Update its effects on the treatment or prevention of important gastroenterological conditions, cancer and anticancer therapy.
Introduction
If intestinal bacteria can cause disease, can they create a healthy state by changing them? This is where the concept of probiotics comes into discussion. Probiotics are living microorganisms which, when given in adequate quantities, confer a health benefit to the host. They act through various mechanisms that affect the microbiota. This effect may be evidenced through changes in bacterial populations or in bacterial metabolic activity.
A recent study showed that a probiotic yogurt changed urinary bacterial metabolites, but not populations of the fecal bacterial community. Such results suggest that probiotics may have the potential to affect the microbiome's function more than structure. They are currently subject to increasing basic and clinical research and have also been incorporated into a wide range of foods, nutritional supplements and pharmaceuticals.
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A more recent question, for researchers is how to measure the impact of probiotics on healthy individuals, for example, how to evaluate the reduction of risk of developing a disease or how to optimize physiological function within normal ranges.
Probiotics in health and disease
• Irritable bowel syndrome (IBS)
In the absence of accepted biomarkers, the definition of IBS is based on symptoms; recurrent chronic episodes of abdominal pain or discomfort associated with altered bowel rhythm, in the absence of organic disease; feeling of swelling with no visible abdominal distention; anxiety and several extraintestinal symptoms. Although preliminary evidence suggests that there are alterations in the intestinal microbiota in patients with IBS, it has not been determined whether these alterations are the cause or consequence of altered motility and intestinal secretion.
Recent preclinical data support the concept that intestinal microbiota and probiotics affect the enteric nervous system and brain signaling. In rodents beneficial effects have been reported on nociceptive visceral reflexes, but only some preliminary data suggest that such mechanisms may also play a role in healthy or IBS subjects.
There is a growing number of meta-analyzes but their results on the effectiveness of probiotics in IBS are disparate, in part because of the heterogeneity in various aspects of the trials. Better designed studies and larger samples are required to determine the extent to which certain probiotics are useful therapeutic strategies for the treatment of IBS symptoms.
• Infectious diarrhea
Enteric and diarrheal diseases are the leading causes of morbidity and mortality in children <5 years worldwide, with higher burden in low- and middle-income countries. Repeated infections lead to acute and chronic malnutrition, leading to more frequent and serious infections; which ultimately causes developmental deficits during growth and aptitude and cognition, which persist in adulthood with devastating human and economic consequences.
Greater knowledge of the intestinal microbiota and possible mechanisms of action of probiotics has led to studies evaluating its efficacy in acute infectious gastroenteritis and in the context of persistent diarrhea. Such approaches have the potential to help reduce the global burden of childhood illness. Treatment with probiotics for acute diarrhea appears to reduce the duration of diarrhea by approximately 1 day (predominantly in developed areas).
In developing areas, persistent diarrhea has been reduced by approximately 4 days, along with improved growth parameters. Several studies with probiotics, including Saccharomyces boulardi , Lactobacillus rhamnosus GG and other strains, report reductions in both rates of nosocomial diarrhea and antibiotic-associated diarrhea and recurrences of Clostridium difficile diarrhea. These effects include a 40-60% reduction in the frequency of antibiotic-associated diarrhea. In contrast, it has been observed that the reduction of C. difficile diarrhea is much lower and remains a controversial issue.
Nosocomial infections remain a major health concern, generating high medical costs, creating a need for preventive approaches. But the authors emphasize that in this regard, the results of the investigations are also controversial. Supplementation of infant formulas with B. bifidum and Streptococcus thermophilus reduced the frequency of episodes of acute infectious diarrhea.
L. rhamnosus GG was effective in reducing nosocomial gastrointestinal diarrhea and respiratory tract diseases in more than 2,000 children = 1 year without underlying emergency hospitalized diseases for reasons unrelated to gastrointestinal or respiratory conditions. Although probiotics are promising to reduce nosocomial infections in some populations, at this time they are not recommended for critical inpatients.
• Inflammatory bowel disease (IBD)
The probiotic treatments of IBD have yet to meet the high expectations derived from studies so far, especially for Crohn's disease. No consistent therapeutic or preventive effects have been observed in the relapse of Crohn's disease. In ulcerative colitis benefits have been observed for a combination of Lactobacillus, Bifidobacterium and Streptococcus probiotic while Escherichia coli Nissle was beneficial in inducing and maintaining remission of activity in mild to moderately severe ulcerative colitis. The primary prevention of pouchitis and the reduction of the likelihood of relapse after successful antibiotic treatment was also successful.
The following table shows the possible reasons for the current disparity in potential and actual clinical outcomes of current probiotic treatment in IBD and strategies to address them.
- Possible reasons and solutions for the poor therapeutic results of probiotic treatment of IBD and other conditions.
- Reason for Failure Proposed solution
- Wrong goals Individualize treatment based on the molecular pattern of dysbiosis.
- Poor choice of probiotic Use protective enteral enteric species, which may be more suitable than probiotics derived from cultured milk or food, complex groups of species diners or even intact normal bacterial communities (fecal transplantation).
- Consider incorrect mechanisms of disease Adapt the therapeutic agent to correct the underlying genetic / inflammatory defect pathway in an individual.
- Product power less than required Genetically improve bacterial function through the addition or elimination of bioactive (pharmacological) genes.
- Product not administered at the beginning of the disease, when it can be effective Direct the therapy to the stage of the disease process.
- Age of subject Adapt the therapy to the age / stage of development of each subject.
Although created for IBD, this conceptual framework is important for other complex disorders such as colorectal and gastric cancer, nonalcoholic steatohepatitis and autoimmune diseases. In these diseases, interactions between genetics, microbial and environmental influences lead to heterogeneous phenotypes in subgroups of patients that are exceptionally sensitive to specific microbial manipulations. Functions associated with more than 160 genetic polymorphisms observed in IBD can be broadly grouped as defects in mucosal barrier function / cure, abnormal immunoregulation, and defective microbial recognition or death.
Immunosuppression in a patient with defective bacterial death may be counterproductive. Similarly, an individual with dysbiosis may respond better to the selective restoration of protective commensal species, such as Faecalibacterium prausnitzii or Clostridium species, than to exogenous agents such as probiotics. Polymorphisms in genes related to IBD, which regulate mucosal glycosylation, such as Fut2 (which encodes α1,2-fucosyltransferase and is associated with abnormal bacterial profiles) may selectively enhance response to alternative bacterial nutritional sources such as the prebiotics.
The extraction or synthesis of molecules derived from probiotics or enteral protective species could also be useful. For example, purified immunoactive products could be synthesized and administered as p40 from L. rhamnosus GG or Bacteroides fragilis polysaccharide A , with defined biological actions. On the other hand, the bacteria can be designed to produce interleukin 10, trefoil (clover) or elafin factors. An alternative approach is to identify and develop dietary strategies to selectively enhance the growth and function of endogenous diners or decrease the activity of harmful bacteria.
For example, prebiotics such as inulin or fructose oligosaccharides increase the endoluminal number of Bifidobacterium species and protective short chain fatty acid concentrations, which are important metabolic substrates for colonic epithelial cells. Unlike refined sugars and food additives, such as iron, they can increase the proliferation of harmful bacterial species, including E. coli , Klebsiella pneumonia and Enterococcus faecalis. These dietary substances could be avoided to provide better maintenance of healthy states.
A potential therapeutic approach for the treatment of IBD could be to induce rapid clinical remission and corticosteroid mucosal healing and / or biological therapy, followed by probiotic and / or prebiotic interventions to maintain remission. This new paradigm of treatment is not yet proven, but is thought to stimulate new clinical and translational research goals, which has the potential to improve therapeutic outcomes while decreasing toxicity and long-term costs.
• Necrotizing Enterocolitis (EN)
Differences in the intestinal microbiota of preterm infants versus term infants may be in the predisposition to EN of preterm infants. Particularly, the microbiota of infants with EN differs from the microbiota of other low birth weight infants in the decrease of Firmicutes and the increase of gamma proteobacteria.
At present, EN is associated with a 30% mortality, with severe and costly sequelae if the patient survives. The disease can be difficult to diagnose before intestinal perforation occurs. The immature intestine of premature babies is especially prone to inflammation and loss of epithelial integrity.
Since probiotics have the potential to interfere with this progression, they have been clinically tested in EN. Although the American Academy of Pediatrics recognizes that there is evidence that probiotics prevent EN in very low birth weight infants and prior to issuing clinical recommendations, they advise further studies to clarify the effective dose and probiotic strains. In these cases, the opinions of various experts regarding the effect of probiotics is discordant.
• Cancer and cancer therapies
There is a set of evidence indicating a prominent causal role of environmental factors, including obesity and diet, which are associated with changes in the intestinal microbiome. The authors note that the incidence and tumor mass are higher in conventional rodents than in germ-free rodents.
Taken together, these findings strongly support the notion that the microbiota plays some role in CRC, but causality has not yet been confirmed. There is evidence that enterotoxigenic B. fragilis can trigger the catabolism of cadherin E, cause intestinal inflammation and thereby increase the risk of colon cancer.
Others have suggested that in these patients bacterial diversity is lower, altered or accompanied by elevated levels of Fusobacterium nucleatum sequences. In rodents, it has been found that probiotic concentrate has effects on precancerous and tumoral lesions. Several possible mechanisms have been proposed: alterations in the metabolism of microbiota species and changes in colon pH, carcinogen binding or inactivation, improvement of immune responses, reduction of colonic inflammation, reduction of epithelial proliferation and increase of apoptosis.
Biomarker studies in humans show that symbiotics reduced genotoxic damage induced by fecal water and increased transepithelial resistance. A symbiotic combination of an inulin preparation enriched with oligofructose combined with two probiotics did not affect epithelial cell proliferation, but there was little evidence of fecal water-induced DNA damage in HT29 and colon epithelial cells.
In another study we found pronounced changes in barrier function, ls immune cell activity, proliferation of immune cells and apoptosis. A consistent observation is that a symbiotic preparation appears to be more effective in altering the risk biomarkers of CRC than a single probiotic or prebiotic.
A human study showed less recurrence of adenomatous atypia after 4 years of administration of Lactobacillus casei . Finally, in an Italian cohort, a 12-year follow-up of more than 45,000 volunteers with high yogurt intake found a reduction in CRC, but there was no comparative group. There are few human studies on CRC, but with diverse endpoints.
Probiotics have been evaluated to help control the side effects of radiotherapy and chemotherapy in abdominal and intrapelvic cancers. In mice and germ-free animals with microbiota modified by antibiotics that received probiotics they are more resistant to radiation toxicity. L. rhamnosus GG reduced intestinal damage and post-radiation apoptosis in the proximal jejunum of mice.
The protection seems to be mediated by an unusual mechanism of increased migration of mesenchymal stem cells into the lamina propria. Benefits were also found in patients with chemotherapeutic or radiant therapy. The studies point to the potential beneficial effect of probiotics to improve radiation damage and chemotherapy in the small and large intestines of cancer patients. Probiotics can effectively mitigate disabling diarrhea, dehydration and secondary malnutrition in cancer treatment.
• Allergy
Allergic disorders have been associated with an aberrant intestinal microbiota. Factors associated with allergy, such as type of delivery (cesarean section vs. vaginal delivery), use of antibiotics in diets for newborns and infants, and diets without breast milk have also been associated with changes in the intestinal microbiota. In the last decades, nearly 10% of children developed allergy in a clinical progression characterized by eczema-rhinitis-asthma, and probiotic supplementation in food has been studied to disrupt this progression.
When there is a family history of allergy, it is advisable to start the administration of probiotics early. However, they have no effect on the expression of posterior asthma during childhood. So far, evidence of efficacy is not convincing enough to warrant pediatric organizations to recommend the routine use of probiotics.
• Common infectious diseases
The intestinal microbiota is being recognized for its role in promoting resistance to non-enteric pathogens, possibly through improved barrier function, production of anti-pathogenic substances or immune function. A review of the research suggests that certain probiotics can regulate critical components of the immune system, such as lymphocytes, antibodies and natural killer cells, which could prevent infections, especially in the upper respiratory tract.
Taken together, studies suggest that probiotics in otherwise healthy individuals can reduce common infectious diseases. However, before treatment can be definitively agreed upon, recommendations for dietary management can not be made and a systematic approach is needed to assess the strength of evidence in order to identify limitations in existing clinical studies.
Challenges for studying the health effects of probiotics
Researchers designing clinical trials should take into account the current relevant regulations in the field of probiotics, and the potential problems imposed by regulatory frameworks, especially in the EE. UU. and Europe.
• Design of a clinical study on probiotics
The value of well-designed, well-designed human trials to elucidate probiotic efficacy is evident. However, the current higher demands of regulatory authorities on health issues, the announcement of benefits in packaging and advertising, combined with the strict interpretations of what constitutes pharmacological research, requires careful consideration of regulatory problems when it comes to do the design and launch of probiotic studies for food or supplements. There are many issues that need to be taken into account in the planning stages by the researchers and sponsors of the study.
Questions to Consider Before Designing, Conducting, and Reporting Probiotic Studies in Humans
- Will the study be done in healthy subjects or in a population disease? Food and dietary supplements are products generally intended for the healthy population. Therefore, trials designed to support claims for products in this category should be conducted on subjects representing the general population. If the target is a disease state, then the study must be performed on a properly selected population that represents the disorder, and the study must conform to the standards of a pharmaceutical product.
- - What is the regulatory approach in your jurisdiction for claims for health benefits, of the type of product you intend to market? Will the product be a food, supplement, drug or other? Efficacy standards, appropriate study endpoints. target populations and risk assessment vary for the different product categories as well as the clinical research program, and these points need to be well differentiated.
- - If you are looking for help to claim a food or probiotic supplement, what exactly is the claim and if it will be supported by the study you propose? The primary endpoint in the research study should be as close as possible to the benefit to be communicated. The results should be clear and measurable, and the study protocol should preferably include a randomized, double-blind, placebo-controlled design. The selected placebo should be very similar to the probiotic food in terms of nutritional profile, taste, texture, color and taste, but should be devoid of probiotic strains.
- - Are the selected strains adequately characterized, in terms of their genome, in vitro properties and activities in vivo, and the ability to survive transit through the gastrointestinal tract? The exhaustive characterization of the deformation is critical for a thorough understanding of the substance being studied, and also to ensure ease of repetition of the study by other research groups.
- - Has the proposed formulation been shown to maintain viability and efficacy over the proposed shelf life and in the environment in which it is likely to be marketed?
- - Has a plausible logic been developed for the use of this / these particular strain (s) in this indication? Although confirmation of a mechanism of action for functional food ingredients (or drug, in that case) is not considered essential, a plausible reason is preferred.
- - Has the optimal target population been clearly defined for this particular probiotic and the specific outcome to be modified? If the target population is any subgroup of the general population for a food or supplement, it is important that it is documented.
- - What dose will be tested? Is there any indication of an effective dose in previous studies? The dose used in the study should be high enough to confer the benefit, but not so much to make the product commercially unsustainable. Since the dose of the product must match the dose in the human test that showed benefit, it is very important to consider the dose used in the study.
A key conceptual problem in probiotics is that clinical trials often fail to address the importance of probiotic viability for physiological benefit, and non-viable controls are rarely used. Although many of the mechanisms proposed for probiotic activity probably require growth and metabolism at the site of physiological action, confirmation of the viability requirement through the design of clinical trials with non-viable control would clarify this problem.
However, a non-viable product is not considered a probiotic, since by definition it must be a living microbe. Such a product would fall under the more general term "pharmacological", which encompasses non-viable microbes and health promoting substances derived from microorganisms.
• Effect of regulatory frameworks on the development of probiotics
The approach to marketing probiotic products is inextricably linked to the regulatory framework. These frameworks, although different in each country, affect research approaches, communication strategies, manufacturing and product labels. At present, regulations have become very important.
The development of trials must meet the requirements of scientific research, but also comply with the regulatory definitions of what constitutes the appropriate end points for specific product categories. The development of pharmacological research is quite clear, but not the way that research should follow to obtain evidence that justifies a health benefit from a food or dietary supplement.
Many probiotic products are marketed as foods or dietary supplements, however, much of the research documenting health benefits is considered by regulators in some countries as endpoints for drug use.
Such research may not be considered appropriate to corroborate the health benefits of food, since they are not regulated as preventive or therapeutic measures of disease, but only to support or maintain normal body functions or reduce the risk of disease in the population general. (The claim that "Food" can treat or prevent disease makes it a drug). So the challenge is how to carry out meaningful studies to show that health has improved or even more that has kept a person healthy? What does "maintained" mean in relation to the primary outcome of a study?
The communication of health benefits in probiotic products emerged as a challenge for probiotic companies. For example, in Europe, no claims for health benefits derived from approved probiotics have been approved, apparently because the level of evidence does not meet the expectations of regulatory authorities. On the other hand, to approve that the probiotic reduces the risk of disease requires the demonstration of changes in the commonly accepted risk factors for specific diseases.
Changes in one clinical end point are not enough, and many of the diseases / disorders for which probiotics are being explored lack validated biomarkers. In the USA Claims presented as "structural / functional" (eg, "this probiotic improves digestive health") do not require approval, however, they should be checked in. Here the challenge is what types of studies support such a general claim.
In spite of the lack of clarity in the way of justifying the claims, in EE. UU. regulatory authorities have increased their inquiry into the structure / function claims, requiring for their justification that regulatory standards be met. There is increasing scientific evidence that some probiotic foods or supplements may prevent or mitigate some diseases or disorders. For consumers, these products can be considered as food or supplements, but for regulatory authorities are drugs.
The future
The association of alterations of the microbioma with a progression of health to the disease seems to be an already clarified concept. However, causality and disease reversal have not yet been demonstrated in response to probiotic-induced changes in the microbiome. Until a healthy microbiome has been clearly defined to establish a microbiological target for probiotic interventions, its benefits should be described in the context of physiological or clinical improvement.
Some immunological and gastrointestinal clinical objectives have been mentioned in this review, including rotavirus infantile diarrhea, antibiotic-associated diarrhea, C. difficile diarrhea, ulcerative colitis, pouchitis, IBD, EN and radiation enteritis . Beyond this, probiotic interventions with effects outside the gastrointestinal tract are increasingly recognized.
Perhaps the most intriguing goal is centered on diabetes conditions, influenced by microbiota, metabolic syndrome and obesity, where studies in animal models indicate the functional involvement of the microbiota. To what extent probiotic interventions affect these diseases is an active and evolving area of research. In the future, probiotics developed to address the conditions associated with the microbiota will probably go beyond the microorganisms that are commonly used as probiotics today.
Genetically modified microorganisms can provide epitopes to develop efficient oral vaccines, improve the natural immune response or vaccines, or restore antigen-specific tolerance. Probiotic strains with altered cell surface components, such as lipoteicoic acid, provide a potential strategy for the treatment of inflammatory bowel disorders.
The use of fecal transplantation to replace dysbiotic bacterial communities with safeners to treat C. difficile , IBD or IBD infections has had some success. Recently, fecal microbiota transplantation of non-diabetic donors infused into the duodenum of patients with metabolic syndrome improved insulin sensitivity, highlighting the broad potential of this intervention.
However, defined microbial cocktails that impart key functionalities may provide a more acceptable approach. Finally, specific strains with useful unique properties, such as Oxalobacter formigines , F. prausnitzii (chronic intestinal inflammation), Bacteroidetes and Fusobacterium (cancer risk), should be further investigated in well-designed clinical trials.
The use of probiotics to extend remission of IBD by its benefits in pouchitis and ulcerative colitis is promising, but as for the benefit in Crohn's disease requires new approaches. Identification of specific protective molecules, such as interleukin 10, ganglioside and trefoil (clover) factors, which can be designed on probiotics to be released in situ.
Effective probiotic interventions for conditions associated with the microbiota require a better understanding of the interactions between genetic, microbial and environmental influences in each person. Such an approach will also facilitate the identification of subgroups of patients most likely to respond to manipulations of the intestinal microbiota and the optimal agents to be used in each subject.
