Does MSM (methylsulfonylmethane) supplementation improve Crohn's symptoms?

Are the Health Benefits of MSM Related to Sulfur?: "As I’ve said, sulfur is an emerging stealth player in nutrition and for a variety of mechanisms, including the detox and anti-inflammatory pathways. Remember, if you don’t have enough sulfur in your diet, you’re not going to be able to naturally produce glutathione, which is absolutely essential for removing heavy metals and many of the toxins you’re exposed to. People who might want to consider using some supplemental sulfur sources such as MSM include those who have: Chronic inflammatory conditions Aches and pains / sore muscles and achy joints" 'via Blog this'

Does olive oil reduce Crohn's imflammation?

Olive oil from Wikipedia

Polyphenol from Wikipedia

"Olive oil, extra virgin" from the world's healthiest foods
"The anti-inflammatory strength of olive oil rests on its polyphenols. These anti-inflammatory compounds include at least nine different categories of polyphenols and more than two dozen well-researched anti-inflammatory nutrients. Research has documented a wide variety of anti-inflammatory mechanisms used by olive oil polyphenols to lower our risk of inflammatory problems. These mechanisms include decreased production of messaging molecules that would otherwise increase inflammation (including TNF-alpha, interleukin 1-beta, thromboxane B2, and leukotriene B4); inhibition of pro-inflammatory enzymes like cyclo-oxygenase 1 and cyclo-oxygenase 2; and decreased synthesis of the enzyme inducible nitric oxide synthase.
...
These anti-inflammatory benefits of extra virgin olive oil do not depend on large levels of intake. As little as 1-2 tablespoons of extra virgin olive oil per day have been shown to be associated with significant anti-inflammatory benefits."

In Crohn's, is IL-6 inflammation a beast worth slaying?

There appears to be a number of nutrients that show promise in attenuating IL-6 inflammation.  These include vitamins like K and choline, antioxidants like astaxanthin, curcumin, and resveratol, and amino acids such as arginine, glutamate, and tyrisone.

Perhaps it is possible to gain some control over IL-6 inflammation by increasing the presence of these nutrients through diet and supplements.  But even then, is IL-6 inflammation a beast worth slaying?  How big a player is it in Crohn's inflammation?  Will a reduction in IL-6 inflammation result in perceptable improvements in Crohn's symptoms?

Interleukin 6 from Wikipedia

"The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer" in Trends in Molecular Medicine, Review (2008) [PDF full article]
"Recent discoveries involving the cytokine interleukin (IL)-6 have originated from diverse disciplines, revealing roles in biological processes that are likewise varied. The most novel findings suggest a connection between inflammation and diseases, such as insulin resistance associated with diabetes mellitus and cancer, which had not or only weakly been appreciated previously. The IL-6 pathway is one of the mechanisms linking inflammation to these disease processes. In addition, new evidence points toward IL-6 as one of the mediators coordinating the interface between adaptive and innate immunity. Here, we review the evidence linking IL-6 to inflammatory diseases and cancer.
...
In acute inflammation, neutrophils form the largest component of leukocytes recruited. As the acute inflammation resolves, the leukocyte population changes from predominately neutrophilic to mostly monocytic. This transition from acute to sustained inflammation is in large part orchestrated by IL-6. ... Thus, IL-6 is a key signal in the transition from the initial innate immune response to infection to a more sustained, adaptive immune response....
More recently, IL-6 has emerged as a key regulatory signal in the development of the newly described effector T-cell subset, so-called Th17 cells, named for their production of the cytokine IL-17.
...
Thus, we find IL-6 at the intersection where T cells can either go on to become suppressors (Treg) or activators (Th17) of the adaptive immune system.  In this way, IL-6 helps to coordinate the innate immune system (from which it comes initially) and the adaptive immune system.
...What about states of chronic inflammation?  It can be said with little hesitation that, in nearly every disease condition involving chronic inflammation, where serum IL-6 levels have been assayed, they are elevated.  Examples include ... IBDs....
...
In idiopathic IBD ... there is pathogenic build-up of CD4*T cells at sites of inflammation, mediated in part by IL-6, which provides ... an anti-apoptotic signa to T cells through the induction of Bcl-2 and Bcl-xL and promotes Th17 lineage differentiation.  IL-17 is upregulated in patients with both types of IBD.  IL-6 levels are elevated markedly in the serum of patients with IBD, decrease with treatment of inflammation and are predictive of IBD relapse.
...
... a chronic inflammatory state is created, in which IL-6 has the part of a proinflammatory effector signal for NF-kB. ... The pathogenic role that IL-6 has in IBD is effected by trans-signaling (on T cells) and induction of STAT3, which decreases T-cell apoptosis in Crohn's disease and colitis models.
...
A pilot trial of a humanized monoclonal antibody to the IL-6 receptor was undertaken in 2004 with Crohn's disease patients and showed clinical improvement ... in the patients receiving the drug.  Despite the clinical improvement, however, there was little improvement seen endoscopically or histologically."

In Crohn's why is autophagy important?

Autophagy from Wikipedia
"In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more essential processes. ...[M]any questions about the actual processes and mechanisms involved still remain to be elucidated. Its role in disease is not well categorized; it may help to prevent or halt the progression of many diseases, such as atherosclerosis, cancer,neurodegenerative disease and chronic infection,[3] however, in some situations, it may actually contribute to the development of a disease.[4]"

"Nutrient modulation of autophagy: Implications for inflammatory bowel diseases" in Inflammatory Bowel Diseases (2012)
"During nutrient deprivation, autophagy provides the constituents required to maintain the metabolism essential for survival. Recently, genome-wide association studies have identified genetic determinants for susceptibility to Crohn's disease (CD) such as ATG16L1 and IRGM that are involved in the autophagy pathway. Both disease-carrying NOD2 mutations and ATG16L1 mutations may result in impairment of autophagy. Impairment in autophagy results in impaired clearance of microbes. Ileal CD is associated with Paneth cell loss of function such as decreased production of α-defensins, which may arise from mutations in NOD2 or autophagy genes. Nutrients are able to modify several cellular pathways and in particular autophagy. We summarize the contribution of a variety of dietary components to activate autophagy. Understanding the crosstalk between nutrients and autophagy in the intestine may provide novel targets that have therapeutics potential in intestinal inflammation. Nutrient activation of autophagy may contribute to restoring the Paneth cell loss of function in ileal CD"
"Pattern recognition receptor and autophagy gene variants are associated with development of antimicrobial antibodies in Crohn's disease" in Inflammatory Bowel Diseases (2012)
"Variants in innate immune genes involved in pattern recognition and autophagy but not the interleukin-23 signaling pathway influence antimicrobial seroreactivity in CD. In particular, the additive effect of NOD2 3020insC and ATG16L1 T300A suggests a role for autophagy in development of ASCA [Anti-Saccharomyces cerevisiae antibodies].

"Abnormal Activation of Autophagy-Induced Crinophagy in Paneth Cells From Patients With Crohn's Disease" in Gastroenterology (2012)
"Autophagy-related 16 like-1 (ATG16L-1), immunity-related GTPase-M (IRGM), and nucleotide-binding oligomerization domain-containing 2 (NOD2) regulate autophagy, and variants in these genes have been associated with predisposition to Crohn's disease (CD). However, little is known about the role of autophagy in CD. Intestinal biopsies from untreated pediatric patients with CD, celiac disease, or ulcerative colitis were analyzed by immunohistochemistry and electron microscopy. We observed that autophagy was specifically activated in Paneth cells from patients with CD, independently of mucosal inflammation or disease-associated variants of ATG16L1 or IRGM. In these cells, activation of autophagy was associated with a significant decrease in number of secretory granules and features of crinophagy. These observations might account for the disorganization of secretory granules previously reported in Paneth cells from patients with CD."

"Modulation of inflammation by autophagy: consequences forCrohn's disease" in Current Opinion in Pharmacology (2012)
"Autophagy, the cellular machinery for targeting intracellular components for lysosomal degradation, is critically involved in the host defence to pathogenic microorganisms. Recent studies have unveiled several aspects of the immune response that are regulated by autophagy, including antigen presentation and production of proinflammatory cytokines. Polymorphisms in autophagy genes result in dysregulation of these processes and affect gut homeostasis. Genetic variants in autophagy genes are associated withCrohn's disease (CD), a disease in which an overwhelming cytokine production induces inflammation on the one hand, while a defective antigen presentation is also found on the other hand. This review summarizes the recent advances in understanding the complex interaction between innate immunity pathways and autophagy, with a focus on the modulatory effects of autophagy on inflammation."

"Use of sirolimus (rapamycin) to treat refractory Crohn’s disease", Case Report in Gut (2008)
"We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn’s disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option. New insights provided by the results of genome-wide association scanning in Crohn’s disease highlight autophagy, a cellular process implicated in the clearance of intracellular bacteria, as a key process in Crohn’s disease pathogeneses. Sirolimus (rapamycin) is a drug used to upregulate autophagy in cell culture in the laboratory, and in clinical practice to prevent rejection following organ transplantation due to independent immunosuppressive action. Our patient was treated with sirolimus for 6 months at a dose that maintained serum trough levels of 5 ng/ml. There was marked and sustained improvement in Crohn’s disease symptoms with the Harvey–Bradshaw index falling from 13 to 3, in serum markers of inflammation (C-reactive protein fell from 79 to 2) and endoscopic appearance. This is the first reported case of the use of sirolimus to treat Crohn’s disease."

"Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis" in Nature Genetics (2007)

"... [W]e demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease."

"Genome-Wide Association Scanning Highlights Two Autophagy Genes, ATG16L1 and IRGM, as Being Significantly Associated with Crohn’s Disease," Addendum to "Sequence Variants in the Autophagy Gene IRGM and Multiple Other Replicating Loci Contribute to Crohn's Disease Susceptibility" (Nat Genet 2007)
"The molecular components of autophagy may provide novel therapeutic targets, and candidate drugs are
already in clinical use in other contexts. Rapamycin (sirolimus), for example, is widely used in human organ transplantation to prevent rejection. The drug is used experimentally to induce autophagy via its inhibition of mammalian target of rapamycin (mTOR), a large multidomain protein kinase that regulates cell growth and represses autophagy.16 In animal studies rapamycin ameliorated progression of animal models of Huntington’s disease—itself characterized by failure of cells to clear abnormally large protein aggregates. It is thought that rapamycin exhibits its protective effect through enhancement of autophagy. If, as seems increasingly likely, CD is in part due to deficits in autophagy, then rapamycin with its autophagy-promoting, immunosuppressant and anti-fibrotic properties would seem to be an excellent candidate therapy."

What is epithelial restitution?

"Epithelial restitution and wound healing in inflammatory  bowel disease" In World J Gastrointerol (2008)
"Repeated damage and injury of the intestinal surface are key features of various intestinal disorders including inflammatory bowel diseases and require constant repair of the epithelium. Enhancement
of intestinal repair mechanisms by regulatory peptides or other modulatory factors may provide future approaches for the treatment of diseases that are characterized by injuries of the epithelial surface. ...  Inflammatory processes especially may interfere with epithelial cell migration and proliferation and thus modulate intestinal epithelial healing."

"Pathophysiologic Rationale for Biological Therapies in IBD: Downstream Effector Mechanisms of Gut Damage and Repair" from Medscape News
"Matrix metalloproteinases (MMPs) are intimately involved in epithelial restitution and ulceration in the gutFlattened epithelial cells at the edge of ulcers secrete MMP-1 (interstitial collagenase), MMP-7 (matrilysin), and MMP-10 (stromelysin-2), presumably to allow them to remodel granulation tissue as they attempt to cover the ulcer. In the ulcer bed, fibroblasts secrete MMP-1 and MMP-13 (collagenase-3), as well as MMP-3 (stromelysin-1) and MMP-2 (gelatinase-A). Macrophages secrete MMP-10 and MMP-12 (metalloelastase). Careful thought will be needed in choosing MMP inhibitors to treat IBD. While inhibition may prevent MMP-mediated degradation of lamina propria matrix, it would not be helpful if the inhibition also prevented epithelial restitution."

What is barrier function?

"Intestinal barrier function" in Curr Opin Clin Nutr Metab Care (2002)
"Intestinal barrier function regulates transport and host defense mechanisms at the mucosal interface with the outside world. Transcellular and paracellular fluxes are tightly controlled by membrane pumps, ion channels and tight junctions, adapting permeability to physiological needs. Food and microbial antigens are under constant surveillance of the mucosal immune system. Tolerance against commensals and immunity against pathogens require intact antigen uptake, recognition, processing and response mechanisms. Disturbance at any level, but particularly bacterial translocation due to increased permeability and breakdown of oral tolerance due to compromised epithelial and T cell interaction, can result in inflammation and tissue damage. New therapeutic approaches including probiotics and peptides to restore disrupted barrier function are evolving."

Does antioxidant dietary supplementation lessen inflammation in CD?

Antioxidants on Wikipedia
"An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When the chain reaction occurs in a cell, it can cause damage or death. ...
Although oxidation reactions are crucial for life, they can also be damaging; hence, plants and animals maintain complex systems of multiple types of antioxidants, such as glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases. Low levels of antioxidants, or inhibition of the antioxidant enzymes, cause oxidative stress and may damage or kill cells"

Oxidative Stress on Wikipedia
"Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of tissues can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Some reactive oxidative species can even act as messengers through a phenomenon called redox signaling.
In humans, oxidative stress is involved in many diseases. Examples include Sickle Cell Disease^[1], atherosclerosis, Parkinson's disease, heart failure, myocardial infarction, Alzheimer's disease, Schizophrenia, Bipolar disorder, fragile X syndrome^[2] and chronic fatigue syndrome, but short-term oxidative stress may also be important in prevention of aging by induction of a process named mitohormesis.^[3] Reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens."

"Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease" in Am J Clin Nutr (2004)
"Dietary supplementation with fish oil plus antioxidants is associated with modified PBMC [peripheral blood mononuclear cell]composition and lower production of PGE2 [prostoglandin E2] and IFN-y [Interferon Gamma] by circulating monocytes or macrophages."


"The Effects of an Oral Supplement Enriched With Fish Oil, Prebiotics, and Antioxidants on Nutrition Status in Crohn’s Disease Patients" in Nutrition in Clinical Practice (2011)
"Background: Research in the treatment of Crohn’s disease (CD) supports anti-inflammatory benefits of n-3 fatty acids from fish oil, prebiotics, and antioxidants. A nutritionally balanced inflammatory bowel disease nutrition formula (IBDNF) enriched with these compounds has the potential to improve nutrition status and disease activity in CD. ...
Conclusions: IBDNF has the potential to deposit fat-free and fat mass, improve vitamin D status, and improve quality of life in CD patients."

How can PGE2 (prostaglandin E2) production and subsequent inflammation be minimized in CD?

"Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease" in Am J Clin Nutr (2004)
"Dietary supplementation with fish oil plus antioxidants is associated with modified PBMC [peripheral blood mononuclear cell]composition and lower production of PGE2 [prostoglandin E2] and IFN-y [Interferon Gamma] by circulating monocytes or macrophages."

What are the secondary effects 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."