Antibiotics are important for saving both human health and life. In some situations it is necessary to apply a broad-spectrum therapy. Antibiotics destroy all bacteria within their spectrum, because they do not distinguish between good and bad bacteria. It is always necessary to remember this before beginning an antibiotic therapy. Both the bacteria causing an infection and the ones which are part of the human physiological microflora will be eradicated. Even if an antibiotic therapy lasts only a few days, it may cause diarrhoea and mycosis. In some cases it may cause pseudomembranous colitis due to the infection with
Both drugs and dietary supplements can be classified as probiotics [30]. If they are applied at a right dose, they may have a beneficial effect on the human body [28, 48]. The properties of probiotics depend on a particular bacterial strain, which has specific biochemical and microbiological parameters. Probiotics mainly contain lactic acid bacteria (LAB) of the
Good probiotics should be easy to produce. The microbial strains they contain should resist and survive fixation processes and they should be stable during storage. It is also important that the organoleptic characteristics of a finished product should not be worse. The criteria defining the properties of probiotic strains and describing the conditions of the production, storage and distribution of probiotic preparations were described in the FAO/WHO recommendations [23]. Probiotic microorganisms must be classified according to their genus, species and strain [69] and the information on the package of a probiotic preparation must be provided only in this form. It is recommended that probiotic strains should come from the population in which they will be used due to age-, region- and living environment-dependent differences in the intestinal microbiome [2, 28]. Some probiotics are composed of one strain, others a few. All these preparations have a different purpose and are used in specific ailments. One-component preparations are used e.g. in the reduction of irritable bowel symptoms, in the treatment of constipation [21] or diarrhea, thus multi-component preparations in the treatment of obesity or mood disorders. It is important that the multi-component preparations are composed so that the strains composed of them do not act antagonistically [28]. It is required to exclude pathogenic and carcinogenic effects of strains, check the degree of adherence to epithelial cells and determine their metabolic activity. The stability of microorganisms should also be controlled after the technological process and at various stages of the shelf life of the preparation. The resistance of probiotic bacteria to antibiotics should also be tested. It is a key element to prove the genetic stability of microbial strains in tests, i.e. to determine the presence of resistance genes on mobile genetic elements (plasmids, transposons) [13, 23]. The final stage is to test probiotics in double-blind and randomised analyses with a placebo group [67].
There are various mechanisms of interaction between probiotic bacteria and microorganisms belonging to the natural microflora or pathogens. Probiotics can interact directly in the intestines, or they can also act indirectly, by modulating the immune response and epithelial mechanisms [18, 37, 69]. One of the mechanisms of action can be observed directly in the intestinal lumen, where probiotic strains limit the possibility of adhesion of pathogens to enterocytes by competing for nutrients and receptor sites on intestinal epithelial cells [30, 48, 49]. The adhesion strength is an individual characteristic of a specific probiotic strain. As chyme passes in the intestinal lumen, weakly attached microbial cells are removed, making new space for stronger microorganisms. The probiotic strains which adhere to enterocytes more strongly are more difficult to remove from the surface of the intestine. In consequence, this reduces the formation of new surfaces, where pathogenic bacteria may appear [28]. Thanks to the production of bacteriostatic substances, probiotic bacteria inhibit the growth of pathogenic microorganisms in the human body. In addition, the production of such metabolites as lactic acid and short-chain fatty acids lowers the pH in the intestines and creates an adverse environment for the development of pathogens [67]. Probiotics are also capable of stimulating cellular and humoral immune responses [48]. The immunological interactions of probiotic microorganisms inhibit the production of pro-inflammatory cytokines, e.g. IL-8, TNF-alpha, and stimulate phagocytosis [69].
The microorganisms contained in probiotics can also use the epithelial mechanism, for example, through the enzymatic modification of receptors of bacterial toxins, the binding and activation of toll-like receptors and stabilisation of the intestinal barrier [68].
The intestines are part of the immune system. The intestinal microflora affects human health both directly and indirectly. In some situations probiotics modulate the immune response in immunodeficient patients. Even if the bacteria contained in the probiotic do not survive, they may also have immunological significance and act as an oral vaccine. Vitamin D is the main precursor of the formation of antibacterial peptides which control the intestinal bacterial microflora. Its deficiency may disorder the synthesis of these peptides and thus, disorder the bacterial microflora. In consequence, the susceptibility to infection will increase. Vitamin D deficiency may result in lower immunity of the human body. The intestinal microflora is a protective barrier against pathogens and infections. When good bacteria colonise the intestines, they do not allow pathogenic microorganisms to replace them. They provide protection by competing with pathogenic bacteria for nutrients[21, 44, 47, 83]. Weaker bacteria do not survive because they have no nutrients. The microorganisms contained in probiotics produce short chain fatty acids, which have an anti-inflammatory effect.
Evidence-based adult indications for probiotics, prebiotics, and synbiotics in gastroenterology
acute diarrhea in adults | – |
109 CFU twice daily | [16, 66] |
– |
109 CFU twice daily | ||
– |
5x 109 CFU/capsule | ||
acute gastroenteritis in children | – |
≥ 1010 CFU/day | [16, 22, 66] |
– |
250–750 mg/day | ||
– |
108 to 4 × 108 CFU | ||
antibiotic-associated diarrhea | – |
1010 CFU/capsule twice daily | [28, 66, 68, 69, 71] |
– |
5 × 109 CFU/capsule | ||
– |
1 × 108 CFU twice daily | ||
– Yogurt with |
≥ 1010 CFU daily | ||
– |
|||
Clostridium |
– |
5 × 1010 CFU daily and 4–10 × 1010 CFU daily | [58, 66, 68] |
– |
|||
5 × 109 CFU/capsule | |||
– |
5 × 109 CFU/capsule | [66, 68, 70] | |
– |
6 × 109 twice daily | ||
– |
|||
Irritable Bowel Syndrome | – |
1 × 108 CFU/capsule | [16, 32, 66, 68, 81] |
– |
1010 CFU, twice daily | ||
– |
10 billion CFU once daily | ||
– VSL#3* | |||
ulcerative colitis (mild to moderate CU for the induction of remission) | – |
5 × 1010 viable bacteria twice daily | [6, 47, 66, 72] |
– VSL#3 | |||
infantile colic | – |
108 CFU, once daily | [66, 68, 73] |
– |
1010–1011 CFU, twice daily | ||
hepatic encephalopathy | – VSL#3 | 108 CFU three times daily | [16, 66] |
traveler's diarrhea | – |
250–1000 mg, once daily | [12] |
VSL#3 –
At present there are no established schemes or rules concerning the dosage of probiotic preparations. This issue arouses numerous controversies. It is assumed that the probiotic should be applied at a dose which proved to have a beneficial effect in tests conducted on humans [15]. Patients usually make decisions on the choice and dosage of preparations themselves. They often assume that if the antibiotic has caused so many side effects, it is best to choose a preparation containing several bacterial strains and to take a larger dose of it. However, more does not always mean better. This applies both to the number of strains in the preparation and the content of living cells. If a preparation contains several strains, it is necessary to exclude their antagonistic effect. There is a lot of very divergent information on the dosage of probiotics in reference publications. Some authors recommend a minimum therapeutic dose of 106 CFU (colony forming units), whereas others say that it should be even as high as 1011CFU per day [43, 48, 69, 77]. For example, the administration of
The form of the probiotic (capsules, tablets, powder, drops) considerably affects its efficacy. Capsules may seem to provide the best protection from an acidic environment. The substance should not be removed from the capsule, but manufacturers do not always provide this information in the leaflet. Also, there is no precise data on the count of microorganisms that can be encapsulated. Powder probiotic preparations usually contain more bacteria, probably because at least some of them may survive if others die in a low-pH environment.
The moment when a probiotic therapy should be included and its duration are also controversial issues. As most preparations are registered as dietary supplements rather than medicines, it is not obligatory to provide specific recommendations concerning their use and dosage. There is no information when and which preparation should be included, and whether it should be done during or after an antibiotic therapy. When analysing the problem, it is worth considering what happens to probiotic bacteria during an antibiotic therapy. The probiotic contains the same species that can be found in the intestinal microbiome. Therefore, it is likely that probiotic strains will also be destroyed during an antibiotic therapy if the given species in the probiotic is in the spectrum of the antibiotic used. Therefore, it is worth choosing a probiotic which contains strains not found in the spectrum of the antibiotic that is planned to be included in the therapy. There is still no specific full answer to the question of how long probiotic strains colonize the intestine, and how long they should be used [53]. It is important to administer the probiotic when finished antibiotic therapy, to replenish the lost microbiota.
Another problem related with the dosage of probiotics is the time interval between the administration of the antibiotic and probiotic. According to the recommendations of the Canadian Natural Health Product, the probiotic should be taken 2–3 hours before or after the administration of the antibiotic [52]. It is likely that this time is given to limit the contact of probiotic microorganisms with the antibiotic in the gastrointestinal tract. According to other publications, the probiotic should be taken two hours before or after the antibiotic [61]. Probably this theory is related to the fact that there should be no direct contact between the probiotic and the orally administered antibiotic. However, this theory is wrong because orally administered antibiotics have systemic rather than local effect, which is limited to the intestine. This effect lasts long after the end of the antibiotic therapy.
The type of food consumed while using probiotics also affects the absorption and viability of probiotic microorganisms. An in vitro study with an artificial gastrointestinal tract conducted two experiments. The first study showed that taking the Protec Flor probiotic preparation (
The viability of the bacteria contained in the probiotic is also important. In most cases the probiotic microorganisms can be found in stool only during the supplementation with the preparation. Probiotic strains do not have to colonize the intestine permanently [3, 57]. After supplementation with the preparation probiotic microorganisms can no longer be isolated from stool. It depends on the survival of microorganisms contained in the probiotic during passage through the gastrointestinal tract [61].
In almost 90% of the tested probiotic preparations the count of living bacteria decreased as the time after their production passed, although they were still before the expiry date [61, 66]. Another question arises: How long should probiotics be taken? Even if they are taken for a long time, they cannot change and restore the microflora after the destruction caused by the antibiotic.
The bacterial microflora of the intestines cannot be restored during the antibiotic therapy. The restoration process can only take place after the therapy has been completed. Many doctors recommend the use of probiotics during the antibiotic therapy. However, only some of them recommend taking probiotics also after the antibiotic therapy. This period is the most important. Some doctors rationally recommend that patients should take care of their microbiome after the antibiotic therapy. However, it may be too late, especially if a patient underwent a long therapy with several broad-spectrum antibiotics. Enterol is the only preparation that is effective during an antibiotic therapy, because it contains the fungi which are by nature resistant to antibiotics. The task of S. cerevisiae var.
Probiotics should be treated individually because each of them has a different task. They should be applied at the right time, depending on the antibiotic administered and the underlying disease.
Probiotics are generally considered to be safe. However, sometimes they may have side effects. They cannot be administered to all patients in all clinical situations. It is necessary to remember that probiotic microorganisms may cause infections. There are groups of patients who should be careful when using probiotics, i.e. people with immunodeficiency, pregnant women, premature babies, critically ill patients and patients with venous catheters [13, 30, 35, 67, 69].
Bloodstream infections are some of the most common infections caused by probiotic strains [13, 35, 41]. Only until 1999 89 cases of bacteraemia with the
Probiotics are not recommended to patients with acute pancreatitis as probiotic prophylaxis resulted in a double increase in their mortality. Death may have been caused by an increased demand for oxygen in the intestinal lumen, which was hypoxic due to the disease [4, 30, 35, 69].
Manufacturers issue warnings about dangers only for preparations registered as medicines. There is no such obligation for dietary supplements. A warning might discourage customers from buying a supplement and have a counter-marketing effect. Unfortunately, leaflets attached to various supplements provide information on the count and species of microorganisms contained in these products that is divergent from tests [24, 25, 27, 41, 59, 63]
As probiotics contain strains that are resistant to most antibiotics, they contain resistance genes. Is it safe to use such preparations? Resistance genes may be passed on to microorganisms belonging to the intestinal microbiome. Each probiotic should be tested for the presence of mobile genetic elements, which determine resistance to antibiotics. Plasmid location of resistance determinants should be excluded [1, 8, 11, 62, 67]. In the future tests on genes located on mobile plasmids will enable the withdrawal of dangerous preparations from the market. Thus, it will possible to minimise the risk of spreading resistance from probiotic strains to the microorganisms which are part of the intestinal microflora [41].
There are 1000 species of microorganisms in the intestinal microbiome of a healthy adult human. Many of them die during an antibiotic therapy. Can a probiotic that contains several strains of microorganisms supplement the lost bacteria? Over 98% of all species belong to one of the four dominant phyla:
Probiotics are recommended both by doctors and nutritionists. Some of them speak of targeted probiotics and recommend that patients should have a stool culture test after an antibiotic therapy to check whether the situation is normal or a probiotic should be administered. If it is necessary to apply a probiotic, they choose one based on the results of a stool culture test. This test is based on classical microbiology, and only 20% of microorganisms can be cultured. Most of the other microbes colonising the intestines are absolute anaerobes, which cannot be cultured. Therefore, these tests are not objective and they are misleading both for the doctor and patient. Routine microbiome tests by means of sequencing is a method of the future. At present these tests are conducted mainly for scientific purposes. They are not widely available and they are very expensive. But only these methods will enable assessment of the real situation in the intestinal microbiome.
Many probiotics are dietary supplements [20]. Only products registered as medicines need to undergo numerous tests. The administration of a probiotic containing several strains will not restore the microbiome, which includes several hundred species. A microbiologist should be consulted in difficult clinical situations related with the intestinal microbiome. Taking probiotics makes sense if patients take a preparation containing antibiotic-resistant fungi during an antibiotic therapy, and they start taking a bacterial probiotic only after the end of the antibiotic therapy. It is best to use preparations containing several different strains to ensure the biodiversity of the microflora while it is being restored. It is also important that the patients who received antibiotics in the past and who often have infections should take probiotics to increase their immunity (immunomodulation).
Healthy people should not take probiotics because they may make unnecessary and irreversible changes to their normal microbiome. The administration of probiotic preparations to healthy children to strengthen their immunity is also controversial. If a child is not ill, has no infection and has not taken an antibiotic before, the probiotic will disturb the child’s natural microbiome.
Untested preparations should not be used because they are only dietary supplements rather than medicines. If the exact species composition of the preparation is unknown, it is also risky to take it, because it may be contaminated with other pathogenic species, which are not listed in the composition of the probiotic that is provided in the information leaflet [61].
Patients taking probiotics should have an adequate diet of vegetables with high content of fibre. They should not consume products containing sugar, because it promotes the growth of pathogenic bacteria and Escherichia coli. Even the most expensive probiotics will not cause microbial strains to survive and proliferate if the patient’s diet is inadequate. The host’s diet has enormous influence on the intestinal microbiome. Changes in the microflora might be related with the consumption of specific foods. The influence of various diets on the inhibition of intestinal diseases has been tested. If the diet is appropriate, the intestinal microflora is stable and does not change much. However, long-term inappropriate nutrition may cause irreversible changes in the intestinal microflora.
When doctors prescribe antibiotics, they often recommend patients to eat yoghurts regularly during the therapy. However, it is not the right solution in every situation. For example, calcium, which is contained in dairy products, may inactivate tetracyclines in the drug.
Probiotics only supplement a therapy but they cannot replace the treatment of an underlying disease. Individualised probiotic therapy is the key to success. There is no universal preparation – a specific probiotic should be used in a particular clinical case [33]. Recommendations for the use of probiotics are not consistent [61]. When it is decided to administer probiotic to the patient, the current guidelines and recommendations of major organizations and companies should be considered, depending on the indication: European Society for Paediatric Gastroenterology, Hepatology and Nutrition, European Society of Clinical Microbiology and Infectious Diseases, European Crohn’s and Colitis Organisation, European Society for Clinical Nutritionand Metabolism, World Allergy Organization and European Society for Paediatric Infectious Diseases.
Due to the widespread consumption of probiotics around the world it is necessary to monitor the safety of these preparations [14, 35]. The right probiotics can be applied if the state of intestinal bacteria is known. This can be assessed only in genetic sequencing tests.