VOJNOSANITETSKI AND FECAL BACTERIOTHERAPY: THE LINE BETWEEN DECEPTION AND TREATING

The microflora of the gastrointestinal tract is essential for mucosal protection, immune education, and for metabolism of humans. Disturbances of these processes results in various diseases. Regarding these processes, there is a clinical interest in the utility of microbial therapy – the feeding of non-pathogenic bacteria, originally derived from the alimentary tract. Considering the commercial success of probiotics, there is still a difficulty for consumers as well as for physicians when choosing the specific product. Since they are classified as food supplements, and not subject to drug regulations, there is ongoing skepticism about the benefits they offer. Fecal bacteriotherapy is reported as highly effective in the treatment of various diseases, including those of the digestive tract. The treatment itself consists of feces infusion from a healthy human donor to the gastrointestinal tract of patient. According to current data, fecal bacteriotherapy represents an emerging and promising low-cost solution for diseases with which antibiotic and probiotic products have been struggling for years. Probiotic gut effect prevents the chronic

Probiotics are a living microbial food supplement that favorably affects the host by improving the intestinal microflora, as well as live microorganisms, which by ingestion cause significant improvement of health when compared to a regular diet 1 . Initially, they were applied as an alternative therapy or simply a health food. However, their reputation in medicine had problems due to the extravagant claims of the producers of the probiotics.
While in reality, the consumption of these various strains of bacteria (many of which have not shown any probiotic activity or survival ability) has shown to be inconclusive. The amount of clinical data supporting the use of proven probiotic organisms in the prevention or treatment of many disorders is lacking 2,3 .
Thus, in recent years another approach has gained considerable attention. Fecal bacteriotherapy (FBT) represents a method that consists of feces infusion from a healthy human donor to the gastrointestinal tract of a patient, with the goal of treatment of disease that is related to gut microbiota alteration. Reports of FBT effect in Western literature started to appear in previous 60 years, first as a treatment for antibiotic related diarrhea 4 , although the first use of this treatment was recorded 1700 years ago 5 . Today, the admirable effect of this approach is reported in various conditions, thus it is still classified as investigational treatment, therefore requires further standardization and developing.

Gastrointestinal flora
Co-evolution led to a symbiotic bond between eukaryotes and prokaryotes with the development of a sophisticated two-way signaling system in mucous epithelium and the immune system, as well integration of gut microflora with various signaling pathways in the central nervous system [6][7][8] . It has been clearly established that gastrointestinal flora is of utmost importance for the mucosal protection of the immune function. Laboratory animals without microbiota (germ-free animals) are sensitive, and with a reduced mucous immune function. The reintroduction of the flora to germ-free animals restores intestinal function, mucosal proliferation, immunity development, animal growth, and normal behavioral This complex microbial world is different in composition throughout the length of the intestine with an increased inclination of the host microbe number and diversity from the stomach to the colon [13][14][15][16][17] . The gastrointestinal flora is described as the most adjuvant and renewable metabolic organ in the body whose composition and activity can affect both the intestines and the physiology of the individual 6,7,9,18,19 . Such an effect is not surprising During and after childbirth, the fetus is exposed to microbial contamination. The level of contamination impact is related to the duration and type of the delivery process. For example, initial contacts with cesarean-born neonate microbes are related to air, medical staff and neonatal care 24 . After giving birth (either natural or through the cesarean section), infants are continuously exposed to food-derived microorganisms, both to those useful and to those which are not. Healthy breast milk contains a significant number of bacteria. These transient bacteria include Streptococci, Lactobacilli, Micrococci, propionic bacteria and special Bifidobacteria 25,26 .
For breastfed babies, Bifidobacteria are bacterial species that is dominated microbial flora, and significantly less Escherichia coli, Streptococci, Bacteroides and Clostridium species.
In contrast, newborns on artificial nutrition have a much more complex composition of microflora, and Bifidobacteria and potentially pathogenic anaerobes are predominant 25 .
This has in recent times influenced the development of artificial baby foods by formulas with bifidogenic properties similar to mother's milk in an attempt to reduce the development of enterocolitis. After 12-24 months after birth, independently on diet, or probiotic intake, children's flora becomes much more complex and more similar to that of adults 27 .

Probiotic productsthe world of "arranged chaos"
Lactobacilli and Bifidobacteria are most commonly associated with probiotic activities.
Although, other organisms are used, such as the certain strains of Escherichia and any nonbacterial organisms such as Saccharomyces boulardii 28 . This is primarily due to the understanding that they are members of the intestinal microflora. Furthermore, these bacteria have traditionally been used in the production of fermented dairy products and have the status of "GRAS: generally recommended as safe" 33 . Most of these organisms are derived from feces of healthy people, safe for human use and are available in large numbers. Due to the continuing skepticism of such products, the European Union has established research groups, including medical, scientific and industrial interests that have harmonized the criteria for the selection and application of probiotics. In order to meet the criteria, probiotic micro-organisms should be of human origin, to show non-pathogenic behavior, even in immunocompromised hosts, to demonstrate resistance to technological processes, have proven resistance to acids of the stomach and bile, adhere to epithelial tissue, be able to shortly survive in the gastrointestinal tract, produce antimicrobial substances, modulate immune responses, and can have the ability to influence metabolic activities (such as, for example, cholesterol assimilation, lactase activity, and vitamin production) 1 . Nevertheless, a product can be classified as a probiotic if it contains another bacterium that is accepted as not harmful or commensal, and where no serious adverse effects are expected. As a consequence of its classification as a food supplement, the main challenge of probiotics ariseslack of regulation and rigorosity in the process of manufacturing.
The effects of probiotics are known to be dependent on the strain and dose as well as for their transitory effect. In addition, the commercial formulation of probiotic product can be significant factor in bacteria delivering process 29,30  Regarding future probiotic applications, there is no doubt that treatment should be app oa e in an in ivi alize anne a on i e e pa ien " ie , hygiene habits, comorbidities, and current health status. No space should be left for biased decisions to be made. And indeed, studies that included personalized probiotic treatment showed an advantage over commercial products 40,41 . where aspiration of inoculum during sedation phase occurred 54 . Thus, that incident can be attributed to complications related to application rather than a hazard of FBT itself.

Fecal bacteriotherapy
Addressing the unpleasant method of application of fecal microbiota by colonoscopy or by upper gastrointestinal route infusion, several research groups reported that the effect of fecal microbiota delivered via oral capsules did not differ from classical delivery in adult patients with CDI 44,55,56 . Therefore, with the introduction of more conventional ways of microbiota administration we could expect the elimination of most adverse effects related to FBT. Unlike probiotics, the current situation with FBT is not a case of introducing another poorly regulated food supplement. Thus, it is reasonable to assume that there is still a long way for FBT to become routinely used for wide specter of indications. Furthermore, when compared to probiotic products, its classification as an emerging therapeutic treatment is one of the biggest advantages of fecal bacteriotherapy. One could expect that if fecal bacteriotherapy fulfills given requirements and becomes classified as therapeutic treatment, the much needed line between deception and actual treatment related to microbial therapy will be drawn.

Conclusion
Although probiotics are accepted as beneficial products, there is a great burden of production inconsistencies between manufacturers leading to the deception of patients as well as physicians in cases of non-adequate selection of dose, strain or formulation. The future of probiotic should be oriented to a personalized probiotic treatment that considers patients diets, hygiene habits, comorbidities and current health status. On the other hand, fecal bacteriotherapy is conducted by strict regulations and currently is under process of evaluation as genuine treatment option for many indications. Considering current data, fecal bacteriotherapy represents an emerging and promising low-cost solution to diseases with which antibiotic and probiotic products have been struggling for years.