Does 5-HTP supplementation improve Crohn's symptoms?

Hydroxytryptophan from Wikipedia

5-HTP from The University of Maryland Medical Center


"The serotonin precursor 5-hydroxytryptophan reinforces intestinal barrier function" from Top Institute Food and Nutrition, Wageningen [no date]
"Tight junctions between intestinal epithelial cells form a selective barrier that contributes to gut homeostasis. Alterations in intestinal barrier function are considered to be early factors in the pathogenesis of irritable bowel syndrome (IBS). ... Oral administration of 5-HTP reinforces small intestinal barrier function by lowering intestinal sugar permeability, inducing the expression of the tight junction protein ZO-1 and rearranging tight junction proteins. These changes are associated with 5-HTP-induced alterations in mucosal serotonin metabolism. These data point to a role for serotonergic metabolism in reinforcing intestinal barrier function."

"Production and Peripheral Roles of 5-HTP, a Precursor of Serotonin" in Int J Tryptophan Res (2009) [full text]
"Physiological roles of 5-HTP in the brain have not been reported. On the other hand, 5-HTP has a specific function in the gut. As a unique BH4 [ 6R-L-erythro-5,6,7,8-tetrahydrobiopterin] transport mechanism, BH4 that transiently enters cells can be rapidly oxidized to BH2 and is exported back to the extracellular space. Meanwhile, the intestinal epithelial cells take up BH4 as its reduced form. Therefore, the intestine shares a unique BH4 transporter mechanism and a specific function of 5-HTP. Further studies would clarify the intestine-specific machinery linking the specific mechanism of BH4-dependent 5-HTP production to the specific function of 5-HTP. A 5-HT precursor 5-HTP is sometimes administered to patients with metabolic disorder.27 The finding on the function of 5-HTP in the intestine might create an opportunity to explore the effects of exogenously-applied 5-HTP on the intestine in man."

"Gut hormones: emerging role in immune activation and inflammation" in Clinical and Experimental Immunology (2010) [full article]
"The studies discussed in this review provide evidence in favour of a key role of gut hormones in intestinal inflammation. In addition to the contribution in GI physiology, such as motility and secretion, gut hormones can also play an important role in immune activation and in the generation of inflammation in gut. The precise mechanisms by which gut hormones regulate the inflammation remain to be determined. The data generated from the studies on 5-HT in gut inflammation suggest strongly that increased 5-HT released by luminal inflammatory stimuli can activate immune cells such as macrophages, dendritic cells, lymphocytes and enteric nerves via specific 5-HT receptors, which can enhance the production of proinflammatory mediators via triggering activation of the NF-κB pathway and/or other possible proinflammatory signalling systems, and which subsequently can up-regulate the inflammatory response (Fig. 1). It will be interesting to see roles of specific 5-HT receptor subtype(s) in immune activation and generation of intestinal inflammation.
...
These studies provide novel information on the role of gut hormones in immune signalling and regulation of gut inflammation. Despite being a challenging and complicated area to explore, recent studies on immunoendocrine interaction has generated new interest to elucidate the role of gut hormones in the inflammatory process and immune function. In addition to enhancing our understanding on the pathogenesis of inflammatory changes, these studies give new information on 5-HT and Cgs [chromogranins] in the context of immunoendocrine interactions in gut and intestinal homeostasis. This is very important, due not only to the alteration in enteric endocrine cells functions observed in various GI inflammatory conditions but also in non-GI inflammatory disorders and functional GI disorders such as IBS. These data may have implications in understanding the role of gut hormone in the pathogenesis of both GI and non-GI inflammation, which may lead ultimately to improved therapeutic strategies in inflammatory disorders."

If 5-HTP improves intestinal barrier function, but serotonin stimulates Crohn' symptomology, how can this be reconciled? Is 5-HTP supplementation helpful or ultimately harmful?

See my post entitled Does serotonin production worsen Crohn's symptoms?"

Can NSAIDs exacerbate Crohn's symptoms?

Do L-glutamine supplements reduce Crohn's symptoms?

Glutamine from Wikipedia
"The most eager consumers of glutamine are the cells of intestines...."

Glutamine from The University of Maryland Medical Center
"Glutamine is the most abundant amino acid (building block of protein) in the body. The body can make enough glutamine for its regular needs, but extreme stress (the kind you would experience after very heavy exercise or an injury), your body may need more glutamine than it can make. Most glutamine is stored in muscles followed by the lungs, where much of the glutamine is made.

...
Glutamine helps to protect the lining of the gastrointestinal tract known as the mucosa. For that reason, some have suggested that people who have inflammatory bowel disease (ulcerative colitis and Crohn' s disease) may not have enough glutamine. However, 2 clinical trials found that taking glutamine supplements did not improve symptoms of Crohn' s disease. More research is needed."

"Dietary Factors in the Modulation of IBD: Glutamine" from Medscape Today
"Glutamine is sometimes advocated as being beneficial in the management of inflammation. Although not an essential amino acid, glutamine is believed to play a role in the maintenance of the colonic mucosal barrier, and is an energy substrate for colonic cells. ...
However, not all of the studies regarding glutamine show positive benefit in IBD. When administered in a trinitrobenzenesulfonic acid-induced colitis model, there was actually a worsening of intestinal inflammation. Other studies in different models, however, have shown an improvement. As suggested by Akobeng and colleagues, there may be an optimal level of glutamine necessary for improvement; alteration from that level may have deleterious effects."

"Glutamine Prevents Fibrosis Development in Rats with Colitis Induced by 2,4,6-Trinitrobenzene Sulfonic Acid" in The Journal of Nutrition (2010)
"Our findings suggest that glutamine treatment not only attenuates the outcome of TNBS-induced colitis by reducing the inflammatory response but also by downregulating the increased expression of several gene pathways that contribute to the accumulation of matrix proteins. This molecule may be an interesting candidate for reducing the risk of fibrosis and stricture formation in inflammatory bowel disease."

"Glutamine and Whey Protein Improve Intestinal Permeability and Morphology in Patients with Crohn’s Disease: A Randomized Controlled Trial" In Digestive Diseases and Sciences (2012)
"Glutamine, the major fuel for the enterocytes, may improve IP. ... [A] glutamine group (GG) or active control group (ACG) and were given oral glutamine or whey protein, respectively.... Intestinal permeability and morphology improved significantly in both glutamine and ACG."

Do glycoalkaloids worsen Crohn's symptoms?

Glycoprotein on Wikipedia

Glycoalchalides in Foods, Health Canada (2010)

"Dietary Factors in the Modulation of IBD: Potato Alkaloids" from Medscape Today News
" ... [T]hese molecules have been shown to adversely affect the permeability of epithelial cells in the intestine, and this may aggravate IBD. These compounds have been shown to adversely affect the intestine permeability in an IL-10-deficient mice model of colitis, but not in normal mice, suggesting that those patients with IBD may be predisposed to this adverse effect." [emphasis mine]

"Potato glycoalkaloids adversely affect intestinal permeability and aggravate inflammatory bowel disease" in Inflammatory Bowel Diseases (2002) [full article]
"Disruption of epithelial barrier integrity is important in the initiation and cause of inflammatory bowel disease (IBD). Glycoalkaloids, solanine (S), and chaconine (C) are naturally present in potatoes, can permeabilize cholesterol-containing membranes, and lead to disruption of epithelial barrier integrity. Frying potatoes concentrates glycoalkaloids. Interestingly, the prevalence of IBD is highest in countries where fried potatoes consumption is highest.. ... Glycoalkaloids are natural steroidal toxins occurring in cultivated potatoes (Solanum tuberosum). Breeding for a reduction in the levels of the glycoalkaloids has enhanced the commercial success of the potato. Despite the fact that levels of glycoalkaloids are much lower in modern potatoes than in wild progenitors, if the potato were to be introduced today as a novel food it is likely that its use would not be approved because of the presence of these toxic compounds. Indeed, toxicological effects of potatoes have been well described in humans, ranging from gastrointestinal disturbances to hemolysis and neurotoxic effects. ...
While consumption of potatoes per capita has not changed, what has changed in recent years is the way in which potatoes are prepared for consumption. Specifically, mechanical slicing and frying of potatoes is more prevalent in developed countries, where, coincidentally, the prevalence of IBD is highest. Mechanical damage to potato tissue increases the concentration of glycoalkaloids available for consumption. In addition, frying potatoes at high temperatures does not inactivate but instead serves to preserve and concentrate glycoalkaloids within the potato, leaving them available for ingestion and delivery to the intestine. In this way the exposure of the small and large intestine to glycoalkaloids from mechanically prepared and commercially fried potatoes exceeds the exposure from an equivalent intake of potatoes boiled in water. Indeed, on boiling peeled potatoes in tap water (i.e., dilute acid), glycoalkaloids are readily hydrolyzed, yielding sugars and solanidine, both completely inactive.

It is thus intriguing to hypothesize that consumption of concentrated glycoalkaloids from mechanically prepared and commercially fried potatoes, in a genetically predisposed human host, is sufficient to disrupt the intestinal epithelial barrier and subsequently initiate or sustain luminal antigen presentation and development of IBD. Indeed, the prevalence of IBD in the world is closely aligned to developing countries, where the preparation and consumption of fried potatoes, a process known to concentrate glycoalkaloids, is common."

Do food allergies worsen Crohn's symptoms?

Crohn's and Colitis Foundation of America, Diet and Nutrition
"Is IBD caused by allergy to food?
No. Although some people do have allergic reactions to certain foods, neither Crohn's disease nor ulcerative colitis is related to food allergy. People with IBD may think they are allergic to foods because they associate the symptoms of IBD with eating."

"Immune sensitization to food, yeast and bacteria in Crohn’s disease" in Alimentary Pharmacology and Therapeutics (2001) [full article]
Discussion: "This study has demonstrated a marked sensitization to a broad range of food, bacterial and yeast antigens in patients with Crohn’s disease.
... Disease distribution, disease activity and the use of drug therapy, did not appear to influence the patients’ lymphocyte responses to the antigens tested.
... Whether the lymphocyte sensitization to lumenal antigens in Crohn’s disease is due to breached epithelium or is a part of the pathogenic process in some other way, such as a general immune cell hyper-responsiveness, is unknown.
... Crohn’s disease patients demonstrated abnormal rectal blood flow responses to yeast and citrus fruits, when group data were analysed."
Conclusions: "... These sensitized lymphocytes may contribute to the inflammatory process."

"Gut mucosal response to food antigens in Crohn's disease" in Alimentary Pharmacology and Therapeutics (2002) [full article]
"This study has shown that patients with Crohn's disease have a markedly increased response to food antigens, demonstrated both in vivo and in vitro, compared with healthy subjects. Markedly increased responses were observed to all the food antigens tested in the Crohn's disease patients, although the particularly stringent statistical criteria which were applied suggested that the most significant responses occurred to yeast and citrus fruits. ...

Whether the immunological and vascular changes observed are primary or secondary events in the pathogenesis of Crohn's disease remains to be determined. The responses obtained in patients with Crohn's disease may be secondary to sensitization that has occurred due to the breached gut epithelium, although substantial evidence suggests that antibody responses do not occur in other conditions in which the epithelium is breached, such as ulcerative colitis. If related to breached epithelium, the response may result from a genetically determined susceptibility.

... Even if these are secondary events, the dramatic in vivo changes in blood flow support the possibility that this sensitization is of clinical relevance. These data, together with the clinical response to purified liquid diets, provide strong evidence for a pivotal role in the ongoing inflammation which characterizes this disease.

... Given that food exposure is greatest in the proximal gut, it might be that disease is more common in the distal small bowel and colon. We do not believe that exposure to food antigens is the primary abnormality in Crohn's disease. However, exposure to food in the proximal gut may lead to immune sensitization, as demonstrated by several techniques in this study, resulting in activation of immune cells which circulate and re-home to where they are most concentrated (the ileum), with resultant mucosal inflammation.
... Although the strongest data were obtained for a response to citrus fruit and yeast antigens, the individual data supported the possibility of an abnormal response to the full range of antigen groups tested. In an individual, any one or more of these protein groups may be important.
... In a study of patients with Crohn's disease, ulcerative colitis, other miscellaneous diarrhoeal illnesses and healthy controls, the presence of ASCA was strongly associated with Crohn's disease, in particular small bowel disease. ... IgG and IgA ASCA were significantly raised in Crohn's disease, especially in the presence of small bowel disease.
... The specificity of the antibody response in Crohn's disease to S. cerevisiae, but not to Candida albicans, further supports the concept that ASCA are not simply the result of a generalized increase in intestinal permeability.
... Levels of IgE/IgG anti-IgE immune complexes were determined. In Crohn's disease sera, no food-specific IgE could be detected, but levels of immune complexes of IgE and IgG anti-IgE autoantibodies were significantly increased compared to healthy controls.
... If sensitized lymphocytes and specific antibodies play a pathogenic role, the exclusion of relevant foods may provide therapeutic benefit, even in the short term.
...  there were no differences between patients and controls in skin antigen testing. This finding is in agreement with other reports of the failure of skin testing to diagnose food sensitivities in patients with suspected food allergies or inflammatory bowel disease.  This difference between skin testing and blood and gut testing also suggests distinct compartmentalization of immune responses, with gut sensitization leading to a specific gut response." [emphases mine]

"What Is the Role of Food Allergy and/or Intolerance in the Genesis of IBD?" in General Gastroenterology (2006)
"True food allergies constitute a different pathogenesis and pathology from true IBD. Although the true cause of IBD remains elusive, it appears to involve a combination of genetic susceptibility, immune dysregulation, and environmental pressures. Patients with IBD are more likely to suffer from food allergies or intolerances than the normal population, but there is not good evidence to suggest that an allergy is the trigger for the underlying inflammatory process. Whereas some groups have been able to demonstrate immune responses to certain food antigens in patients with Crohn's disease, these findings cannot be replicated in other populations, making this mechanism for a pathogenesis unlikely. In patients with subclinical disease, an allergy can precipitate IBD phenotypes, but again, the link between allergies and causation is weak. Certainly those patients who have undiagnosed food intolerances are less likely to respond to standard IBD therapies.
Patients should be counseled regarding their dietary habits to monitor which specific foods or food groups may trigger worse gastrointestinal or systemic symptoms. Elimination diets, however, are rarely needed in the IBD patient."

"Clinical Relevance of IgG Antibodies against Food Antigens in Crohn’s Disease: A Double-Blind Cross-Over Diet Intervention Study" in Digestion (2010)
Results:  "The daily stool frequency significantly decreased by 11% during a specific diet compared with a sham diet. Abdominal pain reduced and general well-being improved. "
Conclusion:  "A nutritional intervention based on circulating IgG antibodies against food antigens showed effects with respect to stool frequency. The mechanisms by which IgG antibodies might contribute to disease activity remain to be elucidated." [emphasis mine]
My 5% better comment:  If 10 trips to the bathroom are the norm, this would be reduced by 1.  If each trip takes on average 15 minutes, this would save approximately 8 hours per month, which is the equivalent of one working day.  Would identifying IgG antigens and eliminating them be meaningful for a CDer?  You bet.

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."

What is the significance of positive ASCA?

What are Anti-saccharomyces cerevisiae antibodies?

Relationship to Celiac Disease

Antibodies anti-Saccharomyces cerevisiae (ASCA) do not differentiate Crohn's disease from celiac disease in Arquivos de Gastroenterologia (2010)
From the article:

"The protective function of the intestinal mucosa is called "permeability"(12). When the intestinal mucosal barrier is broken, with junctions-mediated barrier defects, an influx of luminal antigens may result in inflammation, even by chronically stimulating resident, with consequent recruitement of immunocompetent cells from the lamina propria(3, 7). In patients with autoimmune diseases, like CD, or in infectious disease, and in various other clinical conditions, ASCA can be positive. The presence of ASCA may reflect a shared permeability disorder, leading to the enhanced exposure to various antigens that, depending on the genetic background, may provoke various or multiple autoimmune disorders.(3, 4, 5, 7, 9, 14). The antibodies in the sera of the analysed ASCA positive cases proved a systemic immune response against Sacharomyces cerevisiae (generally accepted as not a pathogen) and suggested the end of the oral tolerance against the yeast's antigens(3).  ...
In conclusion, the results show that ASCA was found in patients with CeD and disappear after a GFD. So, it is presumed that ASCA positivity is not a specific marker for Crohn's disease but correlates with the (auto) immune inflammation of the small intestine."

Relationship to CD subtype

"Serologic Investigations in Children with Inflammatory Bowel Disease and Food Allergy" in Mediators of Inflammation (2009)
" The occurrence of ASCA antibodies (IgA and/or IgG) was observed in 73.7% of children with Crohn’s disease, 17.5% with ulcerative colitis and almost 30% with allergic colitis, statistically significantly more frequent in children with Crohn’s disease in comparison with the other examined groups and controls. Statistically, patients with Crohn’s disease and the presence of ASCA revealed a significantly more frequent localization of lesions within the small bowel and a tendency towards older age (mean age 15.5). Sensitivity ASCA (IgG or IgA) for diagnosing Crohn’s disease was determined as 73.7%, specificity (in relation to controls) was 91.3%.
... In our examination we found a relation between the examined mutations of gene NOD2/CARD15 and the presence of antibodies. Similary Annese in a large group of patients with Crohn’s disease proved a relation between mutation NOD2/CARD15 and the localization in the small bowel, the narrowing form of the disease and the early age of diagnosis, but she also showed a relation between the mutation and the presence of ASCA [31]. The presence of ASCA is important for patients with undetermined colitis, however, 50% of these patients do not produce ASCA and p-ANCA."

"Genetic variants of the mannan-binding lectin are associated with immune reactivity to mannans in Crohn’s disease" in Gastroenterology (2004)
"Conclusions: A subgroup of CD patients is characterized by ASCA positivity, T-cell proliferation on mannan stimulation, and mutations in the MBL gene that result in MBL deficiency. Thus, we propose that enhanced mannan exposure stimulates specific immune responses in a subgroup of CD patients with genetically determined low MBL concentrations. This enhanced exposure contributes to the generation of ASCA."

How can subclinical Crohn's be diagnosed earlier?

"Prodromal Irritable Bowel Syndrome May Be Responsible for Delays in Diagnosis in Patients Presenting with Unrecognized Crohn’s Disease and Celiac Disease, but Not Ulcerative Colitis" in Digestive diseases and sciences (2011)
" This is the first study to make direct comparisons of prodrome periods between celiac disease and IBD. Prodrome duration in celiac disease is significantly longer and more often characterized by P-IBS than IBD. In celiac disease and CD, P-IBS increases prodrome duration. This may represent a failure to understand the overlap between IBS and celiac disease/IBD."

"The Manitoba Inflammatory Bowel Disease Cohort Study: Prolonged Symptoms Before Diagnosis—How Much Is Irritable Bowel Syndrome?" in Clinical Gastroenterology and Hepatology (2006)

"Background & Aims: The Manitoba Inflammatory Bowel Disease (IBD) Cohort Study is a population-based prospective cohort study of recently diagnosed IBD (n = 396). At enrollment, 162 (41%) indicated gastrointestinal symptom ≥3 years before diagnosis. We aimed to determine whether coexistence of irritable bowel syndrome (IBS) had a role in symptoms before IBD diagnosis.
Conclusions: These data suggest that older patients and those with likely and possible preexisting IBS are more likely to experience longer symptom duration before diagnosis of IBD. The prevalence rate of IBS was similar to estimated base rates in the general population."

"Isolated Ileal Erosions in Pts With Mildly Altered Bowel Habits: Discussion" from Medscape Today (2006)

"These cases raise the issue of the appropriate diagnostic approach in this situation. There are no formal guidelines about whether similar lesions should be classified by pathologists as nonspecific or as "suggestive of Crohn disease." One option is to use the diagnosis of "isolated ileal erosion" and add a comment stating "this lesion is idiopathic in most patients; however, in approximately one third, the disease will eventuate into typical Crohn disease, often after a prolonged interval."

"Identification of a prodromal period in Crohn's disease but not ulcerative colitis" in The American Journal of Gastroenterology (2000)

"There is a significant prodromal period before the time of diagnosis of Crohn's disease that is not found in ulcerative colitis even after exclusion of subjects with IBS."

"Family studies in Crohn's disease: new horizons in understanding disease pathogenesis, risk and prevention" in Gut (2011)
"Specific physiological abnormalities associated with CD, such as increased intestinal permeability and raised faecal calprotectin, are also abnormal in some relatives of patients with CD. The combination of genotypic factors and biomarkers of risk makes the development of models of disease prediction a realistic possibility. Furthermore, enhanced understanding of the genotype and phenotype of the at-risk state in relatives of patients with CD allows the earliest stages in the pathogenesis of CD to be investigated and may allow intervention to prevent disease onset."