A Review of Research Conducted with Probiotic E. coli Marketed as Symbioflor
The production of B‐vitamins, especially folate and riboflavin (B2), by probiotic bacteria has been extensively researched as described in a recent review [7, 8]. This review summarizes the commercial applications of Bacillus probiotics. the use of antibiotics as growth promoters in its pig industry and is the date Finally, it should be mentioned that this review expands on two excellent reviews in that have been shown to act as preferred sites for spore formation . I think many of you have heart b2, it;s so far the biggest mistake I have ever made with online dating site. I paid 5 CDN for a first month tryout.
Oral health As compared to general health improvement, probiotics have been less explored in the field of oral health as is evident from a very small number of patents in this area. This could be due to the late surge of research post on the oral health aspect. Though many devices and chemicals such as tooth brushes, dental floss, tongue cleaners, toothpastes, mouthwashes, mouth fresheners, etc.
Use of probiotic formulation seems to be a promising new approach to address the issue of oral health. The probiotic or synbiotic compositions patented for oral health include bacteria predominantly from genus Streptococcus and Lactobacillus formulated alone or in combination with each other or an appropriate prebiotic ingredient. The composition can be used in a variety of dosage forms including toothpaste, mouthwash, oral spray, cream or gel, chewing gum, candy, lozenges, dissolvable pill, strip or powder.
Where most of these bacteria have been the normal flora of human oral cavity or intestine, Hillman has exploited a notorious dental caries causing bacterium-Streptococcus mutans by using its Lactate dehydrogenase LDH deficient strain [ ]. The general type of dosage forms protected under oral probiotic patents is not just restricted to the common lozenges, chewing gums center filled and coatedoral rinses, pills, tablets, capsules, topical agents etc.
An Unconventional composition by Knusten et al. Castellana Jordi provides a composition of L.
Novel Applications of Probiotics Anticancer activity In-vitro studies on anticancer potential of probiotics and prebiotics has shown promising results as reported by Macfarlane etal. This kind of fundamental research has further lead to the development of probiotic composition patents assigned to various organizations like London Health Science Centre and California Institute of Technology, etc .
Hani El-Nezamy et al. The probiotic composition includes 3 bacteria namely heat inactivated L. Efficacy of such a composition in cancer development is suggested by scientific evidence related to increasing immune cell activation, increase of antitumor surveillance immune activity, promotion of anti-inflammation and suppression of bacteria converting procarcinogens.
Thus probiotics offer a secondary reliable treatment in preventing onset of cancerous tumors. Further the patent also provides methods for relieving gastrointestinal distress to the subject suffering from the disorder. The inventors have disclosed that the anti-tumour activity could be related to suppressing the expression of pro inflammatory cytokines, chemokines and inducible nitric oxide synthase iNOS.
The invention also reveals methods of using probiotic bacterial compositions of Lactobacillus rhamnosusEubacterium hallii and Bifidobacterium longumor a combination thereof in the prevention, risk reduction and treatment of breast cancer.
Such work in future could be reliable in early detection and management of the disease. Cardiovascular disorders Pang et al.
An effective amount of one or more of these agents upregulates a cytokine profile characteristic of a Th1 T-cell response relative to a cytosine profile of a Th2 T-cell response associated with inflammation of blood vessels in a cardiovascular disorder.
Thus this noteworthy invention is concerned with methods for diagnosing or detecting significant Th2- mediated atheroma e. This is based on the assessment of various markers and indicators of a Th2 response in blood.
Peter Rothschild et al. A method of selecting such strains and products containing inflammation-reducing component from cell free supernatants has been disclosed. The formulations are also claimed to have beneficial effects on obesity and related conditions, metabolic syndrome, tissue inflammation, hepatitis, myositis and cardiovascular conditions.
The probiotic bacteria are said to show anti-diabetic effects by normalizing plasma glucose concentrations, improving insulin sensitivity, and reducing the risk of its development in pregnant women and preventing gestational diabetes.
Such dietary supplements also function by controlling weight gain, preventing obesity, increasing satiety, prolonging satiation, reducing food intake, reducing fat deposition, improving energy metabolism as obesity increases the risk of developing diabetes and metabolic syndromes.
Similar notable and interesting work has been carried out by Park et al. The work claims to reduce the amount of monosaccharide or disaccharide which may be absorbed into human body by converting them into non-digestible polymeric materials like isomaltotriose, dextran and pullulan which cannot be absorbed by the intestine and thus inhibit the increase of blood glucose level originating from glucose.
Antiviral activity Park et al. Rotavirus infections are difficult to treat when accompanied by secondary bacterial infections enhancing the severity. The usual approach in such cases is based on supportive treatment addressing starvation and dehydration.
Antibiotic treatment in such cases is effective only against the secondary bacterial infections. Hence the above mentioned invention is of prime importance to reduce the severity of rotavirus attacks. James Allen Lemke has disclosed a method for preventing as well as treating HIV infection in a subject [ ]. The method makes use of a genetically modified probiotic L. Rare diseases related to inborn errors of metabolism A patent has been filed by Naz Al-Hafid et al.
The bacterium is capable of expressing phenylalanine ammonia lyase PAL and thus metabolizes phenylalanine to metabolically insignificant amounts of ammonia and trans-cinnamic acid, even when the PAL was expressed intracellularly. The claims were supported with animal studies in mice models for PKU following administration of the amino acid.
The probiotic was able to survive exposure to conditions mimicking various compartments of the human GIT. Individuals with kidney disease, as well as a number of other diseases such as inborn errors in urea cycle enzyme deficit result in waste nitrogen accumulation in the body thereby manifesting toxic symptoms.
Also provided are methods of alleviating symptoms of uremia in patients which comprises of administering orally the above mentioned composition comprising of Bifidobacterium or Lactobacillus probiotics and prebiotics like fructan oligosaccharide or araban oligosaccharide to a patient suffering from it.
These synbiotic compositions are beneficial in treating renal and hepatic diseases and bacterial overgrowth in the gastrointestinal tract.be2 Dating Site: LOVE. RIGHT. NOW.
Matar and Martin claim to have identified a bacterial strain of Serratia vaccinii to be used to increase the antioxidant potential of food products including probiotics [ ].
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In addition to the personality test and basic information, Be2 will also ask about your views, goals, and lifestyle. Making Contact Sending and reading messages are for premium users only Contacting only through matches Search criteria can be edited anytime There is a number on the bottom right of your matches' profile photo that denotes your compatibility.
The higher the number, the more compatible you are. You can use this number to be redirected to their profile where you can see more details on your compatibility. Only one message for free per match is given to free users. Because the system relies on how many registered recently and how many are compatible with you, only a few new matches are added to your existing list everyday. This invited researchers to examine Symbioflor bacteria as a means to transfer bioactive molecules safely inside the human body.
For instance, it was tested if the bacteria could be used to express recombinant IL, as this would be a nice delivery vehicle to get the interleukin in the gut, where it is required for functionality [ 22 ]. Expression in a probiotic strain of the yeast Saccharomyces boulardii had more success [ 22 ].
The study concentrated on E. Two differentiation marker genes of intestinal cells Hes1 and Hath1 were downregulated as a result of incubation with E. Their Figure 1, however, suggests that G2 resulted in stronger downregulation of Hes1 than G3. In vitro upregulation of hBD-2 was shown for G2 i. Becker and colleagues further showed upregulation of Muc1 by E. The authors suggested that the observed effects by E.
However, this does not explain the observed effects with the Symbioflor bacteria, since these do not express flagellin. One would think that the science behind probiotics had finally matured, but in a highly critical paper was published in which the research conducted on the subject of probiotics was severely criticised [ 24 ].
The authors highlighted the difficulties of legislators to decide on definitions of probiotics or assessment of their safety, and the diversity in international safety and regulatory standards that were being employed. They pointed at the lack of an independent organisation to direct and conduct research, criticising the wide variety of products being marketed and the commercial stakes at playthe fuzzy end goals of clinical trials, and the fact that a limited number of products were tested for a wide variety of conditions [ 24 ].
The authors were right about all these points, of course, but science is not following logical, targeted, and centrally directed paths, nor would science make the progress it does when scientists were told what to do by a centralized agency. Moreover, the authors were much less critical about the relationship between probiotic agents and the innate immune system, although a lot of those insights are exclusively based on murine models, with questionable relation to the human host.
They even considered the work on Segmented Filamentous Bacteria SFB noteworthy to mention in a positive light, which disharmonized with their long complaint about undirected and imprecise research.
They concluded that probiotic substances do not need to be alive, as bacterial-derived molecular bioactive compounds might be able to do the job [ 24 ]. Time will tell if they were right about this. A second systematic review on the effects of probiotics was published in Since it covered an even broader collection of intestinal disorders than the study Hungin and colleagues released a year earlier, a total of relevant publications were identified, of which 81 were assessed qualitatively [ 25 ].
The clinical symptoms for which trials were conducted were divided into 9 different disorders, of which IBS was the most frequently studied 21 included studies followed by antibiotic associated diarrhoeainfectious diarrhoea including viral gastroenteritisand necrotizing enterocolitis [ 25 ]. Of these, 3 had used E. Unfortunately, neither the Enck trial of which was published in German nor the Martens study of which dealt with pediatric patients was included.
Instead, another trial on IBD performed by Enck and coworkers was listed, where Pro-Symbioflor the product containing lysed bacteria of E. That study is not described here any further as it did not deal with live Symbioflor E.
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- Patents in the Field of Probiotics, Prebiotics, Synbiotics: A Review
- Be2 Review January 2019
A further systematic review and meta-analysis was published in the same year, this time concentrating on IBS and chronic idiopathic constipation [ 27 ].
This time papers were identified to begin with, of which 73 were retrieved for evaluation. After exclusion of 30 papers for various reasons, 43 trials remained, of which 35 described the use of probiotics.
The two trials on E. The position of the Nissle study on the forest plot was comparable to that of the Enck trial, in terms of effect on persistence of IBS symptoms, while the Enck results were amongst the most favourable outcomes RR 0. Considering the genotypic and phenotypic diversity within this species, this results in misleading conclusions. In a special issue on irritable bowel syndrome published in the same year, a review was included on IBS in children [ 28 ].
Naturally, the authors cited the trial by Martens and coworkers and summarize their results.
International Journal of Bacteriology
In their conclusions the authors recommended the inclusion of probiotics in what they called a biopsychosocial approach to treat pediatric IBS, and they specifically mentioned the commercial products VSL 3 and LGG both not containing E.
When an invasive E. In vitro experiments showed that this overexpression of ivy indeed resulted in higher resistance to lysozyme. The ivy expression levels of Symbioflor E.
However, the observed difference in ivy expression did not correlate with lysozyme resistance in the Symbioflor isolates. Based on sequence analysis, the authors held a naturally mutated promoter in front of the ivy gene of E. The authors speculated that other, unidentified lysozyme inhibitors might exist that were responsible for the observed effects.
As such, the relevance of ivy upregulation in mild intestinal inflammation remains uncertain. One of the still outstanding questions from the original expert opinion publication [ 2 ] that had not yet been addressed was dealt with in a publication in which this author was involved.
It described five volunteers who took a single, high dose of Symbioflor E. It turned out that the bacteria did this surprisingly well: This was established with the use of genotype-specific probes that had been designed with the help of the genome sequences.
With these findings it was finally established that Symbioflor bacteria are indeed able to colonise the human intestinal tract for multiple weeks, even after a single dose, without causing any side effects.
One after another, the concerns expressed in by Beutin and colleagues [ 2 ] were proven irrelevant. An in vitro model was developed to mimic the human gut during onset of an immunological response; the model was used to demonstrate that EDTA releases the epithelial layer from healthy epithelial cells, resulting in activation of immune lamina propria cells. In that way immune cell migration as well as transcriptional responses could be studied.
The model was employed to study the effect of bacteria, including Symbioflor [ 31 ]. After standardization, drugs such as dexamethasone were tested, which inhibited emigration of lymphocytes in a concentration-dependent manner. The plasmids present in these genes were also completely sequenced, and all sequences were made publically available in GenBank.
This will enable other research groups to use and employ the genome sequences of Symbioflor E. The finding that there were a number of virulence genes present in the genomes of probiotic Symbioflor, as outlined by Wassenaar and colleagues [ 33 ], was no longer a surprise, as by now there was ample evidence that virulence genes are not exclusively found in pathogenic bacteria. The results of the volunteer study were also incorporated in this paper, as well as a ten-year long collation of all side effects collected from commercial use [ 33 ].
In view of the large number of sold doses, this list of collected side effects was surprisingly short. These findings, though not surprising, make it more difficult to predict the virulent properties of a given E. In their publication the authors also drew attention to the genomes of Symbioflor E.
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The publication by Didari and coworkers focused once more on IBS, with an updated systematic review and meta-analysis [ 35 ]. Their analysis started with trials, of which 24 were included based on their eligible criteria. Thus only 15 studies remained to be compared, and patients were combined as is the aim in meta-analyses when possible.
This resulted in an analysis where the patients of Enck et al. In part this mistake may have been caused by unclear descriptions of the products in the original trials, but it also illustrates how difficult it is to perform meta-analyses in this subject, as probiotic products are so heterogeneous. Mazurak and coworkers also conducted a systematic review, recognizing the weaknesses of the reviews reported here, and for that matter many others were omitted in this summary as they did not include results on Symbioflor [ 36 ].
In their systematic review of which Enck was one of the authorsthe study by Enck that used bacterial lysate was omitted, as it was not considered probiotic in the pure sense. Why they also omitted the study by Enck and coworkers is unclear.
Patents in the Field of Probiotics, Prebiotics, Synbiotics: A Review
The authors recognized the wide diversity in products, applied doses, and treatment duration that limited the possibility of conducting a meta-analysis.
They pointed out that over the years the heterogeneity in studies had increased instead of decreasing towards consensus and that few trials followed the rules and proper practice of randomised clinical trials RCT as outlined by the FDA, EMA, and the Rome group [ 36 ].
In particular, very few trials were registered prior to their start, which is considered an essential step to prevent omission of unwanted data in the final analysis. Many studies were performed with patient numbers being too small to generate the required statistical power to overcome placebo effects.
Crossover studies were discouraged by the authors, and they recommended that the EMA and FDA guidelines for clinical trials should always be followed. Lastly, they recommended trials using single-strain probiotics only, thus avoiding the use of products containing multiple strains [ 36 ]. This advise would have been clearer if they had advised against the use of mixed species in a product, as that is probably what the authors meant. These complex interactions were reviewed by [ 37 ].