Their germs are closer to the body

Yana Khlyustova, "Newspaper.Ru" 

In the body of children, starting from birth and almost to adolescence, there are strains of bifidobacteria-"long-livers", which, as the child grows up, are gradually replaced by age-specific ones. Scientists told the Department of Science why a person needs bifidobacteria and why the use of probiotics may be ineffective.

Bifidobacteria were discovered by the French research physician Henry Tissier at the end of the XIX century - it was then, working at the Pasteur Institute, that he described bacteria of an unusual, Y–shaped shape, which were present in large quantities in the stool of breastfed children.

A colony of bifidobacteria under a microscope. Photo: Vladimir Smeyanov 

Tissier suggested that bifidobacteria protect a child from infections, and already in 1905 described the use of a culture ("biomass") of live bifidobacteria for the treatment of diarrhea in children, thus becoming one of the pioneers of bacteriotherapy, namely, its variety, which is now called "probiotic therapy".

Tissier's assumption about the beneficial role of bifidobacteria in the human body was confirmed in numerous subsequent, more than a century-old studies: modern work using molecular methods confirms that bifidobacteria are one of the main bacteria-symbionts of the human intestine. In newborns, they account for up to 80% of all bacteria, and their share in the microbiota of adults reaches 34%. 

This is a huge figure: if the total number of microorganisms coexisting with the human body is about 100 trillion cells, then the number of bifidobacteria present in one person is approximately equal to the number of his own cells.

Bifidobacteria play an important role in stimulating the immune system of the body, produce antibacterial substances, prevent the attachment of pathogenic microbes to the intestinal wall, synthesize vitamins and participate in digestion due to the ability to break down complex dietary carbohydrates that cannot be absorbed by the body. That is why in case of a violation of the balance of the microbiota – for example, after the use of antibiotics – it is necessary to restore the normal level of bifidobacteria in the body.

A research group of scientists from the Russian National Research Institute and the Medical Institute of the North Caucasus State Humanitarian and Technological Academy published an article in the journal PLoS One, which presents the results of a study of the individual stability of bifidobacteria for more than ten first years of children's life (Chaplin et al., Interspecies Genomic Diversity and Long-Term Persistence of Bifidobacterium longum).

In the course of the study, using comparative genomics methods, the authors found that at least some children in the intestinal microbiota from the age of about 1 year and up to 11 years really retain extremely similar and closely related (that is, having a common recent ancestor) strains of bifidobacteria with a percentage of genome identity of 99.7-99.8%. 

Such strains can be called "long-lived" or "universal" strains, since they are able to inhabit the body of a particular child throughout childhood.

In addition, scientists have found out that during the development of a child, strains of bifidobacteria are replaced by unrelated ones: such a replacement can occur both in the interval from 1 year to 5-6 years, and later, between 5-6 and 10-11 years. Apparently, "age-specific" strains have some genetic features that make them more competitive compared to their predecessors, but additional research is needed to identify such genes.

The authors of the study told the science department of "Gazeta.Ru" about the details of the work, as well as about what practical application their conclusions can find.

– What questions did you ask yourself when you started working? 

Vladimir Smeyanov, Associate Professor of the Department of Natural Sciences of the Medical Institute (North Caucasus State Humanitarian and Technological Academy):

– First of all, we were interested in the following: will certain strains of bifidobacteria, transmitted, as it is believed, to the child from the mother at birth, exist in the intestines of the child for several years? If so, what genetic factors determine the ability of specific strains of bifidobacteria to form a stable bond with the human body? Will there be a change of bifidobacteria strains? If so, for what reason?

These issues are extremely important: the fact is that the species and strains of bifidobacteria differ significantly from each other in biological properties, in particular in their ability to compete with pathogenic microbes, in the nature of the nutrients they process, as well as in the nature of their effect on the immune system.

For example, some strains are able to stimulate inflammatory reactions, while others are able to suppress them. In addition, information about the mechanisms of long-term stability of the intestinal bifidoflora is indispensable for the creation of more effective probiotic drugs.

– You found out that children have closely related strains of bifidobacteria in their bodies during the first decade of life. What role do they play in the body?

Andrey Shkoporov, Senior Researcher at the Laboratory of Microbiology and Biological Safety (Russian National Research Medical University): 

– Our data suggest that in the intestines of newborns there is a population of very close variants of one strain of bifidobacteria, acting as a kind of "bench" or adaptive reserve, from which, during the growth and development of the child, as well as under the influence of external factors, the selection of the most suitable for these conditions, currently competitive variants occurs.

Our bioinformatic analysis allowed us to preliminarily identify a set of genes, the presence of which, perhaps, determines the ability of these "universal" strains to colonize the intestines of children for a long time. Nevertheless, the actual role of these genes in the processes of long-term survival has yet to be confirmed experimentally.

– What practical application can the results of your work have?

Lyudmila Kafarskaya, Head of the Department of Microbiology (Russian National Research Medical University): 

– The results of the study indicate the need to revise the current concept of probiotic therapy using bifidobacteria (at least bifidobacteria of the type Bifidobacterium longum). Currently, the same strain of bifidobacteria is used as a probiotic for both children of all ages and adults.

– Is it possible to use the "long-lived" or "universal" strains selected by you when conducting probiotic therapy in the case of children?

Lyudmila Kafarskaya: Despite the fact that "universal" strains do exist, the process of their survival is collective, that is, it is provided by a group of closely related strains of bifidobacteria. Perhaps, if it is necessary to restore the normal balance of the intestinal microbiota for a long time, it makes sense to use a combined probiotic containing several "universal" strains.

For children of a specific age group, it is possible to use strains of Bifidobacterium longum obtained from children of a similar age. This will allow us to take into account both the physiological changes of the growing organism and the nature of the child's nutrition.

– What is the uniqueness of each strain of Bifidobacterium longum?

Andrey Chaplin, PhD student of the Department of Microbiology (Russian National Research Medical University): 

For the first time, the analysis of all genomes of the Bifidobacterium longum species available by the beginning of 2015 allowed us to establish that the totality of all genes available in the bacterium is "open". The "openness of the genome" means that each unrelated strain of Bifidobacterium longum (for example, the one that exists in the intestines of a particular person) will most likely contain new genes, that is, be more or less unique for this person.

This is complemented by a fairly high frequency of the so-called horizontal transfer of genetic information, which mixes genes in the population of bifidobacteria and even sometimes borrows them from other microorganisms.

It is hoped that someday researchers will be able to predict the properties of a particular strain of bacteria well enough just by looking at its genome. Only in this case will the real management of the human microflora be possible.

– How effective can you call the action of the currently existing probiotics?

Boris Efimov, Professor of the Department of Microbiology (Russian National Research Medical University): 

The effectiveness of existing probiotics, including preparations of bifidobacteria, is not ideal and is not confirmed in every study. The fact is that in order to ensure a pronounced effect of probiotic therapy, a number of conditions, both technological and biological, must be met. The drug must contain a sufficient number of viable bacteria that are able to survive when passing through the acidic environment of the stomach and be resistant to other aggressive factors, such as the action of bile.

And finally, if the surviving bacteria reach their main place of action – the large intestine, they should be able to stay in this organ for a sufficient time to have an effect.

Due to the fact that probiotic bacteria, as a rule, do not have the ability to colonize the intestine for a long time, probiotic therapy should be carried out in long courses and using adequate dosages, implying the content of relatively high concentrations of viable bacterial cells in the preparation.

If the problems with the survival of probiotic bacteria can, in principle, be solved by technological approaches, the mechanisms of long-term colonization of the intestine by bifidobacteria remain practically unexplored. This means that it is not yet possible to routinely monitor the survival of probiotic bifidobacteria in each individual patient, and therefore to improve the effect of their use, taking into account the current level of knowledge.

– And how can you comment on the results of some studies, in particular, published in the journal Infection Control & Hospital Epidemiology, the authors of which claim that probiotics do not have a pronounced positive effect on the human body?

Vladimir Smeyanov: Indeed, periodically there are publications in which the authors do not detect the expected effects from the use of probiotics. In this case, we are talking about the absence of statistically significant differences in the contamination of nosocomial infections with bacteria with multiple antibiotic resistance between critically ill patients who received or did not receive a probiotic drug based on lactobacilli, strain L.rhamnosus GG.

It is necessary to dwell on the very idea of conducting an experiment. Imagine: a person gets to the hospital, he is connected, for example, to a ventilator. In such a situation, the patient can receive a whole "bouquet" of various nosocomial microbes. Of course, he will be prescribed a "bouquet No. 2" of various antibiotics to prevent infections, which was done with most of the patients described in the article.

And then a probiotic drug is prescribed to patients, which should cure everything and everyone. But can anyone imagine an antibiotic that works equally effectively against all bacteria? No, of course, there is no such thing, at least not yet.

Similarly, the anti–infective effect of a probiotic bacterium is based on the phenomenon of bacterial antagonism - one bacterium can inhibit the growth of another specific bacterium (or even kill it), but will not do anything with any other.

In addition, the researchers injected patients with a fairly low dose of probiotics – 1x10!!!10 cells (not tested, by the way, directly by the researchers themselves).

The same amount of probiotics is contained, for example, in a bottle of yogurt, which is sold in our stores and is intended for the daily nutrition of children. 

Perhaps it was necessary to test different dosages of LGG, because the official definition of a probiotic, given in 2014 by WHO and the UN, states: probiotics are living microorganisms that, when administered in adequate quantities, benefit the health of the host organism. However, the authors themselves admit problems with the experimental design of their research. To the self–criticism of the authors, it is also necessary to add that probiotics are living bacteria, and, of course, it is difficult to expect any effect from their use in patients undergoing intensive antibacterial therapy. Unless, of course, the probiotic used is resistant to antibiotics used simultaneously with it, such as, for example, a strain of bifidobacteria, which was developed and successfully used to treat patients, including critically ill, in the 1980s in our country.

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09.11.2015