May 9/May 2011 NutraSolutions -- Products marketed to help maintain gastrointestinal health make claims for reducing problems with diarrhea and constipation; for reducing bloating and flatulence; for boosting immunity; lowering the glycemic index of co-consumed foods; suppressing appetite and interfering with cholesterol absorption; and, lastly, for improvements in intelligence, beauty and the ability to speak foreign languages.


Well, perhaps not those final three, but claims for benefits for gastrointestinal health range from the plausible to the highly optimistic. Government agency actions and class action suits have been brought against companies too forward in their health claims, so an understanding of what is provable and what is not is warranted.


Understanding the Gastrointestinal System
A good way to imagine the gastrointestinal system is as a shopping mall with an entrance at one end, an exit at the other, and a tremendous number of transactions going on in between. Broadly speaking, a meal starts to move out of the stomach at 1 hour and is gone by 4 hours. Large meals high in fat or protein are slower to leave the stomach compared to small, carbohydrate-dominated meals. Food starts to enter the small intestine at 1 hour and is almost entirely out by 7 hours. Food starts to enter the large intestine as early as 4 hours after the meal and exits 24-36 hours later. Under normal health status, bacteria reside only in the large intestine. However, many species of bacteria have the capacity to survive passage from mouth to the large intestine, which is the whole premise behind probiotics--the deliberate consumption of live bacteria.


Given that almost all of the nutrients in a meal will be extracted during a few hours’ transit through the small intestine, this begs the question of why humans have a large intestine several feet in length, and what important functions take place there. The primary role of the large intestine appears to be recovery of water and electrolytes from the highly fluid, small intestine discharge. Be that as it may, the content of what enters the large intestine and the types of bacteria residing there do appear to impact health.


Fiber
Dietary Reference Intakes (DRIs) define dietary fiber as non-digestible carbohydrates in intact forms naturally occurring in foods, whereas functional fiber is defined as non-digestible carbohydrates that have been isolated or extracted, in order to provide health benefits. Total fiber combines the two. Mammals lack enzymes to digest these fibers, so they pass through to the large intestine relatively intact. Once in the large intestine, a subset of fiber referred to as soluble fiber can be fermented by resident bacteria, and by being metabolized to short-chain fatty acids, provide some caloric energy. This calorie yield is estimated at 1.5-2.5Kcal/g, less than the 4.0Kcal/g for digestible carbohydrates, but more than the 0 for insoluble fiber.1


Depending on the type and amount of fiber in the diet, benefits can include laxation, less absorption of cholesterol and attenuation of blood glucose responses. While population studies suggest fiber as protective against colorectal cancer, intervention studies have been mostly disappointing. Ditto reducing risk of diabetes or obesity. Current DRI recommendations for fiber are 38g/day for adult men and 25g/day for adult women to age 50 years, stepping down to 30g/day and 21g/day, respectively, above 50 years.1 According to the National Health and Nutrition Examination Survey (NHANES), actual total fiber consumption is on the order of 17-19g/day for adult men and 13-15g/day for adult women.2


Probiotics
Bacteria are people’s friends. Or more exactly, friendly bacteria are people’s friends. The human large intestine is home to more than 800 species of bacteria. Beneficial bacteria, such as Lactococcus acidophilus, Bifidobacterium longum and Bifidobacterium bifidum, are purported to promote proper digestion and absorption of nutrients, boost immune function and increase resistance to infection by displacing harmful bacteria. Diarrhea, constipation, flatulence and many other intestinal discomforts are caused by an imbalance of intestinal microflora. People complain of alternating episodes or constipation and diarrhea, as the lower gastrointestinal tract first slows down due to a low-fiber diet, then explosively empties, when undesirable bacteria, such as C. difficile, proliferate and produce gas and toxins. Typical probiotic dosing in clinical trials ranges from 1-100 billion live bacteria per day.3-6


Basic health claims for probiotics utilize what is known as “Structure:Function” wording. Very briefly, this is wording the Food and Drug Administration allows, when evidence is less than what is needed to support an FDA-approved health claim. S:F wording is often along the lines of: “[ingredient name here] helps maintain a healthy digestive system.” Results from consumer focus groups suggest that S:F wording is preferred to health claims language, as the latter infers a more emotionally negative context of disease treatment, as in: “Buy this food, because you have this disease!”


Probiotics stand on thinner ice, when essaying claims beyond the gastrointestinal system. The gastrointestinal tract contains many cells involved in immunity. Arguments are made for beneficial bacteria reducing the duration of a cold and its symptoms, by stimulating immune cells in the gut. This triggers a systemic immune response that extends to anti-viral function and to the secondary bacterial respiratory infections, which may occur in conjunction with a viral infection.7-9 However, the evidence is not conclusive.


Prebiotics to Synbiotics
Another approach is to provide not live bacteria, but rather nutrients and other compounds to promote the growth of beneficial bacteria residing in the intestine. In 2007, the Food and Agriculture Organization of the United Nations defined prebiotics: “A prebiotic is a non-viable food component that confers a health benefit on the host associated with modulation of the microbiota.” Clarifications include not being a living organism, not being a drug and the value of the health benefit over­riding any adverse side effects.10


Most prebiotics fall into the category of soluble fiber products, such as fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), inulin, pectin, xanthan, glucomannan and beta-glucan. All are partially metabolized in the large intestine to become short-chain fatty acids (SCFAs). SCFAs can be used as fuel in the cells lining the large intestine. FOS are shorter in chain length than inulin; some supplement products use a combination. Most soluble fiber clinical trials evaluate 10-20g/day. Obviously, these amounts are more suitable for incorporation into a functional food vs. a dietary supplement. While many clinical trials report a change in the bacterial make-up of fecal bacteria as an endpoint, in the absence of physiologically significant clinical outcomes, changed bacterial ecology is not sufficient proof of benefit.11


Care must be taken to separate the prebiotic and non-prebiotic actions of soluble fibers. The lipid-lowering action of beta-glucan and psyllium takes place in the small intestine, where these viscous soluble fibers interfere with cholesterol absorption. Likewise, combinations of glucomannan, xanthan and alginate have been touted as not only lowering cholesterol absorption, but also blunting the glycemic index of co-consumed foods. If confirmed, this effect would reduce the risk of diabetes and metabolic syndrome. But, these functions are not prebiotic in nature.


Prebiotic/probiotic combination products, sometimes called synbiotics, are a natural fit for the dairy industry, as there are already product production and distribution systems in place with refrigeration and short shelflife requirements. However, significant amounts of human research are needed, before claims can be made that a combination product has advantages. Results are not automatically synergistic or even additive; a prebiotic could promote growth of endogenous bacteria to the disadvantage of the co-supplemented bacteria.


Digestive Enzymes
With the exception of lactase-treated dairy products, digestive enzymes do not directly impact prepared foods. Lactase digests the milk sugar lactose into glucose and galactose. An estimated 70% of the world’s population, including over one third of the U.S. population, lack this enzyme as adults and are hence referred to as being lactose-intolerant. This is not the same as being allergic to milk, which involves the immune system’s over-reaction to milk proteins. Con­suming lactase-treated dairy products or lactase-containing dietary supplements solves the digestive problems of flatulence and bloating.


Beyond sugar digestive enzymes, the situation gets complex. The body’s digestive enzymes trypsin, chymotrypsin, proteases, lipases and amylases are synthesized at the appropriate points in the digestive system to facilitate the digestion of foods. Some prescription products include Creon, Nutrizym, Pancrease, Pancrex, Ultrase and Zymase. The products are offered in different strengths; for example, Creon 5, Creon 10 and Creon 20. The number refers to the lipase content per capsule, in thousands of USP units. The different strengths are achieved by diluting full-strength pancreatin sourced from pig pancreas. There are microbe-produced enzymes with amylase, protease and lipase activity, but the units are different, and these should not be called “pancreatin.”


Plant-derived enzymes are marketed as protein digestive aids. Bromelain, which has a range of activity, is a mixture of enzymes from ripe and unripe pineapple fruit and plant stem. Bromelain breaks down proteins to form peptides and amino acids with preferential cleavage of peptide bonds, where the carbonyl group is either from a basic amino acid or an aromatic amino acid. Papain is derived from the papaya plant and has been used as an aid to digestion since the 1880s, to relieve dyspepsia and other common digestive disorders.12


Two problems plaguing digestive enzyme marketing are units of measurement and what defines a clinically significant outcome. At present, there are only a few up-to-date, widely recognized standard measurements of activity and digestive power for most of the plant-sourced digestive enzymes used in dietary supplements. The most widely recognized is the Food Chemical Codex (FCC), but USP and NK units are also valid.12
 

Government Actions and Going Forward
Infamously, the Dannon Company was the subject of a multi-state, class-action lawsuit against health claims made for probiotic Activia yogurt and DanActive yogurt drink. At issue was over-claiming results of clinical trials and stating that one serving a day was sufficient for a benefit. In 2009, Dannon created a $35 million fund to reimburse consumers and agreed to make label and marketing changes based on FTC and FDA decisions.

The FTC reached a final decision in December 2010. Dannon agreed to pay states $21 million to resolve state actions. Dannon is prohibited from claiming any probiotic product reduces the likelihood of getting a cold or flu. Dannon may not claim Activia or other probiotic products help with irregularity or slow transit time, or any other health benefits, unless there are two human studies supporting those results.13     


Given the active interest of the FDA and FTC to labeling and advertising for food health claims, any company intending to market based on health claims needs expert regulatory advice. Probiotic claims need to be specific to the species, strain and amount of bacteria per serving. Structure:function wording, carefully parsed, can be a safe haven. A common marketing failing is to believe that evidence from a clinical trial allows a claim based on that evidence, when, in actuality, a label cannot claim something is true, until the FDA agrees it is true (i.e., approves specific wording for that claim). NS

1.Dietary, functional and total fiber. IN: Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Institute of Medicine, National Academies Press, Washington, DC. 2005. 339-421.
2. What we eat in America, NHANES 2007-2008. Accessed March 2001 from: http://www.ars.usda.gov/SP2UserFiles/Place/12355000/pdf/0708/Table_1_NIN_GEN_07.pdf.
3. Sanders ME. Probiotics: considerations for human health. 2003. Nutr Rev. 61:91-99.
4. Minocha A. 2009. Probiotics for preventive health. Nutr Clin Pract.  24:227-241.
5. Farnsworth E. 2008. The evidence to support health claims for probiotics. J Nutr. 138(suppl):1250S-54S.
6. Kaur IP, et al. 2009. Probiotics: delineation of prophylactic and therapeutic benefits. J Med Food.12:219-235.
7. de Vrese M, et al. 2005. Effect of Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3, B. bifidum MF 20/5 on common cold episodes: a double-blind, randomized, controlled trial. Clin Nutr. 24:481-491.
8. Winkler P, et al. 2005. Effect of a dietary supplement containing probiotic bacteria plus vitamins and minerals on common cold infections and cellular immune parameters. Int J Clin Pharmacol Ther. 43:318-326.
9. de Vrese M, et al. 2006. Probiotic bacteria reduced duration and severity but not the incidence of common cold episodes in a double-blind, randomized, controlled trial. Vaccine. 24:6670-74.
10. FAO Technical Meeting on Prebiotics. Food and Agriculture Organization of the United Nations. 2007. Accessed March 2011 from: http://www.fao.org/ag/agn/agns/files/Prebiotics_Tech_Meeting_Report.pdf.
11. Goetze O, et al. 2008. Effect of a prebiotic mixture on intestinal comfort and general well-being in health. Br J Nutr. 100:1077-85.
12. Roxas M. 2008. The role of supplementation in digestive disorders. Altern Med Rev. 13:307-314.
13. Dannon agrees to drop exaggerated health claims for Activia yogurt and DanActive dairy drink. Federal Trade Commission 2010 press release. Accessed March 2011 from: http://www.ftc.gov/opa/2010/12/dannon.shtm.