Bifidobacterium longum ES1 is an internationally patented probiotic bacterial strain. It was originally isolated in 2007 from a three-month-old, healthy breastfed child by researchers at the Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC).
It was selected for its ability to survive passage through the digestive tract, which is a very hostile environment where acidity and the secretion of bile and other compounds kill many bacteria. Another selection criterion was its ability to adhere to mucin, a protein coating the digestive tract.
Then in 2008, studies in a human blood-cell model showed this strain was able to generate an anti-inflammatory response to gluten peptides. Furthermore, it was found to partially inhibit the growth of pathogenic bacteria isolated from the faeces of celiac disease patients. Taken together, these properties were of extreme interest, thus further scientific studies were undertaken.
The IATA-CSIC scientists demonstrated two important properties:
Firstly, in 2009, using a model of laboratory-cultured human intestinal cells, researchers showed that strain B. longum ES1 differentially degraded cereal gliadins, compounds that cause celiac disease. While conventional bacteria and digestive fluids break gliadins down generating small fragments (peptides), strain B. longum ES1 generates other fragments that do not trigger an inflammatory response.
Then, in 2010, using another human-cell model, this time dendritic cells of the immune system, scientists again proved the anti-inflammatory effects of the strain Bifidobacterium longum ES1.
The next step, before starting human trials, was to study the effect of the bacterium in an animal model. This is the point at which BIOPOLIS became interested in strain Bifidobacterium longum ES1 and the BIOPOLIS research team began collaborating with the IATA-CSIC scientists under the Spanish government’s CENIT project, SENIFOOD.
Studies in an animal model
Before starting human trials, the effects of the bacterium were studied in an animal model. To do so, celiac disease was simulated in newborn rats. They were divided into two groups: one was given the bacterium Bifidobacterium longum ES1 while the other received a placebo. The results, obtained in 2011, confirmed the anti-inflammatory capacity that had been observed in cell cultures, though now it was seen in a small mammal, i.e., in a whole organism rather just than in cells. These results were published in early 2012.
Checking the food safety of strain ES1
Before the first human trial was run in volunteers, BIOPOLIS and IATA-CSIC scientists decided to check the food safety of strain ES1, which they did in late 2010. Importantly, as mentioned above, strain ES1 belongs to the species Bifidobacterium longum but although this species is considered safe, a decision was taken to check it thoroughly, following the recommendations of the World Health Organization (WHO). The compounds produced by bacteria grown in the laboratory were analysed and none were found to be toxic. Studies were also performed to check whether the bacterium was resistant to any antibiotics for hospital use. Results showed it was not. Even so, further studies were run in a mouse model to discover the effect of giving a huge amount of the strain daily, around over two thousand times the dose that would be taken by a child weighing 30 kg. This was done in normal mice and mice with a deficient immune system, to simulate the worst possible scenario. No toxicity problems were detected in any of the groups tested. Finally, researchers decided to make use of the latest technologies and sequenced all the genes in this bacterium. No gene posing a threat to consumers’ health was found.
Human clinical trials
The first human trial was run in healthy adult volunteers in 2011. They were given the probiotic for two weeks and did not report any problems of gastrointestinal pain, constipation, nausea or diarrhoea. Thus everything was ready for the trial to begin with celiac children.
The trial was monitored by the IATA-CSIC and was conducted in two hospitals: Hospital Universitari Sant Joan in Reus and Hospital Sant Joan de Déu in Barcelona, beginning in 2011 and ending in 2012. The trial was with celiac children, who were beginning a gluten-free diet, and were divided into two groups. For three months, one group was given the bacterium Bifidobacterium longum ES1 while the other received a placebo. Results showed a decrease in the inflammatory response in the group taking B. longum ES1, as well as greater weight gain. Furthermore, children who had ingested celiac ES1 strain were observed to have less potentially pathogenic celiac disease-associated microorganisms in their faeces than children who had ingested the placebo.
Turning the scientific development into a product designed for celiacs
As the clinical trials advanced during early 2012, BIOPOLIS scientists began to set up the industrial-scale production strain ES1. This was a complex process, requiring optimisation at laboratory scale first, then at the pilot plant and finally at industrial scale.
Scientists at the dairy company Central Lechera Asturiana, who also participated in the CENIT-SENIFOOD project, took an interest in the strain. Thus, together with scientists at BIOPOLIS they began to define what was to become the first commercial product designed for the celiac community, incorporating the probiotic strain Bifidobacterium longum ES1.
Scientific publications on strain B. longum ES1
Izquierdo E, Medina M, Ennahar S, Marchioni E, Sanz Y. (2008). Resistance to simulated gastrointestinal conditions and adhesion to mucus as probiotic criteria for Bifidobacterium longum strains. Current Microbiology 56: 613-618
This article describes the strategy employed to select probiotic bacteria able to withstand bile salts and acidity and to adhere to mucin, which is a protein forming a gel on the gastrointestinal tract walls. Strain B. longum ES1 was selected like this and fulfils all these requirements, thus it can be considered a probiotic strain
Medina M, de Palma G, Ribes-Koninckx C, Calabuig M, Sanz Y. (2008). Bifidobacterium strains suppress in vitro the pro-inflammatory milieu triggered by the large intestinal microbiota of coeliac patients. Journal of Inflammation 3: 5-19
This article reports the use of a human blood-cell model, describing how the bacterium B. longum ES1 is able to reverse the pro-inflammatory response caused by the bacteria found in the digestive tract of celiac patients. It was the first time the anti-inflammatory effect of strain B. longum ES1 was demonstrated.
Laparra JM, Sanz Y. (2010). Bifidobacteria inhibit the inflammatory response induced by gliadins in intestinal epithelial cells via modifications of toxic peptide generation during digestion. Journal of Cell Biochemistry 109: 801-807
This paper describes how the bacterium B. longum ES1 can degrade gliadin, which is responsible for celiac disease, in a different way to other bacteria. Consequently, it generates a set of peptides that differs from those triggering the inflammatory response in a model of human intestinal epithelial cells.
Olivares M, Laparra M, Sanz Y. (2011). Influence of Bifidobacterium longum CECT 7347 and gliadin peptides on intestinal epithelial cell proteome. Journal of Agricultural and Food Chemistry 59: 7666-7671
This article is closely linked to the previous one. It describes how human intestinal epithelial cells exposed to groups of gliadin peptides obtained in the presence of strain B. longum ES1 cause less damage and modify the expression of proteins with different functions than those obtained in the absence of bifidobacteria. Cells exposed to gliadins not degraded by B. longum ES1 trigger pathways of inflammation and cell death while those treated with B. longum ES1 did not induce these pathways, but others linked to calcium homeostasis and cell survival and function.
Laparra JM, Olivares M, Gallina O, Sanz Y. (2012). Bifidobacterium longum CECT7347 modulates immune responses in a gliadin-induced enteropathy animal model. PLoS ONE 7: e30744
This article describes the effect of the probiotic B. longum ES1 in an animal model of gliadin-induced enteropathy. It shows how the intake of strain ES1 attenuated the inflammatory effects of gliadins, which did not happen in experimental animals taking a placebo.
de Palma G, Kamanova J, Cinova J, Olivares M, Drasarova H, Tuckova L, Sanz Y. (2012). Modulation of phenotypic and functional maturation of dendritic cells by intestinal bacteria and gliadin: relevance for celiac disease. Journal of Leukocyte Biology 92: 1043-1052
This article describes the effect of co-incubating a special type of immune system cells, dendritic cells, with B. longum ES1 or with pathogenic bacteria (enterobacteriaceae) detected in the gut of celiacs. While enterobacteria caused changes in the shape of dendritic cells, making them trigger an inflammatory response, the presence of B. longum ES1 did not give rise to these changes in morphology and reduced inflammatory activity, even inducing the synthesis of some compounds exerting anti-inflammatory activity.
It does not replace the gluten-free diet
The goal of commercial products incorporating the strain Bifidobacterium longum ES1 is not to replace a gluten-free diet, but to provide greater protection to the intestinal lining of celiacs and help them recover.
As demonstrated by numerous studies, the strain B. longum ES1 exerts a dual effect in the gut:
1. Reducing the abnormal inflammatory parameters in celiac individuals;
2. Favourably modifying the composition of the intestinal microbiota, reducing the concentration of Gram-negative bacteria detected in celiac individuals, which are more pathogenic and have greater inflammatory potential.
While these developments may help improve the quality of life and health status of celiacs, it is still important for them to stay on a gluten-free diet.
Spain and Andorra
The first product developed for celiacs and incorporating strain Bifidobacterium longum ES1 is Proceliac, sold through the food distribution network by Central Lechera Asturiana, in Spain. This is a product developed through collaboration between BIOPOLIS researchers and Central Lechera Asturiana scientists, during their participation in the CENIT-SENIFOOD project, under which the in vivo studies and clinical trials of strain ES1 were run. Both parties were interested in defining a potentially marketable product.
Proceliac is a nutritional supplement, designed for celiacs. In addition to the strain Bifidobacterium longum ES1 it also contains micronutrients (vitamins and minerals) of importance in a celiac’s diet. Thus, we can conclude that Proceliac is a product designed and developed scientifically and focussing specifically on celiacs.
Our commitment at BIOPOLIS
BIOPOLIS is committed to finding the best companies to bring the benefits of the strain Bifidobacterium longum ES1 to the greatest number of celiacs. To do so we are in contact with different companies in Europe, USA, Canada, Latin America and Asia to make this commitment a reality.
Where can I buy this product?