Does L-carnitine improve Crohn's symptoms?

L-carnitine from Wikipedia

"L-carnitine and intestinal inflammation" in Vitamins and the immune system (2011) (pp. 353-366)
"The intestinal barrier is one of the most dynamic surfaces of the body. It is here where a single layer of epithelial cells mediates the intricate encounters that occur between the host's immune system and a multitude of potential threats present in the intestinal lumen. Several key factors play an important role in the final outcome of this interaction, including the state of oxidative stress, the level of activation of the immune cells, and the integrity of the epithelial barrier. This chapter describes the main evidence demonstrating the impact that L-carnitine has on each of these factors. These findings, combined with the demonstrated safety profile of L-carnitine, underscore the potential therapeutic value of L-carnitine supplementation in humans suffering from intestinal inflammation and highlight the functional data supporting an association between Crohn's disease and mutations in the L-carnitine transporter genes."

L-carnitine to Treat Fatigue Associated With Crohn's Disease, University of California, San Francisco

ClinicalTrials.gov identifier: NCT01523106
Estimated Enrollment:  200
Study Start Date:  February 2012
Estimated Study Completion Date:  February 2013
Active comparator:  Patients will take 4 grams of L-carnitine (2 grams twice daily) for 3 months

"Role of carnitine in disease" in Nutrition and Metabolism (2010)
"Carnitine transporter mutations in Crohn's disease consists of missense mutation(s) in the gene coding plasma membrane transporter OCTN1 (SLC22A4) and/or mutation(s) in the promoter of the gene encoding OCTN2 (SLC22A5) [14,35]. Manifestation of these mutations results in disruption of a heat shock binding element decreasing the transport function (OCTN1), and reduced expression (through OCTN2 mutation) which both result in carnitine deficiency [14]. These mutations are in strong linkage disequilibrium, creating a two-allele risk haplotype and hence increasing the overall risk of this disease [14]."

"Identifying new therapeutic targets for treatment of Crohn's disease: The role of CD47 and L-carnitine in the pathogenesis and treatment of a murine model of intestinal inflammation", Geneviève Fortin
McGill University (2010)
"L-carnitine is an amino acid derivative normally present in meat and dairy products and is also available as an over-the-counter nutritional supplement. Since mutations in the L-carnitine transporters, OCTN1 and OCTN2, were found to be associated with CD, we sought to examine its role in the development of intestinal inflammation. Remarkably, L-carnitine displayed immunosuppressive properties both in vitro and in vivo, effectively suppressing both the innate and the adaptive arms of the immune response and resulting in a significant reduction in the development of intestinal inflammation."
"We have thus identified CD47 as an important regulator of SIRPα+ DC trafficking, and demonstrate that this DC subset is implicated in the development of intestinal inflammation. Additionally, we have identified two promising new therapeutic candidates, CD47-fc and L-carnitine, for the treatment of CD."

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."