347, 1212–1217. https://doi.org/10.1016/S0140-6736(96)90734-5

  • This genetic analysis of 74 families suggests that ulcerative colitis and Crohn’s disease do not share the same genetic etiology (genetic heterogeneity) and that the human leukocyte antigen (HLA) genes are only weakly involved in the pathogenesis of Crohn’s, which slightly contrasts with previous findings (Satsangi et al., 1996). 

Targan, S.R., Hanauer, S.B., van Deventer, S.J.H., Mayer, L., Present, D.H., Braakman, T., DeWoody, K.L., Schaible, T.F., Rutgeerts, P.J., 1997. A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor α for Crohn’s Disease. New England Journal of Medicine 337, 1029–1036. https://doi.org/10.1056/NEJM199710093371502

  • Chimeric monoclonal antibody cA2, which acts against tumor necrosis factor TNF-α, was found to decrease the severity of Crohn’s disease in 81% of patients in a clinical trial involving 108 patients. This trial greatly impacted treatment options for those with Crohn’s disease (Targan et al., 1997).

2001-2010

Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cézard, J.-P., Belaiche, J., Almer, S., Tysk, C., O’Morain, C.A., Gassull, M., Binder, V., Finkel, Y., Cortot, A., Modigliani, R., Laurent-Puig, P., Gower-Rousseau, C., Macry, J., Colombel, J.-F., Sahbatou, M., Thomas, G., 2001. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411, 599–603. https://doi.org/10.1038/35079107

  • Variants of NOD2 (nucleotide-oligomerization domain 2), an apoptosis regulator, that change the leucine-rich repeat (LRR) domain of the protein increase susceptibility to Crohn’s disease. The identification and analysis of these variants suggests that the condition is inherited in a recessive manner, as do other studies, and is consistent with the theory that NF-kβ pathway dysregulation is involved in CD. This was among one of the first papers to associate NOD2 with CD  (Hugot et al., 2001).

Ogura, Y., Bonen, D.K., Inohara, N., Nicolae, D.L., Chen, F.F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R.H., Achkar, J.-P., Brant, S.R., Bayless, T.M., Kirschner, B.S., Hanauer, S.B., Nuñez, G., Cho, J.H., 2001. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411, 603–606. https://doi.org/10.1038/35079114

  • This study demonstrates that a frameshift mutation in a leucine-rich repeat region of NOD2, a protein in the NF- kβ pathway, is associated with Crohn’s disease. In HEK293T cells, NF- kβ pathway activation via NOD2, a mechanism of innate immunity, was reduced in cells with mutant NOD2 (Ogura et al., 2001).

Filip, B., Maja, N., Severine, V., Gert, V.A., Geert, D.H., An, C., Paul, R., 2003. Influence of Immunogenicity on the Long-Term Efficacy of Infliximab in Crohn’s Disease. The New England Journal of Medicine 8. https://doi.org/10.1056/NEJMoa020888

  • Efficacy of Infliximab, a chimeric monoclonal antibody against TNF and a treatment for Crohn’s disease, is reduced if/when antibodies against infliximab are produced by the body. Results show that immunosuppressive treatments can help mitigate infusion reactions, or immune responses to infliximab, and increase duration of response to infliximab, thereby increasing efficacy of the drug (Filip et al., 2003). 

Barrett, J.C., Hansoul, S., Nicolae, D.L., Cho, J.H., Duerr, R.H., Rioux, J.D., Brant, S.R., Silverberg, M.S., Taylor, K.D., Barmada, M.M., Bitton, A., Dassopoulos, T., Datta, L.W., Green, T., Griffiths, A.M., Kistner, E.O., Murtha, M.T., Regueiro, M.D., Rotter, J.I., Schumm, L.P., 2008. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nature Genetics 40, 955–962. https://doi.org/10.1038/ng.175

  • Through genome-wide association studies, researchers confirmed 11 loci reported by previous studies and identified 21 loci implicated in Crohn’s disease susceptibility, some of which are involved in innate immunity, like intelectin-1 and leucine-rich repeat kinase 2 (Barrett et al., 2008).

2011-2019

Joossens, M., Huys, G., Cnockaert, M., Preter, V.D., Verbeke, K., Rutgeerts, P., Vandamme, P., Vermeire, S., 2011. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut 60, 631–637. https://doi.org/10.1136/gut.2010.223263

  • Levels of five bacterial species, Dialister invisus, Faecalibacterium prausnitzii, Bifidobacterium adolescentis, Ruminococcus gnavus, and an uncharacterized species of Clostridium cluster XIVa, were consistently altered in the microbiome of patients with CD, comprising a “dysbiosis signature” involving species primarily involved in mucin degradation. Additionally, the authors found that the gut microbiota populations were different in healthy relatives of those with CD compared to individuals with no familial history of CD (Joossens et al., 2011).

Adolph, T.E., Tomczak, M.F., Niederreiter, L., Ko, H.-J., Böck, J., Martinez-Naves, E., Glickman, J.N., Tschurtschenthaler, M., Hartwig, J., Hosomi, S., Flak, M.B., Cusick, J.L., Kohno, K., Iwawaki, T., Billmann-Born, S., Raine, T., Bharti, R., Lucius, R., Kweon, M.-N., Marciniak, S.J., Choi, A., Hagen, S.J., Schreiber, S., Rosenstiel, P., Kaser, A., Blumberg, R.S., 2013. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272–276. https://doi.org/10.1038/nature12599

  • Certain variants of the autophagy-related 16-like 1 (ATG16L1) gene and consistent ER stress are implicated in Crohn’s disease. The authors demonstrate in mice that impairment of autophagosome formation via mutation of ATG16L1 (or another gene Xbp1) can lead to ER stress and ileitis, especially if both proteins are simultaneously dysfunctional (Adolph et al., 2013).

Gevers, D., Kugathasan, S., Denson, L.A., Vázquez-Baeza, Y., Van Treuren, W., Ren, B., Schwager, E., Knights, D., Song, S.J., Yassour, M., Morgan, X.C., Kostic, A.D., Luo, C., González, A., McDonald, D., Haberman, Y., Walters, T., Baker, S., Rosh, J., Stephens, M., Heyman, M., Markowitz, J., Baldassano, R., Griffiths, A., Sylvester, F., Mack, D., Kim, S., Crandall, W., Hyams, J., Huttenhower, C., Knight, R., Xavier, R.J., 2014. The Treatment-Naive Microbiome in New-Onset Crohn’s Disease. Cell Host & Microbe 15, 382–392. https://doi.org/10.1016/j.chom.2014.02.005

  • Tissue and stool samples were collected from pediatric patients with Crohn’s disease and were analyzed for microbiome composition. Levels of some bacterial species, including Enterobacteriaceae, were elevated, while others were diminished, like Bacteroides and Clostridiales. These deviations in microbiome composition were exaggerated, i.e. the dysbiosis increased, in those taking antibiotics compared with those that were not. Results were better seen in tissue samples than stool samples, suggesting that tissue biopsies may be a better diagnostic tool for CD (Gevers et al., 2014).

Keestra-Gounder, A.M., Byndloss, M.X., Seyffert, N., Young, B.M., Chávez-Arroyo, A., Tsai, A.Y., Cevallos, S.A., Winter, M.G., Pham, O.H., Tiffany, C.R., de Jong, M.F., Kerrinnes, T., Ravindran, R., Luciw, P.A., McSorley, S.J., Bäumler, A.J., Tsolis, R.M., 2016. NOD1 and NOD2 signalling links ER stress with inflammation. Nature 532, 394–397. https://doi.org/10.1038/nature17631

  • ER stress contributes to inflammatory diseases, including CD, and activation of the inflammatory response involves the NF-κB pathway. Here, researchers investigate the expression of several proteins, such as IL-6 and TRAF, and demonstrate by using mice models and bacterial cultures that NOD1 and NOD2 are involved in initiating inflammatory responses induced by ER stress. This provides another connection between the innate immune response and ER stress-induced inflammation. (Keestra-Gounder et al., 2016).

Vandeputte, D., Kathagen, G., D’hoe, K., Vieira-Silva, S., Valles-Colomer, M., Sabino, J., Wang, J., Tito, R.Y., De Commer, L., Darzi, Y., Vermeire, S., Falony, G., Raes, J., 2017. Quantitative microbiome profiling links gut community variation to microbial load. Nature 551, 507–511. https://doi.org/10.1038/nature24460

  • In addition to developing a unique method of quantitative microbiome profiling, researchers found that microbial counts were overall lower in stool samples of those with CD and levels of Bacteroides bacteria were particularly low. Although, numbers given in this study are absolute, whereas most studies use comparative analyses and investigate relative proportions of species (Vandeputte et al., 2017).

Butera, A., Paola, M.D., Pavarini, L., Strati, F., Pindo, M., Sanchez, M., Cavalieri, D., Boirivant, M., Filippo, C.D., 2018. Nod2 Deficiency in mice is Associated with Microbiota Variation Favouring the Expansion of mucosal CD4+ LAP+ Regulatory Cells. Nature 8, 14241. https://doi.org/10.1038/s41598-018-32583-z

  • When NOD2-deficient mice are housed with Nod2+/+ mice, gut microbiota composition in the neighboring mice was affected. It lead to an increase in beneficial bacteria and immune cells in Nod2+/+ mice, while exposure to Nod2+/+ mice can lead to acquisition of potentially harmful bacteria in NOD2-deficient mice, exacerbating colitis symptoms (Butera et al., 2018).

Ding, K., Tan, Y.-Y., Ding, Y., Fang, Y., Yang, X., Fang, J., Xu, D.-C., Zhang, H., Lu, W., Li, M., Huang, S.-C., Cai, M.-L., Song, Y., Ding, Y.-J., Zhang, S.-M., 2019. β-Sitosterol improves experimental colitis in mice with a target against pathogenic bacteria. J. Cell. Biochem. 120, 5687–5694. https://doi.org/10.1002/jcb.27853

  • β-sisterol, a plant sterol, improved symptoms of colitis induced in mice, reduced levels of proinflammatory cytokines, and increased production of antimicrobial peptides, thereby opening another potential therapeutic avenue for CD (Ding et al., 2019).

Rolandsdotter, H., Jönsson-Videsäter, K., L Fagerberg, U., Finkel, Y., Eberhardson, M., 2019. Exclusive Enteral Nutrition: Clinical Effects and Changes in Mucosal Cytokine Profile in Pediatric New Inflammatory Bowel Disease. Nutrients 11. https://doi.org/10.3390/nu11020414

  • Exclusive Enteral Nutrition (EEN) is an effective treatment for Crohn’s disease, yet the mechanism of action is not yet well-understood. Children diagnosed with IBD were given EEN and levels of blood proteins and cytokines were measured, which showed a decrease in markers of inflammation (ESR, CRP), increases in IL-12βα and IL-23α (known to play a role in CD) compared to controls, and significant mucosal healing (Rolandsdotter et al., 2019).

*References in red are landmark references.

Link to first paper: Regional-Ileitis.pdf

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