Editing Crohn's disease (section)

=== Microbes ===
It is hypothesized that maintenance of [[commensal]] [[microorganism]] growth in the [[GI tract]] is dysregulated, either as a result or cause of [[immune dysregulation]].<ref>{{cite journal | vauthors = Sartor RB | title = Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis | journal = Nature Clinical Practice. Gastroenterology & Hepatology | volume = 3 | issue = 7 | pages = 390–407 | date = July 2006 | pmid = 16819502 | doi = 10.1038/ncpgasthep0528 | s2cid = 3329677 }}</ref><ref name="pmid22508665">{{cite journal | vauthors = Dogan B, Scherl E, Bosworth B, Yantiss R, Altier C, McDonough PL, Jiang ZD, Dupont HL, Garneau P, Harel J, Rishniw M, Simpson KW | title = Multidrug resistance is common in Escherichia coli associated with ileal Crohn's disease | journal = Inflammatory Bowel Diseases | volume = 19 | issue = 1 | pages = 141–150 | date = January 2013 | pmid = 22508665 | doi = 10.1002/ibd.22971 | s2cid = 25518704 | doi-access = free | title-link = doi }}</ref>

There is an apparent connection between Crohn's disease, ''[[Mycobacterium]]'', other pathogenic bacteria, and [[genetic marker]]s.<ref>{{cite journal | vauthors = Subramanian S, Roberts CL, Hart CA, Martin HM, Edwards SW, Rhodes JM, Campbell BJ | title = Replication of Colonic Crohn's Disease Mucosal Escherichia coli Isolates within Macrophages and Their Susceptibility to Antibiotics | journal = Antimicrobial Agents and Chemotherapy | volume = 52 | issue = 2 | pages = 427–434 | date = February 2008 | pmid = 18070962 | pmc = 2224732 | doi = 10.1128/AAC.00375-07 }}</ref><ref>{{cite journal | vauthors = Mpofu CM, Campbell BJ, Subramanian S, Marshall-Clarke S, Hart CA, Cross A, Roberts CL, McGoldrick A, Edwards SW, Rhodes JM | title = Microbial mannan inhibits bacterial killing by macrophages: a possible pathogenic mechanism for Crohn's disease | journal = Gastroenterology | volume = 133 | issue = 5 | pages = 1487–1498 | date = November 2007 | pmid = 17919633 | doi = 10.1053/j.gastro.2007.08.004 }}</ref> A number of studies have suggested a causal role for [[Mycobacterium avium subspecies paratuberculosis|''Mycobacterium avium'' subspecies ''paratuberculosis'']] (MAP), which causes a similar disease, [[Johne's disease]], in cattle.<ref name="pmid16306778">{{cite journal | vauthors = Naser SA, Collins MT | title = Debate on the lack of evidence of Mycobacterium avium subsp. paratuberculosis in Crohn's disease | journal = Inflammatory Bowel Diseases | volume = 11 | issue = 12 | pages = 1123 | date = December 2005 | pmid = 16306778 | doi = 10.1097/01.MIB.0000191609.20713.ea | doi-access = free | title-link = doi }}</ref><ref name="PMC4064085">{{cite journal | vauthors = Naser SA, Sagramsingh SR, Naser AS, Thanigachalam S | title = Mycobacterium avium subspecies paratuberculosis causes Crohn's disease in some inflammatory bowel disease patients | journal = World Journal of Gastroenterology | volume = 20 | issue = 23 | pages = 7403–7415 | date = June 2014 | pmid = 24966610 | pmc = 4064085 | doi = 10.3748/wjg.v20.i23.7403 | doi-access = free | title-link = doi }}</ref> In many individuals, genetic factors predispose individuals to ''[[Mycobacterium avium]]'' subsp.'' [[paratuberculosis]]'' infection. This bacterium may produce certain compounds containing [[mannose]], which may protect both itself and various other bacteria from [[phagocytosis]], thereby possibly causing a variety of [[secondary infection]]s.<ref>{{cite web |title=New insights into Crohn's Disease |url=http://www.liv.ac.uk/researchintelligence/issue33/crohns.htm|url-status=dead|archive-url=https://web.archive.org/web/20130923151342/http://www.liv.ac.uk/researchintelligence/issue33/crohns.htm|archive-date=September 23, 2013}}</ref>

NOD2 is a gene involved in Crohn's genetic susceptibility. It is associated with [[macrophage]]s' diminished ability to [[phagocytize]] MAP. This same gene may reduce innate and adaptive immunity in gastrointestinal tissue and impair the ability to resist infection by the MAP bacterium.<ref>{{cite journal | vauthors = Glubb DM, Gearry RB, Barclay ML, Roberts RL, Pearson J, Keenan JI, McKenzie J, Bentley RW | title = NOD2 and ATG16L1 polymorphisms affect monocyte responses in Crohn's disease | journal = World Journal of Gastroenterology | volume = 17 | issue = 23 | pages = 2829–2837 | date = June 2011 | pmid = 21734790 | pmc = 3120942 | doi = 10.3748/wjg.v17.i23.2829 | doi-broken-date = September 12, 2024 | doi-access = free | title-link = doi }}</ref> Macrophages that ingest the MAP bacterium are associated with high production of [[TNF-α]].<ref>{{cite journal | vauthors = Clancy R, Ren Z, Turton J, Pang G, Wettstein A | title = Molecular evidence for Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn's disease correlates with enhanced TNF-alpha secretion | journal = Digestive and Liver Disease | volume = 39 | issue = 5 | pages = 445–451 | date = May 2007 | pmid = 17317344 | doi = 10.1016/j.dld.2006.12.006 }}</ref><ref>{{cite journal | vauthors = Nakase H, Tamaki H, Matsuura M, Chiba T, Okazaki K | title = Involvement of mycobacterium avium subspecies paratuberculosis in TNF-α production from macrophage: possible link between MAP and immune response in Crohn's disease | journal = Inflammatory Bowel Diseases | volume = 17 | issue = 11 | pages = E140–E142 | date = November 2011 | pmid = 21990211 | doi = 10.1002/ibd.21750 }}</ref>

Other studies have linked specific strains of [[entero]]adherent ''[[Escherichia coli|E. coli]]'' to the disease.<ref name="Baumgart_2007">{{cite journal | vauthors = Baumgart M, Dogan B, Rishniw M, Weitzman G, Bosworth B, Yantiss R, Orsi RH, Wiedmann M, McDonough P, Kim SG, Berg D, Schukken Y, Scherl E, Simpson KW | title = Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving the ileum | journal = The ISME Journal | volume = 1 | issue = 5 | pages = 403–418 | date = September 2007 | pmid = 18043660 | doi = 10.1038/ismej.2007.52 | doi-access = free | title-link = doi | bibcode = 2007ISMEJ...1..403B }}</ref> Adherent-invasive [[Escherichia coli]] (AIEC), more common in people with Crohn's disease,<ref>{{cite journal | vauthors = Sasaki M, Sitaraman SV, Babbin BA, Gerner-Smidt P, Ribot EM, Garrett N, Alpern JA, Akyildiz A, Theiss AL, Nusrat A, Klapproth JM | title = Invasive Escherichia coli are a feature of Crohn's disease | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 87 | issue = 10 | pages = 1042–1054 | date = October 2007 | pmid = 17660846 | doi = 10.1038/labinvest.3700661 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N, Bringer MA, Swidsinski A, Beaugerie L, Colombel JF | title = High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease | journal = Gastroenterology | volume = 127 | issue = 2 | pages = 412–421 | date = August 2004 | pmid = 15300573 | doi = 10.1053/j.gastro.2004.04.061 | doi-access = free | title-link = doi }}</ref><ref name="Baumgart_2007" /> have the ability to make strong [[biofilm]]s compared to non-AIEC strains correlating with high adhesion and invasion indices<ref>{{cite journal | vauthors = Nickerson KP, McDonald C | title = Crohn's disease-associated adherent-invasive Escherichia coli adhesion is enhanced by exposure to the ubiquitous dietary polysaccharide maltodextrin | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e52132 | year = 2012 | pmid = 23251695 | pmc = 3520894 | doi = 10.1371/journal.pone.0052132 | veditors = Mizoguchi E | doi-access = free | title-link = doi | bibcode = 2012PLoSO...752132N }}</ref><ref>{{cite journal | vauthors = Martinez-Medina M, Naves P, Blanco J, Aldeguer X, Blanco JE, Blanco M, Ponte C, Soriano F, Darfeuille-Michaud A, Garcia-Gil LJ | title = Biofilm formation as a novel phenotypic feature of adherent-invasive Escherichia coli (AIEC) | journal = BMC Microbiology | volume = 9 | issue = 1 | pages = 202 | date = September 2009 | pmid = 19772580 | pmc = 2759958 | doi = 10.1186/1471-2180-9-202 | doi-access = free | title-link = doi }}</ref> of [[neutrophil]]s and the ability to block [[autophagy]] at the autolysosomal step, which allows for intracellular survival of the bacteria and induction of inflammation.<ref name="pmid23272151">{{cite journal | vauthors = Chargui A, Cesaro A, Mimouna S, Fareh M, Brest P, Naquet P, Darfeuille-Michaud A, Hébuterne X, Mograbi B, Vouret-Craviari V, Hofman P | title = Subversion of autophagy in adherent invasive Escherichia coli-infected neutrophils induces inflammation and cell death | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e51727 | year = 2012 | pmid = 23272151 | pmc = 3522719 | doi = 10.1371/journal.pone.0051727 | doi-access = free | title-link = doi | bibcode = 2012PLoSO...751727C }}</ref> Inflammation drives the proliferation of AIEC and [[dysbiosis]] in the ileum, irrespective of genotype.<ref name="pmid22848538">{{cite journal | vauthors = Craven M, Egan CE, Dowd SE, McDonough SP, Dogan B, Denkers EY, Bowman D, Scherl EJ, Simpson KW | title = Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn's disease | journal = PLOS ONE | volume = 7 | issue = 7 | pages = e41594 | year = 2012 | pmid = 22848538 | pmc = 3404971 | doi = 10.1371/journal.pone.0041594 | doi-access = free | title-link = doi | bibcode = 2012PLoSO...741594C }}</ref> AIEC strains replicate extensively inside macrophages inducing the secretion of very large amounts of TNF-α.<ref>{{cite journal | vauthors = Barnich N, Darfeuille-Michaud A | title = Adherent-invasive Escherichia coli and Crohn's disease | journal = Current Opinion in Gastroenterology | volume = 23 | issue = 1 | pages = 16–20 | date = January 2007 | pmid = 17133079 | doi = 10.1097/MOG.0b013e3280105a38 | s2cid = 23564986 }}</ref>

Mouse studies have suggested some symptoms of Crohn's disease, ulcerative colitis, and [[irritable bowel syndrome]] have the same underlying cause. [[Biopsy]] samples taken from the colons of all three patient groups were found to produce elevated levels of a [[serine protease]].<ref>{{cite journal | vauthors = Cenac N, Andrews CN, Holzhausen M, Chapman K, Cottrell G, Andrade-Gordon P, Steinhoff M, Barbara G, Beck P, Bunnett NW, Sharkey KA, Ferraz JG, Shaffer E, Vergnolle N | title = Role for protease activity in visceral pain in irritable bowel syndrome | journal = The Journal of Clinical Investigation | volume = 117 | issue = 3 | pages = 636–647 | date = March 2007 | pmid = 17304351 | pmc = 1794118 | doi = 10.1172/JCI29255 }}</ref> Experimental introduction of the serine [[protease]] into mice has been found to produce widespread pain associated with irritable bowel syndrome, as well as colitis, which is associated with all three diseases.<ref>{{cite journal | vauthors = Cenac N, Coelho AM, Nguyen C, Compton S, Andrade-Gordon P, MacNaughton WK, Wallace JL, Hollenberg MD, Bunnett NW, Garcia-Villar R, Bueno L, Vergnolle N | title = Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2 | journal = The American Journal of Pathology | volume = 161 | issue = 5 | pages = 1903–1915 | date = November 2002 | pmid = 12414536 | pmc = 1850779 | doi = 10.1016/S0002-9440(10)64466-5 }}</ref> Regional and temporal variations in those illnesses follow those associated with infection with the protozoan ''[[Blastocystis]]''.<ref>{{cite journal | vauthors = Boorom KF, Smith H, Nimri L, Viscogliosi E, Spanakos G, Parkar U, Li LH, Zhou XN, Ok UZ, Leelayoova S, Jones MS | title = Oh my aching gut: irritable bowel syndrome, Blastocystis, and asymptomatic infection | journal = Parasites & Vectors | volume = 1 | issue = 1 | pages = 40 | date = October 2008 | pmid = 18937874 | pmc = 2627840 | doi = 10.1186/1756-3305-1-40 | doi-access = free | title-link = doi }}</ref>

The "cold-chain" hypothesis is that [[psychrotrophic bacteria]] such as ''[[Yersinia]]'' and ''[[Listeria]]'' species contribute to the disease. A statistical correlation was found between the advent of the use of refrigeration in the United States and various parts of Europe and the rise of the disease.<ref name="pmid14683664">{{cite journal | vauthors = Hugot JP, Alberti C, Berrebi D, Bingen E, Cézard JP | title = Crohn's disease: the cold chain hypothesis | journal = Lancet | volume = 362 | issue = 9400 | pages = 2012–2015 | date = December 2003 | pmid = 14683664 | doi = 10.1016/S0140-6736(03)15024-6 | s2cid = 10254395 }}</ref><ref>{{cite news |title=Fridges blamed for Crohn's disease rise |work=Medical News Today |date=December 12, 2003 |url=http://www.medicalnewstoday.com/articles/4849.php |url-status=live |archive-url = https://web.archive.org/web/20090103190132/http://www.medicalnewstoday.com/articles/4849.php |archive-date=January 3, 2009}}</ref><ref>{{cite journal | vauthors = Forbes A, Kalantzis T | title = Crohn's disease: the cold chain hypothesis | journal = International Journal of Colorectal Disease | volume = 21 | issue = 5 | pages = 399–401 | date = July 2006 | pmid = 16059694 | doi = 10.1007/s00384-005-0003-7 | s2cid = 13271176 }}</ref>

There is also a tentative association between ''[[Candida (fungus)|Candida]]'' colonization and Crohn's disease.<ref>{{cite journal | vauthors = Kumamoto CA | title = Inflammation and gastrointestinal Candida colonization | journal = Current Opinion in Microbiology | volume = 14 | issue = 4 | pages = 386–391 | date = August 2011 | pmid = 21802979 | pmc = 3163673 | doi = 10.1016/j.mib.2011.07.015 }}</ref>

Still, these relationships between specific pathogens and Crohn's disease remain unclear.<ref name="scah_out38">{{cite web |title=Possible links between Crohn's disease and Paratuberculosis |url=http://ec.europa.eu/food/fs/sc/scah/out38_en.pdf|url-status=dead|archive-url=https://web.archive.org/web/20081217094053/http://ec.europa.eu/food/fs/sc/scah/out38_en.pdf|archive-date=December 17, 2008|access-date=November 7, 2009 |publisher=European Commission Directorate-General Health & Consumer Protection}}</ref><ref>{{cite journal | vauthors = Gui GP, Thomas PR, Tizard ML, Lake J, Sanderson JD, Hermon-Taylor J | title = Two-year-outcomes analysis of Crohn's disease treated with rifabutin and macrolide antibiotics | journal = The Journal of Antimicrobial Chemotherapy | volume = 39 | issue = 3 | pages = 393–400 | date = March 1997 | pmid = 9096189 | doi = 10.1093/jac/39.3.393 | doi-access = free | title-link = doi }}</ref>