Functional dyspepsia and associated gastrointestinal diseases are becoming more prevalent in a population weaned on processed modern foods. Mark J Tallon PhD reviews the clinical relevance of a growing number of natural products that target gut health.
The gastrointestinal tract is diverse in its physiological, biochemical and molecular structure and functions. It is therefore of no surprise that disease states have a highly varied etiology often characterised according to the organ of involvement such as ulcerative colitis, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). The direct effects of these diseases or malnutritive states can result in loss of mucosal immunity and integrity, microflora degradation, excessive inflammation or ulceration of the gastrointestinal tract.
Therefore, the role of any medicinal or immuno-therapeutic intervention must be to counter-balance the loss of optimum gut function by reducing the action of aggressive factors such as proteolytic enzymes, hydrochloric acid and abhorrent immune responses. Many of the current medicinal approaches are imperfect for improving gastrointestinal health. As such, the demand for safe and effective natural and over-the-counter therapies has increased. Because of the range of conditions that fall under the umbrella of the gut health category, a myriad of functional nutrients are purported to be viable dietary prophylaxes.
This article reviews the current role of a selection of supportive and therapeutic nutrients for better gut health and provides an overview of the escalating advances in novel nutrients outside medicines long established in the anti-inflammatory and immunosuppressive pharmacopoeia.1
Crohn?s disease is one condition in which dietary fat content and fish oil-derived n-3 polyunsaturated fatty acids (PUFAs) influence the severity of the condition. Crohn?s is an IBD that can be characterised by sporadic inflammation throughout the gastrointestinal tract, though primarily affecting the small intestine, leading to diarrhoea, abdominal pain, and loss of appetite and weight. Five mechanisms are involved in the pathogenesis of IBD, including altered intestinal motility, increased visceral sensitivity, disturbed intestinal reflexes (intrinsic and extrinsic),2 hyperreactivity against bacterial antigens, and unrestrained activation on the intestinal immune system.3
Although diet has been established for patients with IBD (including Crohn?s) as a control treatment due to their aberrant fatty acid profile, the influence of dietary fats is still unclear. Nevertheless, a recent study seems to indicate total dietary fat intake can influence markers of IBD and remission rates.4 This study showed that not only was total fat intake an important factor in the treatment of Crohn?s disease, of equal importance was fat composition. As long-chain triglyceride content increased, there was a decrease in the therapeutic effect of lower dietary fat intake.4
The n-3 fatty acids derived from fish have been shown to inhibit leukotriene B4, a chemo-attractant and pro-inflammatory eicosanoid implicated in IBD. As mentioned, Crohn?s leads to abnormal fatty acid metabolism but also an attenuated antioxidant status, giving some rationale for the use of n-3 PUFAs as therapeutic nutrients for Crohn?s patients.5 Supplementation with a liquid formula containing n-3 and antioxidants has been shown to increase antioxidant status.6
Further data demonstrate the efficacy of fish oil capsules (equivalent to 2.7g of EPA [eicosapentaenoic acid] and DHA [docosapentaenoic acid]) in maintaining remission rates of Crohn?s sufferers.
Although the data look promising in this condition, other inflammatory bowel diseases—namely ulcerative colitis—have study results indicating that n-3s are ineffective in maintaining remission rates.7 There are two excellent reviews on fish oils and the use of lipids in the treatment of ulcerative colitis.8,9
Pre- and probiotics
A disturbance of bacterial intestinal flora may be a triggering factor for both Crohn?s disease and ulcerative colitis.10 Probiotics—living micro-organisms that exert health benefits beyond basic nutrition—are still relatively under-researched when it comes to human studies. Nevertheless, late 2003 and early 2004 have seen the release of two new human clinical trials on a highly concentrated probiotic formula and a bifidobacteria-fermented milk (BFM) supplement for ulcerative colitis and pouchitis.11,12 The first of these studies was a randomised clinical trial using BFM as a dietary adjunct to treat ulcerative colitis.11 The BFM group was given 100mL/day (containing B. breve, B. bifidum and L. acidophilus YIT 0168—in quantities of 10x1012/mL) BFM for one year vs. a standard control. At the end of the study, supplementation with BFM maintained remission in nine out of the 10 subjects, compared to only three in the control group. This datum suggests BFM may help prevent ulcerative colitis relapse.
Concentrated multiple probiotic formulas containing as many as eight bacterial species are a novel advancementA very recent study used a concentrated multiple probiotic formula containing eight bacterial species (Streptococcus salivarius ssp. thermophilus, Bifidobacterium [B. breve, B. infantis, B. longum], Lactobacillus acidophilus, L. plantarum, L. casei, L. delbrueckii ssp. bulgaricus).12 This is a novel advancement in the fledgling field of bacteriomedicine, as most studies have applied only one or two bacterial species to treat IBD.
Pouchitis is often considered to be a form of chronic ulcerative colitis and is a complication for the 40 per cent of ulcerative colitis sufferers who will need their colons removed and an internal pouch created to store stool using a portion of the small intestine. In one study, 36 patients were randomised to receive either a placebo or 6g of a patented probiotic formulation called VSL #3 (containing numerous strains of bacteria at high concentrations) once a day for one year, or until relapse. Only three of the 20 patients receiving VSL #3 did not remain in a remissive state compared to 15 people in the placebo group.
Prebiotics are dietary fibres that provide another way to promote the growth of preferential intestinal bacteria over bacteria that may potentially be pathogenic. Two recent studies show prebiotics enhance calcium absorption and improve antioxidant capacity. 13,14
The use of inulin as a prebiotic has also been studied for its beneficial influence on IBD. In patients who have undergone ilial re-section, 24g/day inulin increased butyrate (a short-chain fatty acid), decreased pH and showed a real decrease in inflammation (assessment made endoscopically).15 A similar study also reported positive preliminary data using prebiotics obtained from germinated barley (20?30 g/ day for four weeks).16 An open-label, randomised study compared another fibre, Platago ovata seeds, to a traditional pharmacological intervention, mesalazine, in 102 patients with ulcerative colitis who were in remission. Results showed that after 12 months, the treatment failure rate was 40 per cent with the fibre, 35 per cent with the drug, and 30 per cent with a combination of the two.17 These few studies have opened up the door for more effective therapeutic management of IBD.
A host of novel therapies is currently under investigation for gut health including arginine, epidermal growth factor, nucleic acids, albumin and nitric oxide modulators. The following selection is an overview of emerging therapies reaching the natural products supply chain but with limited or emerging human clinical data.
Glutamine, while not a new therapy, is an amino acid that appears to serve as a fuel for the cells that line the small intestines. Glutamine supplementation has been shown to ameliorate declining levels of glutathione and growth hormone.18 This is important because around 20?30 per cent of children and adolescents with IBD show growth retardation.19 Therefore, the primary focus has been to restore a normal growth hormone concentration. Both free and total forms of insulin-like growth factor (IGF-1) are significantly reduced (53 per cent and 35 per cent, respectively) in patients with Crohn?s and ulcerative colitis.20 It is therefore no surprise glutamine has been used as a therapy. In a double-blind, randomised control study, 15 children were assigned to a polymeric diet (complete nutrition in a very easily digested liquid form) or to a glutamine-enriched diet (all subjects had clinically depressed IGF-1 levels prior to the study). After four weeks of therapy, no significant change in IGF-1 was observed.21
Levels of—and the balance between—the most important antioxidants are impaired within the intestinal mucosa from IBD patientsIt has been hypothesised that in glutamine-deficient parenteral nutrition cases, mucosal atrophy and increased bacterial translocation occurs that may exacerbate IBD symptoms.22 Although glutamine supplementation in animal and critically ill patient interventions has been shown to enhance mucosal integrity, decrease bacterial translocation,23 and improve nitrogen balance24 and amino acid profiles,25 the case for those suffering with IBD or IBS is less encouraging. Dietary glutamine supplementation in patients with Crohn?s disease was not effective in restoring intestinal permeability26 or inducing remission.27 Overall, therefore, nutritional support with glutamine seems at this time to be an ineffective method of correcting IBD derangements in IGF-1 or mucosal integrity at the dose used in these studies.
Peppermint (Mentha piperata) is usually taken after a meal to reduce indigestion and colonic spasms by acting locally in the stomach and duodenum to produce smooth-muscle relaxation.28 It is a naturally occurring hybrid, a cross between water mint (M. aquatica) and spearmint (M. spicata). Peppermint can be an effective means of alleviating some dyspeptic symptoms.29,30
Artichoke (Cynara scolymus L.) leaves may treat dyspepsia, primarily through its cholerectic effects (increasing bile secretion), but recent data suggest it may have other medicinal qualities.31 In a double-blind, randomised controlled trial, 247 patients with functional dyspepsia were treated with either a commercial artichoke leaf extract (ALE) preparation (2 x 320mg plant extract) or a placebo.32 The overall symptom improvement over the six-week treatment period was significantly greater with ALE than with the placebo. This improved the disease-specific quality of life in patients with functional dyspepsia. The results of this study were demonstrated previously and suggest that with more research natural botanical therapies may play a role in the treatment of functional dyspepsia beyond the heavily criticised in-vitro studies of old.33
Antioxidant supplementation may be beneficial for IBD patients. Intestinal inflammation is accompanied by excessive production of reactive oxygen species and nitrogen metabolites. In order to counteract their harmful effects, the intestinal mucosa contains an extensive system of antioxidants. The highly reactive molecules produced by inflammation and oxidative stress can produce tissue damage by compromising cellular integrity and/or function. It has previously been demonstrated that the levels of—and the balance between—the most important antioxidants are seriously impaired within the intestinal mucosa from IBD patients.34,35
In a recent study, researchers from Leiden University Medical Center, in the Netherlands, reported elevated lipid peroxidation, as estimated by the malondialdehyde concentration, in both Crohn?s disease and inflamed ulcerative colitis mucosas.36 Lead researcher Kruidenier suggests, ?The present study underlines the importance of oxidative stress in the pathogenesis of IBD and provides clues regarding the [anti]oxidants involved.?36
Indeed, results from the first randomised controlled trial of antioxidant supplementation in IBD patients may fit directly with this research. Fifty-seven Crohn?s disease patients with evidence of oxidative stress were randomised to receive either an antioxidant supplement (800IU vitamin E and 1,000mg vitamin C) or a placebo for four weeks.37 Markers of oxidative stress decreased over the study period and levels of vitamins C and E increased. This suggests that IBD patients may be oxidatively stressed and have an increased requirement for antioxidant micronutrients.
Synbiotics are pre- and probiotic nutrients formulated in a single product, allowing the concurrent delivery of both microbiotic formulas. Fermented milk sources are probably the only true synbiotics because they provide both live bacteria (probiotics) and the products of fermentation (prebiotics) that may affect the growth and activity of intestinal microflora.
Although a growing body of research is developing, science is still playing catchup with consumer demand. Francisco Guarner, a professor at the University of Barcelona in Spain and a specialist in digestive system research, suggests: ?We really do not know yet what is the contribution of the colonic flora to host health, but we presume that deficiencies in the symbiosis of flora-host may be in the origin of diseases such as allergies and other autoimmune disorders, diabetes and colon cancer. Therefore, improvements in our knowledge of host-flora interactions will certainly lead to the design of probiotics, prebiotics and synbiotics with a real ability to optimize physiology of the colonic flora.?
Recent work has started to shed light on some of these uncertainties, beginning with a study of 58 children with acute gastroenteritis receiving a low-lactose formula with or without a combination of Lactobacillus acidophilus, Bifidobacterium and oligofructose.38 The duration of diarrhoea was significantly shortened in the supplemented group.
A study released in early 2004 has investigated the application over a four-week period of a synbiotic (Lactobacillus rhamnosus GG + Bifidobacterium lactis and inulin enriched with oligofructose) on systemic and intestinal immunity to rats habituated to a high-fat diet.39 The probiotic-supplemented group showed modestly affected immune functions, whereas systemic immunomodulatory effects were observed in rats fed the synbiotic. The prebiotic supplementation primarily acted at the level of the gut-associated lymphoid tissue (the largest lymphoid organ in the body, which is highly sensitive to changes in the gut microflora).39
The authors of the study concluded that the combined application of pre- and probiotics has different effects from those of the individual supplements but does not simply result in additive or synergistic effects.
Carnosine is a synthetic ingredient. It is an imidiazole dipeptide composed of beta-alanine and L-histidine. It may function as an antioxidant, skeletal muscle buffer and anti-glycating agent in human tissues. Zinc-carnosine is an artificially chelated compound studied extensively in vivo and in vitro for its capacity to influence peptic ulceration.40,41 The theory behind the mechanism of action is that it slowly dissociates in the stomach, allowing it to adhere to the mucosal lining and release the zinc ion and L-carnosine. This leads to a greater mucosal integrity and growth factor expression that may heal ulcer-related lesions.42 Although a combined product, most data associate any success primarily via its zinc- delivering capabilities.42
Further research is clearly needed in this field of human health and disease. A clearer understanding of what the long-term health effects may be with regards to changing the composition and/or activity of human microflora is essential if we are to make confident recommendations about their use to the consumer. The future of optimum gut health is likely not to rely solely on one food or nutrient but on a combination of natural therapies.
Seven European laboratories are now co-operating in a joint project (FAIR CT97-3035) to develop, refine and apply molecular methods toward a better understanding of human intestinal microflora and to devise robust methodologies for monitoring the gut flora in response to diet and supplementation.
This is one direction science is taking us. Others may include developing nutritional or pharmacological therapies in a completely different way. One way may be to affect the transport system of epidermal growth factor, a 53-amino acid peptide shown in animals to reverse severe ulceration of the small intestine in ulcerative colitis.43 Epidermal growth factor is notoriously unstable in supplemental form and recent data demonstrate that its transporter, oligopeptide (pept-1), is induced in patients with Crohn?s disease and therefore will play a role in the inflammatory response in these patients.44
In essence, the use of all these new therapeutic perspectives will offer hope for sufferers of common dyspeptic conditions as well as less publicised diseases such as celiac disease and autoimmune diseases such as food allergies. Therefore, further research must lead to an amicable solution fulfilling the delicate balance between the efficacy of disease management based upon the principles of medical and scientific evaluation and the rapidly growing gut-health market led by consumer demand.
1. Sands BE. Therapy of inflammatory bowel disease. Gastroenterology 2000;118(2 Suppl 1):S68-82.
2. Goh J, O?Morain, CAO. Review article: nutrition and adult inflammatory bowel disease. Aliment Pharmacol Ther 2003;17:307-20.
3. Guarner F, Malagelada FG. Gut flora in health and disease. Lancet 2003;361:512?9.
4. Bamba T, et al. Dietary fat attenuates the benefits of an elemental diet in active Crohn?s disease: a randomized, controlled trial. Eur J Gastroenterol Hepatol 2003;15(2):151-7.
5. Geerling BJ, et al. The relation between antioxidant status and alterations in fatty acid profile in patients with Crohn?s disease and controls. Scand J Gastroenterol 1999;34(11):1108-16.
6. Middleton SJ, et al. Long-chain triglycerides reduce the efficacy of enteral feeds in patients with active Crohn?s disease. Clin Nutr 1995;14:229-36.
7. Sakurai T, et al. Short-term efficacy of enteral nutrition in the treatment of active Crohn?s disease: a randomized, controlled trial comparing nutrient formulas. J Parenteral Enteral Nutr 2002;26(2):98-103.
8. Endres S, et al. Lipid treatment in inflammatory bowel disease. Curr Opin Clin Nutr Metabo Care 1999;2:117-20.
9. Aslan A, Triadafilopoulos, G. Fish oil fatty acid supplementation in active ulcerative colitis. Am J Gastroenterol 1992;87:432-7.
10. Campieri M, Gionchetti P. Probiotics in inflammatory bowel disease: new insight to pathogenesis or a possible therapeutic alternative? Gastroenterology 1999;116(5):1246-9.
11. Ishikawa H, et al. Randomized controlled trial of the effect of bifidobacteria-fermented milk on ulcerative colitis. J Am Coll Nutr 2003;22(1):56-63.
12. Mimura T, et al. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 2004;53(1):108-14.
13. Bosscher D, et al. Availabilities of calcium, iron and zinc from dairy infant formulas is affected by soluble dietary fibers and modified starch fractions. Nutrition 2003;19(7-8):641-5.
14. Bengmark S. Colonic food: pre- and probiotics. Am J Gastroenterol 2000;95(1 Suppl):S5-7.
15. Welters CF, et al. Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with an ileal pouch-anal anastomosis. Dis Colon Rectum 2002;45(5):621-7.
16. Kanauchi O, et al.Treatment of ulcerative colitis by feeding with germinated barley foodstuff: first report of a multicenter open control trial. J Gastroenterol 2002;37 (Suppl 14):67-72.
17. Fernandez-Banares F, et al. Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Spanish Group for the Study of Crohn?s Disease and Ulcerative Colitis (GETECCU). Am J Gastroenterol 1999;94(2):427-33.
18. Johnson AT, et al. Effect of glutamine on glutathione, IGF-I, and TGF-beta 1. J Surg Res 2003;15;111(2):222-8.
19. Griffiths AM. Growth and clinical course of children with Crohn?s disease. Gut 1993;34(7):939-43.
20. Gronbaek H, et al. Low free and total insulin like growth factor I (IGF-I) and IGF binding protein-3 levels in chronic inflammatory bowel disease: partial normalization during prednisolone treatment. Am J Gastroenterol 2002;97:673?78.
21. Akobeng AK, et al. Low serum concentrations of insulin-like growth factor-I in children with active Crohn?s disease: effect of enteral nutritional support and glutamine supplementation. Scand J Gastroenterol 2002;37(12):1422-7.
22. Flaring UB, et al.Glutamine attenuates post-traumatic glutathione depletion in human muscle. Clin Sci (London) 2003;104(3):275-82.
23. Chen K, et al. Glutamine-supplemented parenteral nutrition improves gut mucosa integrity and function in endotoxemic rats. J Parenteral Enteral Nutr 1994;18(2):167-71.
24. Jackson NC, et al. Effects of glutamine supplementation, GH, and IGF-I on glutamine metabolism in critically ill patients. Am J Physiol Endocrinol Metab 2000;278(2):E226-33.
25. Kolstad O, et al. Combination of recombinant human growth hormone and glutamine-enriched total parenteral nutrition to surgical patients: effects on circulating amino acids. Clin Nutr 2001;20(6):503-10.
26. Den Hond E, et al. Effect of long-term oral glutamine supplements on small intestinal permeability in patients with Crohn?s disease. J Parenteral Eneral Nutr 1999;23(1):7-11.
27. Akobeng AK, et al. Double-blind randomized controlled trial of glutamine-enriched polymeric diet in the treatment of active Crohn?s disease. J Pediatr Gastroenterol Nutr 2000;30(1):78-84.
28. Micklefield G, et al. Effects of intraduodenal application of peppermint oil (WS(R) 1340) and caraway oil (WS(R) 1520) on gastroduodenal motility in healthy volunteers. Phytother Res 2003;17(2):135-40.
29. Madisch A, et al. Treatment of functional dyspepsia with a fixed peppermint oil and caraway oil combination preparation as compared to cisapride. A multicentre, reference-controlled double-blind equivalence study. Arzneimittelforschung 1999;49(11):925-32.
30. May B, et al. Efficacy and tolerability of a fixed combination of peppermint oil and caraway oil in patients suffering from functional dyspepsia. Aliment Pharmacol Ther 2000;14(12):1671-7.
31. Gebhardt R. Anticholestatic activity of flavonoids from artichoke (Cynara scolymus L.) and of their metabolites. Med Sci Monit 2001;7(Suppl 1):S316-20.
32. Holtmann G, et al. Efficacy of artichoke leaf extract in the treatment of patients with functional dyspepsia: a six-week placebo-controlled, double-blind, multicentre trial. Aliment Pharmacol Ther 2003;18(11-12):1099-105.
33. Marakis G, et al. Artichoke leaf extract reduces mild dyspepsia in an open study. Phytomedicine 2002;9(8):694-9.
34. Miralles-Barrachina O, et al. Low levels of glutathione in endoscopic biopsies of patients with Crohn?s colitis: the role of malnutrition. Clin Nutr 1999;18(5):313-7.
35. Reimund JM, et al. Antioxidant and immune status in active Crohn?s disease. A possible relationship. Clin Nutr 2000;19(1):43-8.
36. Kruidenier L, et al. Intestinal oxidative damage in inflammatory bowel disease: semi-quantification, localization and association with mucosal antioxidants. J Pathol 2003;201(1):28-36.
37. Aghdassi E, et al. Antioxidant vitamin supplementation in Crohn?s disease decreases oxidative stress. a randomized controlled trial. Am J Gastroenterol 2003;98(2):348-53.
38. Ahmad A, et al. Effect of combined probiotic, prebiotic and micronutrient supplementation in reducing duration of acute infantile diarrhea. J Paediac Gastroenterol Nutr 31, A984.
39. Roller M, et al. Prebiotic inulin enriched with oligofructose in combination with the probiotics lactobacillus rhamnosus and bifidobacterium lactis modulates intestinal immune functions in rats. J Nutr 2004;134(1):153-6.
40. Hirasihi H, et al. Polaprezinc protects gastric mucosal cells from noxious agents through antioxidant properties in vitro. Aliment Pharmacol Ther 1999;13(2):261-9.
41. Miyoshi A, et al. Clinical trial of Z-103 on gastric ulcer. Jpn Pharmacol Ther 1992;20(1):181-97.
42. Cho CH, et al. The membrane-stabilizing action of zinc carnosine (Z-103) in stress-induced gastric ulceration in rats. Life Sci 1991;49(23):PL189-94.
43. Itoh M, et al. Protection of gastric mucosa against ethanol-induced injury by intragastric bolus administration of epidermal growth factor combined with hydroxypropylcellulose. J Clin Gastroenterol 1992;14(Suppl 1):S127-30.
44. Adibi SA. Regulation of expression of the intestinal oligopeptide transporter (Pept-1) in health and disease. Am J Physiol Gastrointest Liver Physiol 2003;285(5):G779-88.
The Market: References
1. Moayyedi P, Mason J. Clinical and economic consequences of dyspepsia in the community. Gut 2002;50 (Suppl 4):Siv10-2.
2. IMS Retail Drug Monitor 2001-2003. IMS health consultancy (Fairfield, CT www.imshealth.com).
3. Gastrointestinal health condition specific markets: Supp, OTC, Rx 2003, 9-40. Nutrition Business Journal. (San Diego, CA, www.nutritionbusiness.com).
4. European and United States Probiotics Market 2003. Frost & Sullivan Limited (San Antonio, Texas, www.frost.com).
Marketing Applications: References
1. Schmucker D, Owen R. Ageing and the gastrointestinal immune response. Curr Opin Gastroenterol 1997;13:534-41.
2. Hopkins MJ, Macfarlane GT. Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection. J Med Microbiol 2002; 51:448?54.
3. Gill HS, et al. Enhancement of immunity in the elderly by dietary supplementation with the probiotic bifidobacterium lactis HNO19. Am J Clin Nutr 2001;74: 833-9.
4. Fang H, et al. Modulation of humoral immune response through probiotic intake. FEMS Immunol Med Microbiol 2000;29:47-52.
5. Boehm G, et al. Bifidogenic oligosaccharides in a preterm infant formula. J Pediatr Gastroenterol Nutr 2000;31(2):26.
6. Boehm G, et al.Prebiotic concept for infant nutrition. Acta Paediatr Suppl 2003;91(441):64-7.
7. Moore N, et al. Effects of fructo-oligosaccharide-supplemented infant cereal: a double-blind, randomized trial. Br J Nutr 2003;90(3):581-7.