Role of bifidobacteria in the function of the human body
ABSTRACT
Bifidobacterium animalis ssp lactis Bb12 is a probiotic strain that has received considerable attention from the scientific community. It has tolerance to higher temperatures and lower, acidic pH than other bacteria. When administered for 12 months to infants and children together with S. thermophilus this was associated with lower incidences of acute diarrhea. Studies in different countries and with different experimental designs confirmed these results. It was also shown that its administration did not interfere with the growth or normal weight gain of the children. Bifidobacterium animalis ssp lactis Bb12 was associated with decreases in the fecal excretion of rotavirus during episodes of diarrhea, a fact that represents an epidemiological benefit. Bifidobacterium animalis ssp lactis Bb12 exerts positive effects on manifestations of atopy / eczema, with decreases of the parameters of inflammation such as CD4 in blood serum and eosinophil protein X in urine. This was associated with changes in the severity and severity of skin lesions. No modifications of the normal growth parameters were observed when Bifidobacterium animalis ssp lactis CNCM I-3446 was given.
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Administration of Bifidobacterium animalis ssp lactis Bb12 is associated with higher levels of fecal sIgA and calprotectin, which are considered parameters of immune responses and ofthe capacity to initiate inflammatory responses. The statements made by some groups that infants under 4 months of age who are not breastfed should not receive probiotics have weak support if it is considered maternal milk contains a large number and variety of strains of bacteria which may be considered the probiotics. These may not only protect from acute diarrhea but also from upper respiratory infections. Although cases of septicemia due to probiotic have been reported these represent an infinitely small proportion of the total numbers of consumers. No outbreaks have been reported that would point to invasive properties in a strain. It is not advisable to administer any living bacteria to individuals in shock or with innate or severe defects of immunity. However, carriers of HIV or AIDS patients benefit from probiotic agents. A study carried out in Chile showed that despite no clinical evidence L. rhamnosus HN001, significantly increased fecal symptoms as a manifestation of improved mucosal defense in the digestive tract.
SUMMARY
Bifidobacterium animalis ssp lactis Bb12 is one of the strains Bifidobacterium animalis ssp lactis Bb12 is one of the most studied probiotic strains. It has advantages that make it useful for industrial use: tolerance to acid environments and temperatures higher than other probiotics. In a 12-month study Bifidobacterium animalis ssp lactis Bb12 was administered for a year associated with S. thermophilus and it was observed that children experienced fewer episodes of acute diarrhea. Studies with follow-up of different duration and design endorsed these results and their administration did not exert negative influences on growth. This bifido-bacterium induced decreases in the excretion of rotavirus during episodes of diarrhea, which reduces the possibility of contagion. Bifidobacterium animalis ssp lactis Bb12 exerts positive effects on the manifestations of atopy such as eczema with the decrease of markers of inflammation such as CD4 in serum and protein X of eosinophils in urine; and improvements in permeability alterations. Studies with Bifidobacterium animalis ssp lactis CNCM I-3446 administered with ARA and DHA showed alterations of growth and biochemical parameters in infants and preschoolers in 14 to 119-day follow-ups. Administration of Bifidobacterium animalis ssp lactis Bb12 together with immunizations was associated with higher levels of sIgA specific anti-poliovirus and calprotectin, the levels of which would be associated with those of this immunoglobulin. It has been argued that there is no justification for administering probiotics to infants less than 4-6 months not breastfed, the fact that breast milk provides them in quantity and variety supports the possible advantages of their administration. Probiotics would protect not only infections of the gastrointestinal tract but also upper respiratory tract infections. There are isolated cases of sepsis in individuals with various conditions, but the proportion of affected is minimal. No outbreaks have been reported that would indicate probiotic strains with invasive capabilities. It is probably not advisable to administer them to subjects in shock or with defects in intestinal barrier function. HIV carriers and AIDS patients experience improvements in receiving probiotics. In a study in Chile it was shown that although without clinically obvious effects , administering L. rhamnosus HN001 produced increases in fecal secretory IgA, which represents an increase in the defenses of the digestive tract.
Key words : Bifidobacterium animalis ssp lactis Bb12; acute diarrhea; secretory immunoglobulin A, immunity, human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS).
Of the multiple species of bifidobacteria that colonize the human organism, Bifidobacterium animalis ssp lactis is one of the most studied and one of its strains, the so-called Bb12 has wide use in human nutrition.
Bifidobacterium animalis ssp lactis is a Gram-positive anaerobic that is frequently found in the intestines of humans. Bifidobacterium animalis and Bifidobacterium lactis were considered separate species but are currently classified as Bifidobacterium animalis subspecies animalis and Bifidobacterium animalis subspecies lactis, of which Bb12 is a strain; the old denominations are still in use in food labeling. Bifidobacterium animalis ssp lactis Bb12 is able to grow at elevated temperatures for this type of microorganisms (41 ° - 43 ° C) and is more tolerant to acid environments compared to other bacteria of human origin, which favors its use in industrial processes of the production of some foods (1).
A study in France evaluated the efficacy of Bifidobacterium animalis ssp lactis Bb12 in preventing acute diarrhea in 90 infants less than 8 months of age who attended day care centers or remained in family setting for at least 4 months. Of these, 46 infants received the formula with the probiotic and the other 44 served as controls. Both groups were comparable to admission in terms of their anthropometric characteristics. Of the infants who received the probiotic, 28.3% experienced episodes of diarrhea compared to 38.7% in the control group. The number of days with episode diarrhea was 1.2 ± 2.5 in the group receiving the probiotic, with a daily probability of developing an episode of 0.84 compared to 2.3 ± 4.5 days of duration diarrhea and a daily probability of an episode of 1.6 in the control group (p <0.0002 and 0.0014, respectively). Consumption of the formula with Bb12 decreased the risk of diarrhea by a factor of 1.9 (range 1.33 - 2.60). According to the authors, these results support the hypothesis that Bifidobacterium animalis ssp lactis Bb12 added to acidified milk provides protection against acute diarrhea (2).
Other researchers published results that support these initial findings. Saavedra et al. Evaluated the effects of a mixture of Bifidobacterium lactis and S. thermophilus administered for 18 months on healthy infants 3 to 24 months of age when incorporated into the study. Their findings included a decrease in the frequency of colic and irritability (p <0.001) and less need to resort to antibiotics (p <0.001). On the other hand, there were no differences in growth velocity, absenteeism in day-care centers and other health-related variables (3). Another study carried out in day care centers in Israel showed that in comparison to the control group the administration of Bifidobacterium animalis ssp lactis Bb12 to daycare children was associated with a lower number of febrile episodes and diarrhea, which were of shorter duration (p < 0.001) (4). The absence of both negative and positive repercussions by probiotic on weight and height growth was explored by the same authors in another publication (5).
The effects of Bifidobacterium Bb12 on acute diarrhea have also been explored in other studies. This probiotic, administered in a cereal in association with S. thermophilus, L. acidophilus and zinc decreased the duration of episodes of diarrhea although it is not clear what would have been the effect of each of them alone to effect different combinations; in addition the number of children treated was relatively low (6). In another study, administration of two levels of Bifidobacterium Bb12 (10 8 CFU and 10 9 CFU per gram of powder) was compared in a lactose-free formula which also contained S. thermophilus (5 x 10 7 or 5 x 10 8 CFU per gram of powdered formula) and the duration of diarrhea and rotavirus excretion were evaluated, among other parameters. The higher dose of Bifidobacterium animalis ssp lactis Bb12 was associated with lower fecal excretion of rotavirus, which may be of epidemiological importance because it would contribute to a decrease in the efficiency of virus transmission (9).
The effect of Bifidobacterium lactis was compared with Saccharomyces boulardii in children 5 months to 5 years of age affected by episodes of liquid diarrhea and mild dehydration . Infants who received Bifidobacterium lactis had significantly shorter episodes (4.1 ± 1.3 days) than those who received S. boulardii (6.6 1 ± 1.7 days) or in the control group ( 7.0 ± 1.6 days) (p <0.001 Bifidobacterium lactis vs. S. boulardii or control). These results reinforce the concept that Bifidobacterium lactis Bb12 could exert a specific effect on rotavirus diarrhea episodes, comparable to that published for some lactobacilli (8).
Early in the study of probiotics it was evident that these microorganisms exert effects on the quality of immune responses and aroused special interest regarding allergic reactions, especially atopy / eczema. In one study, infants with such pathologies who had never been exposed to milk formulas were weaned with a formula containing extensively hydrolysed whey proteins and Bifidobacterium Bb12 or Lacto-bacillus GG. The initial SCORAD during breastfeeding was 16 and after 2 months significantly decreased (χ 2 = 12.27, p = 0.002): in those receiving Bifidobacterium Bb12 at 0 (range: 0 - 3.8) and in those receiving Lactobacillus GG to 1 (range 0.1-8.7). In contrast, in the control group, not supplemented with probiotics, the median SCORAD was 13.4 (interquartile range 4.5 - 18.2). Along with the decrease in SCORAD, children receiving probiotics experienced decreases in serum soluble CD4 and eosinophil X protein in urine (9). This is a demonstration that specific strains of probiotics are able to modify parameters associated with allergic skin inflammation and produce beneficial effects beyond the digestive tract. One of the mechanisms that can explain this response is the increase of the quality of the intestinal barrier. Stratiki et al. Observed that when administering Bifidobacterium Bb12 (2.7 x 107 CFU / gram of powdered formula) to stabilized preterm infants between 27 and 36 weeks of gestation, increases in fecal excretion of bifidobacteria were observed (p = 0.036 versus control ); these levels remained elevated, although not significantly, at day 30 (p = 0.075). On that day, which marked the end of the study, the lactulose / mannitol ratio in the urine was significantly lower in the group receiving the probiotic than in the control group (p = 0.003), indicating that the intestinal mucosa had become less permeable. In this study in the experimental group the cephalic perimeter increased significantly more (1.1 cm / week vs 0.9 cm / week; p = 0.001) (10). It should be noted that this effect was observed in an interval of only 30 days and it was not possible to determine until such a difference would be maintained over time and if it was truly associated with the administration of the probiotic. On the other hand, it is possible that administration of Bifidobacterium Bb12 induces changes in the resident microbiota, which has been observed in premature infants and is the sum of the action of the bacterium and the changes in the counts of other components of the microbiota resident what truly explains these modifications (11, 12). Unfortunately, there were no long-term controls for anthropometric parameters, measurements that might have shed light on these aspects.
Other studies have shown discordant results regarding bifidobacteria counts in stools, although this may be due to the fact that the trials have been performed in term newborns; in one study, after a considerable increase in fecal bifidobacteria counts during the first 5 days (reaching 65%), there was a gradual decrease, so that at 16 weeks they reached 55% and counts were similar to those observed in the other experimental groups. Administration of GOS / FOS (galactooligosaccharides / fructooligosaccharides in a 90:10 ratio) is associated with changes in fecal pH, which at 10 days is lower in infants receiving Bifidobacterium Bb12 than in those receiving the control formula (13) .
Gibson and colleagues evaluated the effects of an infant formula supplemented with Bifidobacterium animalis ssp lactis CNCM I-3446 and with the essential fatty acids docosahexaenoic (DHA) and arachidonic (AA). The choice of the Bifidobacterium strain was based on the results of its use in older infants and preschoolers, whereas the fatty acid concentrations were similar to those detected in the milk of women consuming a varied diet; in addition, these concentrations had been used in other studies. The main objective was to evaluate the weight gain (grams / day) between days 14 and 119 of the follow-up and as secondary objectives we studied the lying body length, cephalic perimeter, BMI, circulating antibody titres, digestive tolerance and possible adverse events; in addition blood samples were obtained to quantify other biochemical parameters. The study included 72 children in the experimental group and 70 in the control group. No differences were detected in the weight gain, although the experimental group consumed a greater formula volume or for the other anthropometric parameters. At 119 days the concentrations of DHA, AA and eicosapentaenoic acid (EPA) in erythrocyte membranes were increased in children who consumed the supplemented product. The other biochemical parameters were comparable in both groups as well as responses to immunizations. Children in the experimental group reported fewer intercurrent pathologies during follow-up (upper respiratory, cutaneous, or urinary tract infections). The authors concluded that there was no difference between children who received probiotic and long-chain polyunsaturated fatty acids (LC-PUFAs) in relation to their growth and responses to immunizations (14). These results can be interpreted as that in children who have adequate nutrition and a normal nutritional status probiotics and LC-PUFAs do not increase their parameters above their respective normal ranges. Responses to oral immunizations are potentiated by probiotics because they would stimulate the immune system of the intestinal mucosa, but in this study the immunizations were parenteral.
Total secretory IgA (IgA) and specific IgA production for various agents was evaluated by Holscher et al in a study involving 172 healthy 6-week-old infants who received a partially hydrolyzed formula containing Bifidobacterium Bb12 (10 6 CFU / g of powder), with a control group receiving the same formula but without the probiotic (16). As a parallel group we evaluated a group of breastfed infants who had similar anthropometric parameters. The study began with the collection of basal fecal samples at 2 and 6 weeks. Measurements of specific IgAs in feces were aimed at detecting anti-polio and anti-rotavirus antibodies after the respective oral immunizations. Fecal excretion of calprotectin and lactate was also measured and the presence of Bb12 in the faeces was quantified. The type of birth and anthropometry at birth were comparable in all three groups. The volume of prescribed formula resulted in a consumption of 10 8 CFU / day of Bb12 at 8 weeks and 1.1 x 108 CFU / day from 12 weeks. Bb12 was detected in the faeces of 93% and 88% of participants in the experimental group at 2 and 6 weeks of study, respectively. There were no differences in bacterial DNA counts of bifidobacteria in the feces of children fed formula with Bifidobacterium Bb12 and the group fed with breast milk, but in them the DNA copy number of bifidobacteria was higher than in the control group. Breastfed children had higher levels of fecal IgAs and infants born to vaginal delivery who received the probiotic developed increasing fecal levels of IgAs between birth to 6 months of feeding (between V0 to V2) compared to those fed formula conventional. Levels of fecal anti-poliovirus IgAs tended to increase in children receiving Bifidobacterium lactis Bb12, as did calprotectin levels, especially in those born by cesarean section. In contrast, breastfed infants had higher fecal calprotectin levels than the two formula-fed groups. Of infants receiving formula, those receiving Bifidobacterium Bb12 had significantly higher fecal calprotectin levels at 2 weeks of the study than those given the conventional formula. In breastfed infants the fecal pH was lower than in the groups that received formulas and at 2 weeks tended to excrete more lactate in the feces. Some of the potentiation effects observed in vaginally born infants who received Bifidobacterium Bb12 would be explained by the additive effect of the probiotic on the flora they acquired when passing through the birth canal. It is likely that other favorable results observed in this study are the result of the advantages of colonization by a microbiota enriched with bifidobacteria. According to some authors, there would also be a correlation between fecal and calprotectin IgA levels, which would be related to the decrease in the diseases associated with the presence of IgE observed after 2 years of age (16). The addition of Bifidobacterium Bb12 to a milk formula would represent a way of providing an immunomodulatory stimulus to children born by cesarean section or who have not been breastfed.
The effects of B. animalis spp lactis Bb12 in preterm infants were evaluated in a systematic review of randomized and control trials (17). This analysis argues that the administration of Bifidobacterium animalis spp lactis is associated with increases in weight gain, although of low magnitude, whose significance in the long term is unknown. This review also found no higher incidence of sepsis with positive blood cultures for Bifidobacterium animalis spp lactis; however, the administration of this microorganism would have had a positive effect because its administration was associated with decreases in the use of antibiotics. One study postulated that those who received B. lactis would have increased nosocomial infections but the statistical significance of the results was at limit and the density of infections (number of nosocomial infections / total number of patients / day) was not significant in comparison with controls (18, 19). This review also did not find that preterm infants who received Bifidobacterium animalis spp lactis suffered a greater number of adverse effects. The authors postulate that the use of Bifidobacterium animalis spp lactis should be cause for optimism even if the results do not seem entirely convincing. The effect of this bacterium on the prevention and treatment of NEC, its evolution and the medium- and long-term results in terms of mortality and serious sequelae should be investigated.
The effects of Bifidobacterium bifidum associated with S. thermophilus were first explored in a study about the prevention of the intrahospital acquisition of rotavirus and its transmission in infants between 5 and 24 months who had been admitted for the management of chronic conditions. B. bifidum was administered in concentrations of 1.9 x 10 8 CFU / g of powdered formula and S. thermophilus at a rate of 0.14 x 10 8 CFU / g of the formula; the control formula was identical to the above but without the probiotics. The research design was stratified by age (<12 months, ≥ 12 months) and by the proportion of total daily energy provided by the formula (≤50%,> 50%). The study included 47 children (who recorded 57 admissions) and reported information on their nutritional status and episodes of diarrhea if pertinent. During the episodes of diarrhea tests were performed to detect rotavirus, Salmonella, Shigella, Yersinia and Campylobacter. In addition, regardless of the presence or absence of diarrhea, weekly fecal microbiological controls were performed. There were no differences in the anthropometric parameters or the number of days in which the participants consumed the respective formulas or in the volumes consumed. A significantly lower number of children in the probiotic group experienced episodes of diarrhea and in them the cumulative frequency of days with this pathology was also lower. The presence of rotavirus was detected in seven episodes, five of them in the control group, and no bacterial pathogens were detected. The cumulative incidence of diarrhea was significantly higher in infants in the control group and in the experimental group a decrease in fecal excretion of rotavirus was detected (20).
FINAL CONSIDERATIONS
There is a large literature on probiotics and its effects that is the result of numerous investigations in humans and experimental models, and supports the idea that these microorganisms exert positive actions on human health; fundamentally to the enhancement of the innate and acquired immunities, and the investigations have been oriented mainly to pathologies of the mucous of the digestive tube, the respiratory apparatus, of allergic origin and the feminine genital apparatus. The probiotics most studied belong to the genera Lactobacillus and Bifidobacterium although other species and strains have also been studied. The most investigated gastrointestinal pathologies have been acute diarrhea, traveler's diarrhea, diarrhea associated with antibiotic treatment, persistent diarrhea associated with malnutrition, nosocomial diarrhea and chronic infectious diarrhea. Another pathology in which probiotics have shown positive effects is necrotizing enterocolitis of preterm infants, regarding which there is currently a broad consensus about the benefits of its use. The relationship between the resident microbiota and probiotics in cadres such as infant colic, irritable bowel syndrome and periodic abdominal pain is being studied; the positive effects of various strains of probiotics in these tables has been substantiated in clinical investigations.
At the respiratory tract level, there is evidence that some probiotics induce shortening of the duration of upper respiratory infections, which require less antibiotics to manage and reduce the need for school and work absences. Another aspect which has been extensively studied relates to the effect of lactobacilli and bifidobacteria as modulators of immunity, especially at the mucosal and skin level. In this sense more studied pathologies are atopia / eczema, in respect of which there is a high level of consensus about its beneficial effects manifested by a lower surface area affected and less pruritus; positive evidence has also been published about respiratory and digestive allergic disorders in relation to the seasonal allergy associated with local pollen of Japanese cedar.
A publication of the Nutrition Committee of the European Society of Gastroenterology, Hepatology and Nutrition (ESPGHAN) (21) stated that the administration of these agents does not generate problems related to their safety. He stated that administration to children younger than 4 months of age does not produce consistent clinical effects. However, it is important to take into account that breast milk provides the infant with a complex microbiota with high counts of live bacteria that are probably involved in the stimulation and maturation of the infant's immune system and in the defense of its digestive tract; these microorganisms would act in a manner similar to probiotics. In infants who can not be breastfed, the addition of probiotics to infant formulas seeks to mimic and produce effects similar to the natural process since it stimulates the implantation of a microbiota with recognized harmless agents, which probably have the ability to block and displace potentials pathogens and allergens at the surface of the intestinal mucosa. In addition, some probiotics synthesize molecules with antibiotic properties, as is the case of L. reuteri reuterine .
The use of probiotics in acidified milks or as agents isolated and added to formulas or in oily or aqueous bases is already 100 years old and in the last 20 years its use worldwide has become more widespread. Its use has spread freely to all types of population groups, at different ages and different pathologies. The population performs most of these intakes without medical control and without knowledge of the possible pre-existence of pathologies; however, no alarm signals have emerged so far. In strains where antibiotic resistance plasmids have been discovered, they have been discarded or cured of these factors. Clearly, as with any biological agent or drug, a monitoring of its effects on the population should be maintained. It is also important to clarify whether it is possible to complement the functional capabilities of a probiotic by associating with members of other strains, species or even genera. Probiotics possess a strain-specific ability and within a single species a strain may possess capabilities that are considered to be highly beneficial or, conversely, potentially undesirable or even dangerous, so careful studies are necessary. These potential risks are detected more easily and accurately at present by means of specific methods of cultivation and molecular techniques that allow to know the genome of the bacteria in all its detail.
The ESPGHAN Committee concludes that the use of probiotics is not recommended in infants younger than 4 months, but this statement should be based on sound physiological evidence. In addition, the bacteria present in breast milk belong to species that are recognized as probiotics at present. On the other hand, research on the effects of probiotics may occasionally present particular design problems, even when studies are done by experienced groups as shown in the analysis of the Wanke and Szajewska study, in which some factors have not been analyzed in detail (19).
One of the problems with many probiotic strains, which is not valid for the three that are discussed in this review, is that there are only one or at most two studies with good methodological quality and an adequate number of subjects, explains that the statements of the literature review of ESPGHAN acquires a certain level of uncertainty. A recent publication argues that after a thorough review of the literature there appears to be no increase in the risks associated with the use of probiotics, it is difficult to assess adverse effects, which can be said to exist are very rare, and that the available literature has difficulties in answering in a clear way some of the doubts regarding its innocuousness (22). However, probiotics are employed by such a number of people, healthy or diseased with the most diverse pathologies that any adverse manifestation would have become clinically evident in the last 30 years. In October 2011, the World Organization of Gastroenterology published a practical guide which, in its general guidelines, coincides with that expressed by the publication cited above (23).
