How are low mannin-binding lectin (MBL) significant in Crohn's?

"Low Mannan-binding lectin serum levels are associated with complicated Crohn's disease and reactivity to oligomannan (ASCA)." in American Journal of Gastroenterology (2009)
"CONCLUSIONS: Low or deficient MBL serum levels are significantly associated with complicated (stricturing and penetrating) CD phenotypes but are negatively associated with the non-stricturing, non-penetrating group. Furthermore, CD patients with low or deficient MBL are significantly more often ASCA positive, possibly reflecting delayed clearance of oligomannan-containing microorganisms by the innate immune system in the absence of MBL."

"Partial overlap of anti-mycobacterial, and anti-Saccharomyces cerevisiae mannan antibodies in Crohn’s disease" In World J Gastroenterology (2008)

"Abstract CONCLUSION: Similar to ASCA, seroreactivity against mycobacteria may define CD patients with complicated disease and a predisposition for immune responses against ubiquitous antigens. While in some patients anti-mycobacterial antibodies strongly cross-react with yeast mannan; these cross-reactive antibodies only represent a minor fraction of total ASCA. Thus, mycobacterial infection unlikely plays a role in ASCA induction."

"Full article:  In conclusion, we were able to demonstrate that ASCA-positive patients had significantly more immune reactivities to mycobacterial antigens. In a subgroup of ASCA-positive CD patients, anti-mycobacterial immunoglobulins at least partially represent cross-reactive ASCA, while in others there seem to be separate ASCA and anti-mycobacterial antibodies that do not cross-react. Furthermore, purified anti-M smegmatis IgG showed low or no binding to yeast mannan. Therefore, we postulate that our results reflect more the predisposition of CD patients to develop increased immune reactivities to various ubiquitous antigens in general and mannosylated antigens in particular, rather than a role of mycobacteria in the induction of ASCA."

"Mannan-binding lectin deficiency results in unusual antibody production and excessive experimental colitis in response to mannose-expressing mild gut pathogens"
"Conclusions: These results suggest that systemic MBL helps to prevent excessive inflammation upon access of normally mild pathogens across the damaged intestinal epithelium. Lack of this innate defence promotes antibody responses with cross-reactive potential against common mannan epitopes. These interpretations are compatible with the increased prevalence of ASCA and complicated disease phenotypes in MBL-deficient patients with CD."

"Deficiency for mannan-binding lectin is associated with antibodies to Saccharomyces cerevisiae in patients with Crohn’s disease and their relatives" in Gut (2007)
"Therefore, our paper provides further evidence that genetically altered MBL levels in patients with Crohn’s disease and their relatives could be, at least partly, responsible for the enhanced  immune reactivity to yeast antigens seen in a subgroup of these patients and their relatives.  However, other factors also contribute to the development of this unusual immune reaction, as there are MBL-deficient healthy people who are ASCA negative."

c.f. "Mannan binding lectin (MBL) gene polymorphisms are not associated with anti-Saccharomyces cerevisiae (ASCA) in patients with Crohn’s disease" in Gut (2006)
"We found no association between the presence of ASCA and polymorphisms/mutations in the MBL gene in a large cohort of CD patients and conclude that the occurrence of ASCA is not related to MBL polymorphisms/mutations. This is in contrast with a previous report in which such an association was suggested. Therefore, we consider the relationship between ASCA and MBL highly controversial."

Do food antigens worsen Crohn's symptoms?

"Immune sensitization to food, yeast and bacteria in Crohn’s disease" in Alimentary Pharmacology and Therapeutics (2001)
"Evidence in support of the importance of food antigens perpetuating the inflammatory process comes from studies showing that diets whose sole protein source consists of amino acids or simple proteins can induce remission in Crohn’s disease. ...
Laboratory based experimental work has supported the hypothesis that food or bacterial antigens are involved in the pathogenesis of Crohn’s disease. The proliferation of peripheral as well as lamina propria T lymphocytes to bacterial, mycobacterial and fungal antigens has previously been demonstrated."

What causes Crohn's?

"Unravelling the pathogenesis of inflammatory bowel disease" in Nature (2007)
"Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and these have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis. Second, efforts directed towards the identification of environmental factors implicate commensal bacteria (or their products), rather than conventional pathogens, as drivers of dysregulated immunity and IBD. Third, murine models, which exhibit many of the features of ulcerative colitis and seem to be bacteria-driven, have helped unravel the pathogenesis/mucosal immunopathology of IBD."

What is the hygeine hypothesis and how does it explain the pathogenesis of CD?

Hygiene hypothesis in inflammatory bowel disease: A critical review of the literature in World J Gastroenterol (2008)
"IBD is a growing disease that is costly to the individual and society. The underlying premise of the hygiene hypothesis is that decreased microbial exposure in childhood may lead to the subsequent development of IBD appears to be plausible, although the strength of the evidence supporting this varies between many hygiene-related factors. Helminthic infection, H pylori exposure, antibiotic use, breastfeeding and sibship represent the most promising factors supporting the hygiene hypothesis in IBD, but carefully designed prospective evaluation is urgently needed." [Emphasis mine.]

"Helminths and the IBD hygiene hypothesis" in Inflammatory Bowel Diseases (2008)"In the 1990s we proposed the “IBD hygiene hypothesis.” It states that raising children in extremely hygienic environments negatively affects immune development, which predisposes them to immunological diseases like IBD later in life.1 Moreover, we proposed that the modern day absence of exposure to intestinal helminths is an important environmental factor contributing to IBD. Helminths regulate their host's immune system and prevent excessive immune responses.
There is expanding epidemiological data pointing to a protective role for helminth infections in various immunological diseases. For instance, helminth infections inversely correlate with allergic disorders. ...

Epidemiological data supporting a role for helminth infection in protection from IBD is more circumstantial. There is a clear inverse correlation between the frequency of helminth infections and the prevalence of IBD. Direct proof of the concept that helminths acquired naturally protect humans from IBD remains sparse. Reports have now appeared showing IBD control after natural exposure to intestinal helminths.

There have been several clinical trials using helminths to treat IBD. Results from these trials suggest that infection with at least some human or animal helminths improves clinical outcome, which supports the premise that natural helminth infection is protective. ...
Worm-based therapies are under development at several pharmaceutical companies. Some laboratories are isolating agents from helminths that could prove useful as therapeutic agents.56–58 Others have developed pharmaceutical grade helminths that currently are under review at both the US and European food and drug administrations. ... Use of all new experimental therapies must proceed with caution. The vast majority of mild to moderate worm infestations rarely manifest as disease. While many helminths hold little pathogenic potential, others carry risk.  ... Modern-day therapeutics for IBD have limited efficacy and are not without their danger. There may be little therapeutic risk using properly selected and administered helminths or their derivatives in our hygienic societies."

What is the primary defect in CD?

"New insights into the pathogenesis of Crohn's disease: are they relevant for therapeutic options?" in Swiss Med Wkly (2009)
"Data on NOD2/CARD15 expression suggest that macrophages and epithelial cells could be the locus of the primary pathophysiological defect and that T-cell activation might just be a secondary effect inducing chronification of the inflammation, perhaps as backup mechanism to insufficient innate immunity."

What are macrophages and why are they important to CD?

"New insights into the pathogenesis of Crohn's disease: are they relevant for therapeutic options?" in Swiss Med Wkly (2009)
"Data on NOD2/CARD15 expression suggest that macrophages and epithelial cells could be the locus of the primary pathophysiological defect and that T-cell activation might just be a secondary effect inducing chronification of the inflammation, perhaps as backup mechanism to insufficient innate immunity."

"Revisiting Crohn's disease as a primary immunodeficiency of macrophages" in Journal of Experimental Medicine (2009)
"Despite two decades of mouse immunology and human genetics studies, the pathogenesis of Crohn's disease (CD) remains elusive. New clinical investigations suggest that CD may be caused by inborn errors of macrophages. These errors may result in impaired attraction of granulocytes to the gut wall, causing impaired clearance of intruding bacteria, thereby precipitating the formation of granulomas. This theory paves the way for a macrophage-based Mendelian genetic dissection of CD."

Is the immune system over-reacting or under-reacting in CD?

"New insights into the pathogenesis of Crohn's disease: are they relevant for therapeutic options?" in Swiss Med Wkly (2009)
"Crohn's disease is now also discussed as an impaired and inadequate immune reaction and no longer only as a hyper-responsiveness of the mucosal immune system."

Do germs cause CD?

"New insights into the pathogenesis of Crohn's disease: are they relevant for therapeutic options?" in Swiss Med Wkly (2009)
"The "germ-concept" and the "genetic concept" of IBD pathophysiology are converging. However, more time is needed until these important insights in IBD pathogenesis will make their way into routine diagnostic procedures and treatment of patients with IBD."

What is the Intestinal permeability in families with Crohn's?

"Intestinal permeability before and after ibuprofen in families of children with Crohn's Disease in Can J Gasteroenterol (1999)
Conclusions:  "Members of a subset of first-degree relatives of children with Crohn's disease have an exaggerated increase in intestinal permeability after ibuprofen ingestion. These findings are compatible with there being a genetic link between abnormalities of intestinal permeability and Crohn's disease."

"Increased Intestinal Permeability Precedes the Onset of Crohn’s Disease in a Subject With Familial Risk" in Gastroenterology (2000)
"In summary, increased intestinal permeability is com-mon among patients with Crohn’s disease, particularly when their disease is active, and in a subgroup of theirnondiseased relatives. Our case report describes a patientwith a strong family history of Crohn’s disease whose permeability to 51Cr-EDTA was increased 8 years beforethe diagnosis of Crohn’s disease. This contributes to the growing pool of evidence that a permeability defect and exposure of the lamina propria to luminal antigens are seminal events in the pathogenesis of inflammatory bowel disease. Longitudinal studies that stratify patients by their family history of inflammatory bowel disease areneeded to examine this mechanism further." [Italics mine.]

In summary, increased intestinal permeability is com-

"Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease" in Alim Pharmicol Ther (2006)
Conclusion:  "Intestinal permeability is raised in Crohn's disease patients and relatives, with higher rates in familial vs. sporadic healthy relatives. CARD15 mutations are associated with abnormal permeability in ileal Crohn's disease."

"Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence?" in Gut (1999)
Conclusions:  "The findings suggest that baseline permeability is determined by environmental factors, whereas permeability provoked by acetylsalicylic acid is a function of the genetically determined state of the mucosal barrier, and support the notion that environmental and hereditary factors interact in the pathogenesis of Crohn's disease."

"Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?" in Gut (2006)
"In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD."

"Subclinical Intestinal Inflammation in Siblings of Children with Crohn’s Disease" in Digestive Diseases and Sciences (2010)
"This study provides further evidence of subclinical intestinal inflammation amongst first-degree relatives of patients with Crohn’s disease. The presence of sub-clinical gut inflammation may be a risk factor for the subsequent development of Crohn’s disease."

Do viruses cause CD?

"D'oh! Genes and Environment Cause Crohn's Disease" in Cell (2010)Preview:  "Information obtained from genome-wide association studies has cracked open the biology of common chronic diseases by identifying genes that predispose individuals to these disorders. Cadwell et al., 2010 now demonstrate that a viral infection, a toxic insult to the gut, commensal bacteria, and a Crohn's disease susceptibility gene collude to cause inflammatory disease in the mouse gut."

"Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine" in Cell (2010)
Highlights:

• Mice with mutations in the Crohn's disease gene Atg16L1 display intestinal disease
• Disease requires murine norovirus (MNV) infection together with Atg16L1 mutation
• Viral triggering of disease is dependent on virus strain and timing of infection
• Disease in response to mucosal injury involves cytokines and commensal bacteria

"Crohn's disease: Genes, viruses and microbes" in Nature (2010)
Abstract:  "Variations in several genes can increase an individual's susceptibility to complex disorders. But what tips the balance to cause the full-blown disease? For Crohn's disease, viruses could provide part of the answer."

Does diet cause CD?

 "Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn's disease in children" in Am Journal Gastroenterol (2007)
Conclusions:  "Our findings indicate that an imbalance in consumption of fatty acids, vegetables, and fruits is associated with increased risks for CD among Canadian children."

"Dietary patterns and risk for Crohn's disease in children" in Inflamm Bowel Dis (2008) Conclusions:   Four dietary patterns each were observed among both boys and girls. Pattern 1 in girls, characterized by meats, fatty foods, and desserts, was positively associated with CD (OR 4.7, 95% CI 1.6-14.2). Pattern 2, common to both boys and girls, was characterized by vegetables, fruits, olive oil, fish, grains, and nuts and was inversely associated with CD in both genders (girls: OR 0.3, 95% CI 0.1-0.9; boys: OR 0.2, 95% CI 0.1-0.5).

"Role of diet in the development of inflammatory bowel disease" in Inflamm Bowel Dis (2010)
Conclusions:  "There is currently insufficient evidence to support a direct relationship between diet and IBD. However, there is some evidence to suggest a proinflammatory effect from dietary components and obesity, either directly or via gastrointestinal bacteria. The apparent association between sugar intake and IBD, in the absence of a possible mechanism, may indicate that sugar intake is a surrogate marker for smoking, and not an independent risk factor alone. However, more rigorous research is required. The majority of studies to date have concentrated on individual foods or nutrients. Epidemiologic studies of diet and health are increasingly focusing on dietary patterns that may potentially provide a more meaningful picture of dietary exposure. The answer may lie within a genetically susceptible individual with “proinflammatory” eating habits. Future research may need to focus on aspects of the whole diet prior to development of the disease and establishing links between diet and the host microbiota."

"Lifestyle-related disease in Crohn’s disease: Relapse prevention by a semi-vegetarian diet" in World J Gastroenterol (2010)
"[W]e regard IBD as a lifestyle-related disease that is mediated by mainly a westernized diet"

Is a meat diet significant to pathogenesis and relapse in CD?

Meat is a very nutritionally dense food.

Cross-cultural studies of Asian and Western diets suggest that an increase in the consumption of animal meat and fats may be a factor in the pathogensis of CD. 
See "Is there a link between food and intestinal microbes and the occurrence of Crohn's disease and ulcerative colitis?" published in JGHF (2008)
From the Abstract:  We found several papers describing the positive association of animal meat and sweets and sugar with the occurrence of CD and UC.

See also "Epidemiologic analysis of Crohn disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan." in Am J Clin Nutrition (1996)

In Japan, studies show that semi-vegetarien diets (i.e., diets with less meat) prevented CD relapse perhaps due to the prebiotic qualities of some plants).
See "Lifestyle-related disease in Crohn’s disease: Relapse prevention by a semi-vegetarian diet" in World J Gastroenterol (2010)
From the Abstract:  SVD was highly effective in preventing relapse in CD.

In Canadian children, studies show that diets with less meat have a weaker association with CD.
See "Dietary patterns and risk for Crohn's disease in children" in Inflamm Bowel Dis (2008) Conclusions:   Findings:  Pattern 2, common to both boys and girls, was characterized by vegetables, fruits, olive oil, fish, grains, and nuts and was inversely associated with CD in both genders (girls: OR 0.3, 95% CI 0.1-0.9; boys: OR 0.2, 95% CI 0.1-0.5).

Some alternative anectodally successful diets for CD are relatively high in meats, including the SCD and paleo diets.

"What is the reason behind the increase in the number of patients with IBD in the Asian area occurring after that in the USA and western Europe?"

This important research question is quoted from "Is there a link between food and intestinal microbes and the occurrence of Crohn's disease and ulcerative colitis?" published in JGHF (2008)
Conclusions:  The present study supports that intestinal environmental factors, such as food and microbes, are very important for the pathogenesis of IBD. However, further studies are needed, because most studies lack direct evidence of a direct link to the pathogenesis of IBD.
From the Abstract:  We found several papers describing the positive association of animal meat and sweets and sugar with the occurrence of CD and UC. An analysis of Japanese epidemiological data suggested that the registered number of patients with CD or UC started to increase more than 20 years after an increased daily consumption of dietary animal meat and fats, and milk and dairy products, and after a decreased consumption of rice. Many studies implied a positive role of intestinal microbes in the occurrence of IBD. Intestinal environmental factors, such as Westernized food and intestinal microbes, seem to be involved in the increased occurrence of IBD. [emphases mine]

Why would the increase in cases be 20 years after?  Is it related to the extent of the perfusion of a westernized diet?  Or is something else at play?