Probiotic Competition

Increased digestive problems and antibiotic side effects have paved the road for the rising demand for probiotics worldwide. Consumers might not fully understand how beneficial bacteria work and which ones they should take, but they are interested in trying products that contain them. The probiotic industry has responded by developing a broad range of new product vehicles for probiotics, in addition to creating and furthering technologies to enable innovative applications for these sensitive ingredients.

In late summer 2010, Koncept Analytics released a report predicting the global probiotics market will grow an estimated 13 percent (compound annual growth rate, CAGR) through 2014, with Europe and Asia leading the way. The report, Global Probiotics Market: Trends and Opportunities, called the U.S. probiotic market undeveloped, but said the future should offer valuable opportunities for growth.

Just-Food.com had six months earlier placed the global population buy-in of probiotics at about 30 percent, noting probiotics held only about $17.5 billion of the $85 billion global functional-food market, although the probiotics market has more than doubled in value since 2003 and sits at about 15-percent growth per year. According to its report, the global market is dominated by many multinational dairy corporations, at least on the food side, while the supplements market is much more fragmented. It also reported on the challenges probiotic products have had in penetrating the consumer market, attributing the U.K.s Müller Dairy with statements that the public does not have faith probiotics offer any real benefit and fear the market might just be hype, not real science; it also pointed to a skepticism that probiotic products might not have enough beneficial bacteria to confer a real benefit.

In the United States, consumer research is promising. ConsumerLab.com released a survey in February 2010 showing probiotics were used by 30.4 percent of respondents (6,012 consumers), an increase from 25 percent last year. Similarly, one-third of women in the survey reported using a probiotic.

Packaged Facts weighed in with figures revealing sales of probiotic/prebiotic foods and beverages topped $15 billion in 2008, a 13-percent increase over 2007 data. The firm projected the market for functional foods and beverages addressing digestive health will top $22 billion in 2013, representing a CAGR of 12 percent between 2004 and 2013.

The picture painted is one of mixed messages, opportunity clouded by hesitancy, promise dulled only by an infancy in research and standards. This means the gauntlet is thrown down, and suppliers, product developers, manufacturers and marketers need to work together to ensure products that reach consumers interested in probiotics contain viable, beneficial bacteria that are the appropriate type(s) for the expected use/benefit, supported by research, and plentiful enough at the time of consumption.

The Bearable Appropriateness of Being

Latin nomenclature helps categorize probiotics by genus and species, such as Lactobacillus acidolphilus (L. acidolphilus) or Bifidobacterium lactis (B. lactis). The first step in finding the most appropriate probiotic for a product is investigating the research on the different species of probiotics. However, there are many different strains of each given genus/speciesfor example, L. casei DN-114001 or L. rhamnosus VTT E-97800and it is becoming more crucial to choose specific strains that are researched for specific benefits.

Choosing the right strain is absolutely the key to a legitimate probiotic supplement, said Frank Hodal, founder and CEO of Little Calumet Holdings, maker of Vidazorb probiotic supplements. First you have to use a strain that is commercially viable, he said, adding then you must seek those with evidence supporting their use and benefits.

From back in the late 50s when Khem Shahani, Ph.D., found the DDS-1 strain, naming it after the Department of Dairy Science at University of Nebraska where he worked, strain development has steadily become a staple for high-quality probiotics providers. In fact, proprietary strains are popping up all over the research landscape.

Patients treated with a multispecies probiotic containing L. acidophilus (as DDS®-1 strain, from UAS Labs), B. longum, B. bifidum and B. lactis at a combined potency of 12 billion CFU/g helped minimize the symptoms of patients with irritable bowel syndrome (IBS), which affects an estimated 20 to 30 percent of the population.¹ The most significant improvements occurred after 60 days of treatment, including 84 percent of the patients showing improvement in abdominal pain, 73.9 percent in bloating, 92 percent in belching, 88 percent in flatulence, 90.9 percent in diarrhea and 86.9 percent in constipation.

In another trial reported in 2010, a combination of L. acidophilus DDS-1 and B. lactis UABLA-12 (both from UAS Labs) in 90 preschool children (ages 1 to 3 years) with moderate to severe atopic dermatitis (AD) yielded a 33.7-percent decrease in SCORAD (scoring of AD) versus 19.4 percent in the placebo group.² There was also a 33-percent increase in IDQOL (infant dermatitis quality of life), and a 34.4-percent increase in DFI (dermatitis family impact) in probiotic group.

Danisco strains have also addressed both digestive and immune endpoints. HOWARU® Dophilus (Lactobacillus acidophilus NCFM) has been shown to reduce symptoms of lactose intolerance³ and protect against candidiasis infection,⁴ as well as possibly limit colon-cancer development.⁵ HOWARU® Rhamnosus (Lactobacillus rhamnosus HNOOI) has stimulated specific gut mucosal immunity and has reduced the severity of E. coli infection by enhancing humoral and cellular immune responses.^6,7 Research has also found HOWARU Bifido® (Bifidobacterium lactis HN019) enhanced natural immunity in healthy elderly subjects after six weeks of supplementation,⁸ while in another trial, HOWARU® Protect (combination of L. acidophilus NCFM® and B. lactis Bi-07) reduced fever incidence, coughing, runny noses, and the duration and severity of cold and flu symptoms in children.⁹ This a combination ingredient also showed potential reduction of AD symptoms in a double blind, randomized, placebo-controlled study conducted at University of Copenhagen, Denmark, and published in 2010.¹⁰ And HOWARU® Restore, a combination of three Bifido strains and two Lactobacillus strains, helped reestablish pre-antibiotic baseline fecal bacterial microbiota in healthy subjects undergoing antibiotic therapy.¹¹

For adults with postprandial intestinal gas-related symptoms, but no GI diagnoses, Bacillus coagulans GBI-30, 6086 (from Ganeden Labs) was effective in improving the quality of life and reducing gastrointestinal (GI) symptoms in one study.¹² This particular strain also is safe and effective for reducing daily bowel movements in patients with diarrhea-predominant IBS,¹³ and is an option for the relief of abdominal pain and bloating for patients with IBS.¹⁴ It also has been found to aid the digestion of lactose and fructose, making it potentially useful in limiting the occurrence of intestinal symptoms in individuals sensitive to these carbohydrates.¹⁵ On immune endpoints, pilot research suggests GBI-30 6086 as an adjunctive therapy with pharmacological anti-arthritic medications appeared to be a safe and effective for patients suffering from rheumatoid arthritis (RA);¹⁶ it also may be a safe and effective therapeutic option for enhancing T-cell response to certain viral respiratory tract infections.¹⁷

Otherwise healthy adults infected with Helicobacter pylori (H. pylori), which is linked to stomach ulcers and inflammation (chronic gastritis), may benefit from B. lactis and L. acidophilus LA-5, as this combination from Chr. Hansen (5 billion CFU, twice daily in yogurt) reduced the risk of antibiotic side effects, including diarrhea; improved eradication of H. pylori; and restored depletion of Bifidobacterium after antibiotic treatment.¹⁸

In other research, 46 healthy females who took 1 billion colony forming units (CFU)/day of a combination of BB-12®, 0.3 billion LA-5®, 50 billion S. thermophilus FK 303 and S. thermophilus FK 320 in fermented milk (all from Chr. Hansen) experienced significant increase in defecation frequency, significant increase in fecal quantity, improvement in fecal characteristics and improvement in fecal microbiota during probiotic intake compared to no probiotic intake.¹⁹ A combination of L. rhamnosous GR-1 and L. reuteri RC-14 helped maintain a healthy vaginal microbiota by increasing the number of beneficial Lactobacilli and lowering the risk of bacterial vaginosis.²⁰ Other research showed this combo decreased yeast and potential pathogenic bacteria, while lowering the risk of yeast vaginitis.²¹

On immune health, BB-12 intake has been linked to increased phagocytic activity,²² and both immunoglobulin A (IgA) and anti-poliovirus IgA levels.²³ Chr. Hansens Lactobacillus GG and L. casei 431® enhanced immune response after vaccination, while enhancing systemic protection against viruses by increasing virus neutralizing antibodies.²⁴ In another study, children with atopic eczema, an immune disorder, experienced relief from symptoms after taking the BB-12 and LGG combination.²⁵

Institut Rosells Lactobacillus plantarum 299V (LP299V) helped resolve abdominal pain in all IBS patients given the probiotic in liquid suspension compared to only 55 percent placebo patients.²⁶ Researchers reported normalization of stool frequency in six out of 10 constipated patients treated with LP299V, compared with two out of 11 treated with placebo; overall, 95 percent of patients given the probiotic experienced improvement in all IBS symptoms compared with only 15 percent of those in the placebo group.

Among the newer areas of probiotic research, Institut Rosells ProbioStick® product (Lactobacillus Rosell-52 and Bifidobacterium Rosell-175) showed an effect on brain cells in a 2010 trial investigating behavioral signs of depression in a rat model of myocardial infarction (MI).²⁷ Probiotic treatment significantly reduced behavioral signs of depression, while rats on control diet showed increased signs. ProbioStick also prevented the postMI increase of pro-inflammatory cytokine IL-1, a mechanism involved in the onset of post-MI depression via induction of apoptosis, or programmed cell death, in certain parts of the brain. Researchers noted the results confirmed heart attacks have detrimental effects on the intestinal barrier, which can be restored by probiotic treatment.

Targeting Markets, Segments

Despite the range of health issues probiotics are affecting in recent research, insiders report digestion is still driving the probiotics category, although immunity research is certainly on the uptick. The immune issue still not understood, said Michael Shahani, director of operations for Nebraska Cultures, referring to the hot topic in the probiotics market. He added some of the emerging immune research is inconclusive. Major companies have attempted to launch immune-focused probiotic products, but they found the research was not there yet and decided it was better not to do an immune-enhancement product without proper research. He noted there are a number of mechanism of action that are more well-established, such as on general digestion, diarrhea, constipation and lactose intolerance, and these are enough to drive the market to continued growth.

Similarly, the race to the functional-food probiotic prize has not proven easy. New Nutrition Business reported 80 percent of new functional-food and beverage product launches will fail, generally due to a disconnect with consumers. Of course, traditional food vehicles for probiotics, such as yogurt and other dairy, generally do well, but newer attempts at delivering probiotics in other common food items have not fared so well.

Kraft came out with LiveActive probiotic cheese, but sales were disappointing after two years of marketing. Although not the only probiotic cheese failure, Krafts high-profile misstep was chalked up by many insiders as a case of unclear or insufficient science behind the benefits and failure to convey the message effectively to consumers. There is also the idea that consumers dont snap up wheels of cheese for health reasons, so they are less likely to pay a premium for cheese with a healthy functional ingredient they can get elsewhere.

Shahani  noted attempts to infuse chocolate with probiotics suffered similar challenges. People arent eating chocolate because it is healthy, he said, adding probiotic cereal has not fared much better despite cereals ability to be considered healthy. However, one area where he is seeing growth is juice drinks, meal-replacement drinks, energy beverages and other refrigerated drinks.

The Natural Marketing Institute (NMI) has provided some insight on the successes and struggles of finding success with functional foods, citing consumer understanding of the benefits of the functional product and how to incorporate it into their lifestyle among the deciding factors. Strict oversight on health claims restricts the messages a manufacturer or product can deliver to consumers, but NMI stressed ingredient understanding is crucial to help consumers better comprehend product benefits driven by ingredient content in lieu of outward health claims. For example, the firm noted while 53 percent of older consumers are aware of probiotics, only 31 percent realize probiotics can benefit their digestive health. Considering digestive health is still the driver for the entire probiotics category, anyone looking to develop immune or other health condition-specific probiotic products has an uphill climb in convincing consumers of the benefits and appropriateness of their functional product.

Oral Health Probiotics

The gastrointestinal (GI) tract begins at the mouth. Driven by this simple fact and the wealth of scientific knowledge on probiotics in GI health, Oragenics studied the composition and identified oral bacterial species associated with dental and gingival healthreviewing more than 30 years of researchdetermined their mechanisms of action against harmful bacterial challenges, and created a unique and original blend of good strains with clinically documented benefits to oral care. Two of the strains (Streptococcus uberis KJ2V and S. oralis KJ3) in their ProBiora3 blend address gum health, while the other strain (S. rattus JH145) promotes tooth health. According to the company, research with ProBiora3 has demonstrated that the ingredient can also result in fresher breath, as S. uberis and S. oralis are natural antagonists to bacteria that cause bad breath, and the hydrogen peroxide byproduct from S. oralis will naturally and gradually whiten teeth without the harsh side-effects of currently marketed tooth whitening products. 

The company noted the blend of these three strains can be adjusted for the specific needs of different population groups; for instance,  the use of equal proportions of the three strains in a blend specifically for adults can meet their oral care needs for both tooth and gum health, whereas young children generally have only concerns for maintaining tooth health, so the probiotic blend can be adjusted to emphasize the one strain for tooth health.

ProBiora3 has achieved self-affirmed GRAS status as a food/food ingredient and is available in several freeze-dried powder blends for incorporation into oral care products that address the consumer markets for adults and children, the dental professional market, as well as the companion pet product category. Oragenics further reported on-going product development with  fermentation partners and with formulation and micro-encapsulating groups is expected to lead to an extension of the product categories/delivery vehicles, including use of ProBiora3 in formulating dairy products, nutritional drinks, chewing gums, toothpastes and mouth washes.

Viability and the Count

Among the greatest challenges in developing probiotic products is keeping the beneficial bacteria viable throughout processing and storage. Probiotics are sensitive to moisture, heat, light and oxygen. Hodal said some strains will survive manufacturing, but a lot will not. Refrigeration of probiotic products has helped address these issues; however, Hodal argued every time you take the product out of the refrigerator, you introduce humidity. One thing that kills probiotics fast is moisture; it takes the bugs out of stasis, and become activated or perish, he said.

And hows this for competition: in the market for probiotic products, not only are suppliers, manufacturers and marketers trying to outdo each other, but the different probiotic strain themselves can often compete and destroy each other. Bifidobacteria and acidolphilus dont compete, Hodal explained, so they are happy to coexist and work together. However, there are bacteria that are antagonistic with each other and combining them is a recipe for instability, as one strain would dominate.

One common way manufacturers overcome this challenge is to over-formulate, putting in way more bacteria than are needed, assuming all the challenges a probiotic product might face will likely destroy some number of the bacteria.

Another approach is technology. Many companies have turned to freeze-drying probiotic powders, which preserve the bacteria until they are activated in the moisture of the consumers GI system. Others have employed microencapsulation, which forms a protective capsule around the probiotic and protects it from processing stressors, storage problems and acidic GI challengesit needs to reach the intestines.

Nutraceutix approaches this issue by controlling every aspect of production, from organism growth, blending and forming/filling to the bottling and labeling of fully finished products for clients. The centerpiece of this chain, however, is proprietary technology. Tim Gamble, senior vice president of sales and marketing at Nutraceutix, explained the companys patented LiveBac® processing extends the shelf life of probiotic caplets and tablets, even at room temperature, and its patented BIO-tract® delivery technology ensures a significantly higher percentage of organisms survive passage through the stomach to reach and colonize the intestinal tract. With the Bio-tract technology, a protective layer forms around the probiotic payload when it comes into contact with fluids in the stomach; it is then released in the intestines.

Technology comes neither cheap nor easily. Trying to meet the goal of a chewable probiotic tablet that would stand up to rigorous FDA scrutiny, Hodal and his team toiled for seven years in pursuit of technology that produced a pharmaceutical-level product. The bugs are very delicate, because they are anaerobic, and they would crash and burn, he lamented, noting the bacteria would be alive at great potency, then suddenly die. I had to wait three to six months until find out we failed our latest attempt.

The breakthrough finally came in sudden wave of fortune. However, fearing a false positive, Hodal had his supplier Chr. Hansen come to the United States and work with an independent lab to verify the new chewable delivery form was legit. Through luck, persistence and lots of money, according to Hodal, was born the Vidazorb shelf-stable chewable productthe original goal of a five-year shelf life is not far off, with the current life placed at about four years.

Ganeden Labs makes use of a more inherent spore-forming technology of the B. coagulans probiotic to survive manufacturing processes and the acidic gut environment. Mike Bush, vice president of development for Ganeden, explained B. coagulans GBI-30, 6086 (trademarked Ganeden BC30) has a spore inside of its cell that protects its genetic material from the heat and pressure of manufacturing, as well as other challenges during shelf life. Also protected from the gut, the spore germinates in the intestines to produce beneficial bacteria. He noted this protective quality has enabled the inclusion of Ganeden BC30 in numerous shelf-stable functional products, such as protein bars, baked goods, soup mixes, hot and cold beverages, drink mixes and confectionery products.

Being able to keep probiotics alive throughout the many challenges they are likely to face is a huge success, but in addition to strain choice and viability, product developers (not to mention retailers and consumers) are also interested in how much bacteria are in each dose.

In addition to testing incoming product for certificate of analysis verification (C of A), manufacturers also employ stability testing to learn and verify viable probiotic quantities over a specified period of time.

 However you process, store or deliver probiotics, the nature of the bacteria is to decline, Hodal assured. He said it is extremely challenging to figure out how many bacteria there will be at tie of consumption, but it is important to deliver a high enough bacteria count to make a therapeutic difference. He said the research so far points to around 1 billion viable bacteria per day as a good starting point for a therapeutic effect.

The prevailing consensus among top probiotic suppliers and manufacturers is to measure and label the colony forming units (CFUs). There is a debate on whether this count should reflect bacteria numbers at the time of manufacture or consumption, but the move toward the CFU standard is a clearly ringing bell. Id like to see the industry as whole label the number of viable units at time of manufacture, Shahani  said. Labeling the amount in milligrams is completely useless. He is another proponent of over-formulation, noting one or two strains may be sturdy enough to forgo over-formulation, but they are the exception and not the rule.

For consumers, an accurate label claim for probiotics in CFUs is useful, but there is an even greater need for information from manufacturers. For product developers and manufacturers, it is important to note the market research showing consumers need to connect the health potential of a product via health claims (a tricky enterprise) or informative marketing. Despite all the technology, health-condition research and strain development, education is the key to growth in the probiotic market.

References are on the next page...

References for "Probiotic Competition"

1. http://www.naturalproductsinsider.com/news/2010/05/dds1-shows-promise-for-ibs-suffers.aspx

2. Gerasimov SV et al. Presented at the New York Academy of Sciences symposium, Probiotics: From Bench to Market, held on June 11, 2010.

3. Montes RG, et al. Effect of milks inoculated with Lactobacillus acidophilus or a yogurt starter culture in lactose-maldigesting children. J Dairy Sci. 1995 Aug;78(8):1657-64.

4. Wagner RD, et al. Probiotic effects of feeding heat-killed Lactobacillus acidophilus and Lactobacillus casei to Candida albicans-colonized immunodeficient mice. J Food Prot. 2000 May;63(5):638-44.

5. Rao CV, et al. Prevention of colonic preneoplastic lesions by the probiotic Lactobacillus acidophilus NCFMTM in F344 rats. Int J Oncol. 1999 May;14(5):939-44.

6. Gill HS, Rutherfurd KJ. Viability and dose-response studies on the effects of the immunoenhancing lactic acid bacterium Lactobacillus rhamnosus in mice. Br J Nutr. 2001 Aug;86(2):285-9.

7. Shu Q, Gill HS. Immune protection mediated by the probiotic Lactobacillus rhamnosus HN001 (DR20) against Escherichia coli O157:H7 infection in mice. FEMS Immunol Med Microbiol. 2002 Sep 6;34(1):59-64.

8. Arunachalam K, Gill HS, Chandra RK. Enhancement of natural immune function by dietary consumption of Bifidobacterium lactis (HN019). Eur J Clin Nutr. 2000 Mar;54(3):263-7.

26. Chiang BL, et al.  Enhancing immunity by dietary consumption of a probiotic lactic acid bacterium (Bifidobacterium lactis HN019): optimization and definition of cellular immune responses. Eur J Clin Nutr. 2000 Nov;54(11):849-55.

9. Leyer GJ, et al. Probiotic effects on cold and influenza-like symptom incidence and duration in children. Pediatrics. 2009 Aug;124(2):e172-9. Epub 2009 Jul 27.

10. Independent study was conducted by the University of Copenhagen, Denmark. http://www.howaru.com/wps/wcm/connect/howaru/howaru/going_on_with_howaru/news/2009/howaru_news_28_07_2010_bi_07_eczema

11. Engelbrektson A, et al. Probiotics to minimize the disruption of faecal microbiota in healthy subjects undergoing antibiotic therapy. J Med Microbiol. 2009 May;58(Pt 5):663-70.

12. Kalman, D.S., et al. A prospective, randomized, double-blind, placebo-controlled parallel-group dual site trial to evaluate the effects of a Bacillus coagulans-based product on functional intestinal gas symptoms. 2009 BMC Gastroenterology 9:85.

13. Dolin, B.J. Effects of a proprietary Bacillus coagulans preparation on symptoms of diarrhea-predominant irritable bowel syndrome. Methods Find Exp Clin Pharmacol. 2009 Dec; 31(10):655-9

14. Hun, L. Bacillus coagulans significantly improved abdominal pain and bloating in patients with IBS. 2009 Postgraduate Medicine 121 (2): 119-124.

15.Maathuis, A.J.H., et al. Survival and metabolic activity of the GanedenBC30 strain of Bacillus coagulans in a dynamic in vitro model of the stomach and small intestine. 2010 Beneficial Microbes 1 (1): 31-36.

16. Mandel, D.R., et al. Bacillus coagulans: a viable adjunct therapy for relieving symptoms of rheumatoid arthritis according to a randomized, controlled trial.2010 BMC Complementary and Alternative Medicine 2010 Jan 12; 10:1

17. Baron M. A patented strain of Bacillus coagulans increased immune response to viral challenge. Postgrad Med. 2009 Mar;121(2):114-8.

18. Sheu BS, et al. Impact of supplement with Lactobacillus- and Bifidobacterium-containing yoghurt on triple therapy for Helicobacter pylori eradication. Aliment. Pharmacol. Ther. 2002;16:1669-1675.

19. Shioya M, et al. FK 120 on the fecal flora and fecal properties in healthy female volunteers 2000 Food Health and Nutrition Research, Journal of Nutritional Food;3:7-18

20. Petricevic L, Randomized, double-blind, placebo-controlled study of oral lactobacilli to improve the vaginal flora of postmenopausal women European Journal of Obstetrics & Gynecology and Reproductive Biology 2008;141:5457

21. Reid G, et al. Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebocontrolled trial in 64 healthy women. FEMS Immunol Med Microbiol. 2003;35(2):131-4

22. Schiffrin EJ, et al Immune modulation of blood leucocytes in humans by lactic acid bacteria: criteria for strain selection Am J Clin Nutr 1997;66:515S-520S

23. Fukushima Y, et al Effect of a probiotic formula on intestinal immunoglobulin A production in healthy children International Journal of Food Microbiology 1998;42:39-44.

24. de Vrese M, et al. Probiotic bacteria stimulate virus-specific neutralizing antibodies following a booster polio vaccination Eur J Nutr 2005;44:406-413.

25. Chouraqui JP, et al. Acidified milk formula supplemented with bifidobacterium lactis: Impact on infant diarrhea in residential care settings Journal of Pediatric Gastroenterology and Nutrition 2004;38:288-292

26. Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, randomized study on the efficacy of Lactobacillus plantarum 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2001 Oct;13(10):1143-7.

27. Rousseau G et al. Presented at the New York Academy of Sciences symposium, Probiotics: From Bench to Market, held on June 11, 2010.