Download RTF - instaheal.net

Wild Theories on the Nature and Pathophysiology of Ulcerative Colitis.
Author manuscript. (Review and Hypothesis.) Jørgen Marthinsen
Ulcerative Colitis (UC) is a disease process characterized primarily by inflammation of the large
Along with Crohns Disease (CD), UC is categorized as an Inflammatory Bowel Disease (IBD). H
throughout the entirety of the gastrointestinal tract. The respective inflammation seen in both dise
relatively topical on the colonic mucosa, whereas the inflammation in CD can affect much deepe
factors, as well as therapeutic benefits, such as diet, medical history and tobacco smoking, which
to believe they do not share the same etiology.
Both major IBDs have for a long time been categorized as idiopathic autoimmune diseases; But i
advanced pathophysiology. The literature often describes pathological, immunogenic and toxin-r
as opportunistic pathogens and/or as pathobionts native to the normal gut flora that become path
carries out the actual inflammatory response, the underlying causative agent may be of a microb
Sulfate Reducing Bacteria
SRB, as well as their toxic waste-product Hydrogen Sulfide (H2S), have been registered in highe
[24]. SRB are bacteria and archaea that obtain energy trough redox-reactions requiring Sulfate a
sometimes other inorganic sulfur compounds like thiosulfate or even elemental sulfur), whilst oxid
with methanogenic bacteria for the latter substrates, thus impeding colonic fermentation and prod
especially in the form of butyrate, are major metabolites for the colonic epithelial cells. In contras
their respiratory fuels. Butyrate is crucial for proper colonocyte cell function and without a sufficie
immune response as it suppresses inflammation in the colon by inhibiting the IFNy/STAT1 signa
oxidation has been shown to be significantly impaired in UC-patients, and trials with topical SCFA
deficiency and/or defective metabolism of SCFAs/butyrate in UC [24].
The toxic waste-product of SRB, Hydrogen Sulfide (H2S), has in persons with UC been registere
there are enzymes capable of detoxifying it by oxidation back to Sulfate [28]. Thus, the body is a
be highly toxic to most, if not all organs of the human body. It has a toxicity comparable to that of
can play a part in the pathogenesis of UC. When present in the bloodstream, H2S can prevent ce
well as act as a nerve toxin. It has been shown to cause a loss of barrier function in intestinal mu
of cell proliferation decreased in the presence of supplemented butyrate.
Bilophila Wadsworthia
Recently associated with UC is the gram-negative, bile-resistant, sulfite-reducing, asaccharolyti
closely related to colon pathogens Lawsonia Intracellularis and Desulfovibrio sp. It has also been
It was named by Baron et al. for its apparent requirement for 20% bile in the growth medium. Thi
energy by reducing sulfite, which it gets from taurine, and oxidizing organic or inorganic electron
compounds in mammals, and one of its many functions is conjugation with bile acids to form bile
BW has occasionally been isolated in low abundance from the oral cavity and vagina, but its pres
from the colon or feces of 50-60% of healthy adults, yet still in low numbers (ca. 103 to 106 CFU
scrotal abscesses, hepatic abscesses, mandibular osteo-myelitis, axillary hydradenitis suppurativ
its clinical importance as a significant, perhaps opportunistic pathogen [3] [6]. However, BW is m
appendix, as it is the third most common anaerobe recovered from clinical specimens of perforat
Appendicitis and subsequent appendectomy has a noteworthy effect on the prevalence of UC. A
not for nonspecific abdominal pain, has been connected to a lowered risk of development of UC
broad-spectrum antibiotics to decrease wound infection and abscess formation during these proc
susceptible to a variety of broad spectrum antimicrobials such as meropenem and metronidazole
This may also be relevant to the hypothesis of beta-lactam antibiotics as a risk factor in IBD and
In addition to producing toxic byproducts like H2S, BW has demonstrated the ability to adhere to
strains, which where also involved in an immune response and UC [8]. The outer membrane of t
lipopolysaccharides, which have been implicated as a source for inflammation and intestinal perm
related cytokines have been detected in the blood plasma of IBD patients [9].
BW is a very slow-growing bacteria and comprises less than 0.01% of a healthy human microbio
Many microbiologists may not be familiar with its isolation and characterization, and current me
to over-look it during culture analysis.
BIle Acids
UC can be triggered by certain microbial infections, but it is clear that UC is not an infectious dise
underlining change in the conditions for microbial growth (for example an increased availability o
Devkota et al. showed that a diet high in saturated fat changed the conditions for microbial asse
directly associated with a pro-inflammatory TH1 response, and an increased incidence of colitis,
The expansion of BW was attributed to the increase of taurocholic-acid in the bile in response to
fat, in the diet.
It was hypothesized that the current increasing prevalence of UC can be connected to a gradual
diet consisting of an increasing amount of saturated fats, only affecting genetically susceptible in
However, not all patients with UC have food habits pertaining to this phenomenon, as any individ
reasonable to postulate a more advanced and multifaceted pathophysiology, although high amou
An altered composition, and/or increased abundance of bile in the colon can be attributed to seve
malabsorption is now believed to be caused by defective feedback inhibition, rather than an inab
acids are reabsorbed in the terminal ileum and recycled trough enterohepatic circulation. This is
further production of bile acids, but with the lack of this function, the liver will produce more bile a
large intestine. Here, the bile acids themselves can cause diarrhea, even without the influence of
Bile acid malabsorption has traditionally been viewed as a rare cause of irritable bowel syndrome
UC and CD. [11]
The enterohepatic feedback loop is just one of many mechanisms involving hormones in the gut.
abundance of the hormone Cholecystokinin (CCK). Current reports have failed to indicate an ele
diseases like CD, pancreatitis and irritable bowel syndrome [18] [13] [14] ); But used as an exam
acids and many other aspects related to UC (such as a loss of appetite, or the connection to anx
In addition, disturbances in gastric emptying have been registered in a subset of IBD patients, po
CCK-antagonists (Proglumide and Loxiglumide, respectively) have also shown therapeutic benef
The involvement of bile acids in UC may be further implied by the strong relation between UC an
obstruction of intra- and extrahepatic bile-ducts. About 5% of UC-patients may progress to devel
UC, PSC is believed to be caused by auto-immunity, but since UC can be connected to bile-resis
explored in PSC.
Tobacco
Interestingly, UC and CD respond very differently to tobacco useage. Where smoking is universa
UC-patients. Statistically, the prevalence of UC is higher in people who have recently quit smokin
decrease in symptoms after acquiring or resuming a tobacco habit.
It has been theorized that both nicotine and other constituents of tobacco smoke are involved in t
decrease in perceived stress, since stress reportedly ties into the emergence and exacerbation o
long term exposure that exacerbates UC [20]; And as it is well known, smoking habit has a tend
A novel theory suggests that Hydrogen Cyanide (HCN) from the tobacco smoke reacts with the e
[iso]thiocyanate, thus nullifying the toxic, -and perhaps immunogenic properties of the H2S. [5]
Unfortunately, perhaps due to the otherwise negative connotations associated with it, the mecha
unrecognized and unexplored. While it is inadvisable for patients to self-medicate with tobacco, f
Future treatments
Unfortunately, the current scientific knowledge is not sufficient to be conclusive about any postula
imbalances remain somewhat speculative; But at the same time, a steadily growing pool of scie
sole cause of UC. In time, we might develop a greater understanding of this disease-process,
References:
(1)
Microbial pathways in colonic sulfur metabolism and links with health and disease
Franck Carbonero, Ann C. Benefiel, Amir H. Alizadeh-Ghamsari and H. Rex Gaskins
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508456/pdf/fphys-03-00448.pdf
(2)
Identification of Bilophila wadsworthia by specific PCR which targets the taurine:pyruvate aminot
Heike Laue, Theo H. M. Smits, Ulrike K. Schumacher, Marina C. Claros, Ralf Hartemink4 & Alas
http://kops.ub.uni-konstanz.de/bitstream/handle/urn:nbn:de:bsz:352-opus-67364/IdentificationBilo
(3)
Two intriguing bilophila wadsworthia cases from hungary.
Edit Urban, Anna Hortobagyi, Karoly Szentpali and Elisabeth Nagy
http://jmm.sgmjournals.org/content/53/11/1167.full.pdf
(4)
Mapping Bacterial worlds, From sea to stomach.
By Rob Mitchum.
http://www.uchospitals.edu/pdf/uch_027883.pdf
(5)
Fecal hydrogen sulfide production in ulcerative colitis.
Levine J, Ellis CJ, Furne JK, Springfield J, Levitt MD.
http://www.ncbi.nlm.nih.gov/pubmed/9448181
http://www.nature.com/ajg/journal/v93/n1/abs/ajg199821a.html
(6)
Colonic Infection by Bilophila Wadsworthia in Pigs. (2000)
Alexandra L. Mcorist, Michelle Warhurst, Steven Mcorist, and Anthony R. Bird.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC87973/pdf/jm001577.pdf
(7)
Adherence of Bilophila wadsworthia to cultured human embryonic intestinal cells.
Gerardo SH, Garcia MM, Wexler HM, Finegold SM.
http://www.ncbi.nlm.nih.gov/pubmed/16887620
(8)
Adherent-invasive Escherichia coli in inflammatory bowel disease.
Rolhion N, Darfeuille-Michaud A.
http://www.ncbi.nlm.nih.gov/pubmed/17476674
(9)
Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biolog
Caradonna L, Amati L, Magrone T, Pellegrino NM, Jirillo E, Caccavo D.
http://www.ncbi.nlm.nih.gov/pubmed/11052175
(10)
Dietary fat-induced taurocholic acid production promotes pathobiont and colitis in IL-10−/− mice.
Suzanne Devkota, Eugene B. Chang, Yunwei Wang, Mark Musch, Vanessa Leone, Hannah Feh
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393783/pdf/nihms376810.pdf
(11)
Managing Bile Acid Diarrhea
Prof. Julian R. F. Walters and Sanjeev S. Pattni
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002596/
(12)
Primary Sclerosing Cholangitis the Biliary Tree, and Ulcerative Colitis. (1967)
M. E. C. Thorpe, P. J. Scheuer, and Sheila Sherlock
http://gut.bmj.com/content/8/5/435.full.pdf
(13)
Acute taurodeoxycholate-induced PANCREATITIS in the rat is associated with hyperCCKemia
Bodil Ohlsson, Jan Axelson, Unne Stenram, Jens F. Rehfeld, Ingemar Ihse
http://link.springer.com/content/pdf/10.1385/IJGC:27:3:195.pdf
(14)
Relative importance of abnormalities of CCK and 5-HT (serotonin) in Giardia-induced post-infecti
V. Dizdar, R. Spiller, G. Singh, K. Hanevik, O. H. Gilja, M. El-Salhy, T. Hausken
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2010.04251.x/full
http://onlinelibrary.wiley.com/store/10.1111/j.1365-2036.2010.04251.x/asset/j.1365-2036.2010.04
51
(15)
Loxiglumide, a CCK-A Antagonist, in Irritable Bowel Syndrome. A Pilot Multicenter Clinical Study
P. A. Cann, L. C. Rovati, H.L. Smart, R. C. Spiller, and P. J. Whorwell.
http://www.ibs-care.org/pdfs/ref_048.pdf
(16)
Proglumide attenuates experimental colitis in rats.
Al Moutaery A.
http://www.ncbi.nlm.nih.gov/pubmed/15816362
(17)
Oxytocin and cholecystokinin secretion in women with colectomy
Bodil Ohlsson, Jens F Rehfeld, and Mary L Forsling
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC529435/
(18)
Mechanisms of gastric emptying disturbances in chronic and acute inflammation of the distal gas
Jutta Keller, Christoph Beglinger, Jens Juul Holst, Viola Andresen, and Peter Layer
http://www.ncbi.nlm.nih.gov/pubmed/20501434
http://ajpgi.physiology.org/content/297/5/G861.full.pdf
(19)
A comparison of autonomic function in patients with inflammatory bowel disease and in healthy c
S. C. Ganguli, M. V. Kamath, K. Redmond, Y. Chen, E. J. Irvine, S. M. Collins, G. Tougas
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2982.2007.00987.x/full
(20)
Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission
Levenstein S, Prantera C, Varvo V, Scribano ML, Andreoli A, Luzi C, Arcà M, Berto E, Milite G, M
http://www.ncbi.nlm.nih.gov/pubmed/10811330
(21)
Appendectomy and protection agains ulcerative colitis. (2001)
roland e. andersson, m.d., ph.d., gunnar olaison, m.d., ph.d., curt tysk, m.d., ph.d., and anders ek
http://www.nejm.org/doi/pdf/10.1056/NEJM200103153441104
(22)
Antibiotics and appendicitis in the pediatric population: an American Pediatric Surgical Associatio
Steven L. Leea, Saleem Islamb, Laura D. Cassidyc, Fizan Abdullahd, Marjorie J. Arcac
http://xa.yimg.com/kq/groups/19696934/1200179464/name/AB%25C2%25B4S%2BY%2BAPEN
(23)
Sulphate reducing bacteria and hydrogen metabolism in the human large intestine. (1993)
G. R. Gibson, G. T. Macfarlane, J.H. Cummings
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1374298/pdf/gut00555-0017.pdf
(24)
Hydrogen Sulphide: a bacterial toxin in Ulcerative Colitis? (1996)
M. C. L. Pitcher, J.H. Cummings
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1383219/pdf/gut00510-0009.pdf
(25)
Mechanism of malabsorption in giardiasis: a study of bacterial flora and biles alt deconjugation in
B. N. Tandon, R. K. Tandon, B. K. Satpathy, and Shriniwas
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1411381/pdf/gut00472-0016.pdf
(26)
Giardiasis as a chronic disease. (1985)
Chester AC, MacMurray FG, Restifo MD, Mann O.
http://www.ncbi.nlm.nih.gov/pubmed/2578921
(27)
Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and FasZimmerman MA, Singh N, Martin PM, Thangaraju M, Ganapathy V, Waller JL, Shi H, Robertson
http://www.ncbi.nlm.nih.gov/pubmed/22517765
(28)
Sulfide-detoxifying enzymes in the human colon are decreased in cancer and upregulated in diffe
S. Ramasamy, S. Singh, P. Taniere, M. J. S. Langman, and M. C. Eggo
http://ajpgi.physiology.org/content/291/2/G288.full
(29)
Bilophila wadsworthia, gen. nov. and sp. nov., a unique gram-negative anaerobic rod recovered f
Baron EJ, Summanen P, Downes J, Roberts MC, Wexler H, Finegold SM.
http://www.ncbi.nlm.nih.gov/pubmed/2636263
http://mic.sgmjournals.org/content/135/12/3405.full.pdf
(30)
Bilophila wadsworthia: a unique Gram-negative anaerobic rod. (1997)
Baron E.J.
http://www.ncbi.nlm.nih.gov/pubmed/16887567
(31)
Susceptibility of the anaerobic gram-negative non-sporulating rod, Bilophila wadsworthia to betaand quinolones.
Schumacher UK, Single B.
http://www.ncbi.nlm.nih.gov/pubmed/9638871