Since the start of the 20th century and thanks to the scientist, Ilya Ilyich Mechnikov, we are aware of the importance of bacteria for health. The work of the Nobel laureate, conducted at Institut Pasteur, enabled Isaac Carasso, founder of Danone, to create his first yogurts. This was the starting point for the formidable Danone adventure. At the time, Danone yogurts were sold in pharmacies and recommended for children suffering from gastroenteritis. That was in 1919.
Currently, Actimel is the direct descendant of the first yogurt. The history of Actimel is described here. The history, in fact, is only just beginning.
Did you know?
Since Actimel was launched 15 years ago, Actimel and its probiotic strain, Lactobacillus paracasei subsp. paracasei DN-114 001, have been the subject of 49 scientific studies. Twenty-four clinical trial publications have shown the beneficial effects of the product on health.
Birth of Actimel
The discovery of a unique strain
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After decades of developing yogurts and their markets, towards the 1980s, turning to the founding idea behind the fist Danone: 'A yogurt may have a beneficial effect on diarrhea', Danone's researchers asked themselves the following questions: 'Why could only yogurts have a beneficial effect in the intestine? Why yogurt more than cheese?' They then looked to Lactobacillus casei, recognized for its virtues with regard to intestinal health.
The researchers then screened Danone's library of strains (a collection that currently contains over 4000 strains of lactic acid and plant bacteria) and selected several strains, including those derived from L. casei.
One of the first studies was conducted on mice, which were fed with various dairy products fermented by several types of lactic acid bacteria: those used in conventional yogurt, those in a commercially available product containing a strain of L. casei and those selected by Danone. The mice were then exposed to a bacterium inducing intestinal inflammation in order to determine which strain would most effectively combat the inflammation. The study enabled two important conclusions:
conventional yogurt did not completely protect the mice while milk fermented by L. casei protected them to a greater degree;
the various strains selected by Danone had different effects on the model; one of the strains, identified by the code DN-114 001 in Danone's collection, was the most effective.
Subsequently, Danone had the idea of combining the strain with conventional yogurt bacteria. The combination was more effective than the strain alone.
The strain in question, a Lactobacillus of the species Lactobacillus paracasei subsp. paracasei, coded DNâ€‘114 001, was filed in an international collection (reference: CNCM I-1518), and then patented for its special properties. Danone then decided to exploit its scientific knowledge and develop a new dairy product with the strain.
The name 'Lactobacillus casei DN-114 001' was changed commercially to L. casei defensis (or immunitas, depending on the country) to help consumers more easily identify and understand the specific benefit of Actimel. Several years were necessary in order to develop Actimel due to the complex manufacturing process and sensory challenges that had to be overcome. For example, several days of fermentation are necessary in order for Actimel to exert the health benefits of the product, while 4 to 6 h are sufficient for a conventional yogurt. The constraints in sensory terms were related, in particular, to the acidity and bitterness of the milk base fermented by L. casei, which was very difficult to mask.
Actimel was launched in Belgium in September 1994. The name is derived from the translation of 'active milk' in Flemish: actieve melk. Actimel is a fermented milk product containing, in addition to the conventional bacteria in yogurt, a concentration of 1010 (i.e. 10 billion) L. casei defensis per bottle.
The initial clinical trials
The beneficial effects of Actimel on infantile diarrhea
Danone's researchers thought to measure the effects of Actimel on a well known symptom of inflammation of the digestive tract walls: diarrhea. They decided to compare the new product with conventional yogurt and gelled milk, since yogurt was already known to reduce the severity of diarrhea. The scientific team then evaluated the pertinence of conducting the study in infants in daycare. Diarrhea in infants is frequently the cause of marked disorganization of daycare facilities. The change in the babies' environment (feeding, new ambient pathogens, etc.) frequently induces diarrhea reflecting adaptation of the digestive tract and immune system to community life. The first study was initiated at the end 1994 and the results were published in 1999.
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The results of the study, conducted on a limited number of subjects (287), showed Actimel to be more effective in reducing the duration and severity of diarrhea (4.3 days on average with Actimel vs. 5.3 with yogurt and 8.0 with gelled milk) but had no effect on incidence, i.e., on the number of episodes of diarrhea recorded. The protocol consisted in alternating 1 month of Actimel intake with 1 month without intake for 6 months.
The scientific teams wished to confirm the initial results by conducting a second trial , which was initiated two years later, under the same conditions, but with a slight change in the product consumption protocol (daily consumption for 6 months) and a larger study population: 928 subjects. Like the vast majority of trials conducted, the study was conducted under double blind, i.e. neither the infants nor the caregivers knew which product was being consumed, in order to avoid psychological influences (the 'placebo' effect).
The results confirmed the beneficial effect of Actimel consumption. There was a significant reduction in the number of cases, a finding that the first study had not revealed. In all, 22% of the infants in the yogurt group presented with diarrhea vs. 15.9% in the group drinking Actimel. The latter group also showed a lower prevalence of Rotavirus (a pathogen that largely contributes to cases of diarrhea). The study, which showed an approximately 25% decrease in cases vs. yogurt, thus evidenced the importance of daily consumption of the product in order to procure all the benefits, particularly a decrease in the number of episodes of diarrhea and the duration of those episodes.
The probiotic remains effective, even in a hostile environment
Towards the end of the nineteen-nineties, the positive results of the initial studies on a European population led to the question of whether Actimel would also be effective in an environment more exposed to a variety of pathogens. For that reason, in 1999, the scientific teams decided to conduct a study in a New Delhi hospital (India) and another, in parallel and complementary, in a dispensary close to the hospital.
Actimel was compared to a local fermented dairy product (Dahi) and pasteurized milk (not containing live bacteria) as the control product. The dairy products were complementary to the conventional treatment with the rehydration solutions recommended by the World Health Organization (WHO).
The study focused on the severity of diarrhea and the duration of hospitalization for the infants with diarrhea. The results showed that Actimel consumption was associated with a shorter duration of acute diarrhea (1.5 days) compared to the other two groups (1.8 and 2.1 days) and enabled a reduction in hospitalization duration of one half-day, which was very significant in the country considered.
For the first time, the benefit of Actimel on the body's defense capabilities with respect to infectious diarrhea was shown to be transposable to environments exposed to a variety of contaminants. With a view to explaining those effects, it was important to enhance characterization of the impact of Actimel on the body's defense systems, beginning with the most universal of those systems, the immune system.
Danone broadened its investigations to frail and susceptible people
The researchers addressed subjects at greater risk of infection due to 'functionally impaired body defenses'. Review of the scientific studies in the field, showed that the following factors may weaken the body's defenses:
intense and prolonged physical exercise (athletes, military commandos, etc.),
psychological stress (students during examination periods).
Published between 2000 and 2007, the studies enabled the researchers to measure the action of Actimel on specific markers of immunity. The markers were linked to cell-mediated immunity, e.g., the number of white blood cells and, particularly, natural killer (NK) cells and to the molecules related to humoral immune processes such as immunoglobulins (Ig).
The first of the studies was conducted in Barcelona in 1996 and included high-level amateur athletes. At that time, it was known, through the literature, that intense and prolonged sports could decrease immune defenses. Other studies had shown that lactic acid bacteria could stimulate certain immune cells. The effect of Actimel on NK cells after sustained physical exercise was therefore determined: as expected, the athletes who were taking the control product showed a reduction in immune cell activity only two hours after intense physical exercise. In those who were taking Actimel, the reduction in activity was significantly attenuated, thus demonstrating the link between Actimel consumption and modulation of a component of the immune system.
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In 2002, a study was conducted on students at examination time. Actimel intake also had beneficial effects on the number of NK cells and the total lymphocyte count. The effect reflected enhanced maintenance of immune system vigilance in periods of psychological stress.
Another series of studies addressed other indicators such as the number and duration of infections. In winter 2001, the researchers studied the incidence and severity of common winter infections in the elderly. The group that took Actimel daily showed a 20% mean reduction in the duration of infections, demonstrating an effect on the ability of the body to defend itself. In contrast, there was no significant impact on the number of infections.
Another study investigated the effect of Actimel in armed forces personnel on survival training. Although the number of episodes of infection was similar in the two groups, the Actimel group experienced more benign infections (e.g. rhinopharyngitis) than those in the control group.
The studies were decisive with regard to characterizing the action and hence the benefit of Actimel: when the immune system is weakened, Actimel acts to restore the defense potential.
On the basis of the studies, the researchers concluded that:
- Actimel reduced or opposed the weaknesses induced by a reduction in the body's defense capability,
- there was no 'over-stimulation' but 'restoration' of certain functions
- the restoration spared the subject's response capability by reducing the duration and/or severity of diseases but with no significant effect on disease frequency. This explains the difficulty, for the consumer, of perceiving the benefit, i.e. realizing that he/she is sick for a shorter period.
In short, the studies showed that Actimel conferred benefits when the body was challenged (stress, intense physical exercise, aging, etc.).
In parallel with the studies investigating the effect of Actimel, Danone addressed elucidation of the underlying action mechanisms.
How does it work?
Several studies were conducted with a view to investigating the various action mechanisms with encouraging results. The studies addressed three levels of the body's defenses: the intestinal flora, intestinal wall and certain immune cells.
One of the hypotheses investigated was the role of the intestinal flora in the immune response. The researchers were convinced that Actimel acted in part via the intestinal flora. The intestine is host to numerous bacteria and constitutes one of the body's first lines of defense.
By way of an example, a study was conducted in 1998 on children who consumed gelled milk or conventional yogurt or Actimel. The children taking Actimel showed enhancement of their intestinal flora in the form of a significant increase in the number of lactobacilli (greater increase than that in the group taking yogurt). There was also a decrease in certain harmful enzymatic activities reflecting an imbalance in the intestinal flora.
Did you know?
The term 'natural defenses' covers the key components of the body's defenses against pathogenic viruses and bacteria. The term covers, among other things, the skin and bodily fluids, but also the intestinal wall and immune cells. The term also designates the intestinal flora, which consists of a population of living microscopic organisms.
The intestinal flora consists in a population of 1014 microorganisms, i.e. 100,000 billion, i.e. 10 times more than the number of cells in the body. There are approximately a thousand different species. The intestinal flora intervenes in the digestion of certain foods and in the production of certain essential vitamins. The flora also prevents the growth of certain harmful bacteria and, from birth, ensures the training and stimulation of the intestinal immune system.
Numerous links between the intestinal flora and man have yet to be discovered. A vast field thus needs to be explored by today's researchers and numerous research teams worldwide and particularly in Europe are investigating those links.
The latest results
In 2007, researchers in 3 London hospitals had the idea of giving Actimel to their patients on antibiotics. Antibiotics are designed to destroy living microorganisms and can thus impair the intestinal flora of the patients who take them. Diarrhea is a frequent result. The physicians had heard about the research on Actimel and, in particular, the studies of the beneficial effect of Actimel with respect to diarrhea. The researchers hypothesized that Actimel might help maintain the equilibrium of the flora in patients on antibiotics and combat the proliferation of pathogenic bacteria, particularly a dangerous pathogen, Clostridium difficile, whose prevalence is increasing in several countries, including Great Britain.
The results of Actimel intake in the 3 hospitals were particularly probative: while 34% of the patients in the control group presented with diarrhea following antibiotic intake, only 12% in the Actimel group suffered from diarrhea. Moreover, no case of C. difficile-diarrhea occurred in the Actimel group while 9 cases occurred in the control group. The study demonstrated that Actimel contributes to maintaining the equilibrium of the intestinal flora in patients on antibiotics and has a beneficial effect on the body's defenses.
Another study, also published in 2007, was conducted on children suffering from asthma or allergic rhinitis since allergy is known to be an excessive reaction to normally inoffensive agents. Danone researchers thus investigated that aspect of immunity. The study evidenced that Actimel reduced the number of attacks in children suffering from allergic rhinitis (on average, from 5 to 3 during the year of Actimel consumption) but had no significant effect on asthmatic children.
Did you know?
The hygiene theory was controversial in that it called into question the value of permanently combating bacteria. Without denying the importance of hygiene, the theory is that excessively low exposure to bacteria (pathogenic, neutral or even positive bacteria like probiotics) is the cause of the increase in allergies and autoimmune diseases. Excessive hygiene is also reported to be the source of intestinal fragility in travelers to distant countries.
Future studies will address the median age group of the population, adults, and the effects of Actimel over longer periods. For Danone researchers, major questions have yet to be elucidated, particularly with regard to the details of the action mechanisms of probiotics on intestinal flora and, more generally, on the immune system.
The field of research, currently taking off, requires more studies and more time to enable the scientific community as a whole to elucidate the links between diet, intestinal flora and the body's defense systems. Nonetheless, Danone researchers have preferential targets. It would appear that Actimel is particularly effective in restoring degraded intestinal flora. The issue is now to define precisely what a 'good' intestinal flora is.
Did you know?
The ongoing partnerships in the European MetaHit project, coordinated by the French National Institute for Agronomic Research (INRA) aim to respond to questions on the intestinal flora from the scientific community. The project is being implemented by the major universities and companies operating in the field. Danone is naturally one of the contributors to the formidable adventure.
More basic research is to be based on new experimental models since the action mechanisms of probiotics are not easily elucidated in man. In addition, it is now certain that probiotics and particularly L. casei defensis in Actimel act via several mechanisms: on the intestinal flora, supplying transient compensation; on the intestinal wall, facilitating the restoration of functional integrity; and, lastly, on the inflammatory and immune systems which are re-equilibrated.
Did you know?
A functional food, and to an even greater extent, a probiotic food, does not act on one mechanism but on several. A given food may therefore act on various parameters.