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Symbiosis Spring 2011
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Gut flora and the development of the Immune System
GUT FLORA & IMMUNE SYSTEM:
By a variety of measures, the species Homo sapiens is more microbial than human. Although microorganisms only make up a small percentage of a human’s body weight (between 2 and 5 pounds of live bacteria), in terms of cell numbers the human is around 10% human and 90% bacterial cells or genetically 1% human and 99% bacterial
. Consequentially, bacteria play a major role in bodily functions including immunity, digestion and protection against disease. More importantly colonization of the human body by microorganisms occurs at the very beginning of human life yielding distinct microbial communities (Wexler 2007). As the host provides a hospitable habitat (taking into consideration its own species of origin, diet genotype, geographical location, presence or absence of disease, and use of medications) the microbiota in turn configures its species’ consistency, collective genome, transcriptome and metabolome to optimally suit its given ecological environment. Furthermore it is not surprising that co
-evolution has been invoked to describe this symbiotic relationship between mammals (mouse, cow, pig and human) and their gut microbial communities (
Zaneveld et. al 2008)
. Interestingly enough, human infants are actually born without any bacteria in their guts and only acquire their first batch of bacteria depending on their entrance into the world and furthermore via breastfeeding and by the various types of food they eat while developing. H
ow these gut commensal microbes, which colonize neonatal humans, effect the activation and development of the immune system is the focus of this discussion.
THE BASICS OF THE GUT FLORA
As mentioned before the composition of the gut flora differs among individuals as well as throughout the lifespan of the same individual. Some factors that can alter the composition of the gastrointestinal flora are medications (especially antibiotics), diet, climate, aging, illness, stress, pH, infections, geographic location, and even race. Thus it is not surprising to find out that the composition of the gastrointestinal flora not only differs among individuals, and also differs during the life within the same individual. Furthermore, in addition to the different composition of bacterial species of the gut flora, there are also a variety of distinct bacterial communities set up along the long axis of the gut itself, as seen in the figure below. The human gut associated microbiota are dominated by four main types of bacterial phyla: Firmicutes, Actinobacteria, Proteobacteria and Bacteroidetes. Bacteroides, pictured on the left, are a part of one of the major lineages of bacterias and are anaerobic, bile-resistant, non-spore-forming, gram-negative rod bacterial species. For optimum "gut flora balance," the beneficial bacteria, such as the gram-positive Lactobacilli and Bifidobacteria, should be prominent, presenting a barrier to invading organisms (Neish 2009).
“Eubiosis” is the state of balance within the gastrointestinal flora, wherease an imbalance within the microbial ppulation is known as “dybiosis.” Furthermore around 85% of the intestional microflora in a healthy person should consist of “good bacteria” and 15% of “bad bacteria.” The major functions of the gut microflora include metabolic activities, which result in conservation of energy and absorbable nutrients, important trophic effects on the intestinal epithelial cells and on the immune function and protection of the colonized host against invasions by pathogenic microbes. Furthermore gut flora may prove to play essential factors in certain pathological disorders making it an important aspect of the (Tlaskalova et. al 2011). Moreover the greater the imbalance within the gut flora, the greater the symptoms manifested in the host.
BACTERIAL INTERACTIONS WITH THE IMMUNE SYSTEM
Almost 85% of the immunological active cells of the body belong to the mucosal associated immune system. The mucosal immune system is the portion of the immune system, which provides protection to an organism’s various mucous membranes from invasion by potentially pathogenic microbes. More specifically mucous membranes are epithelial tissues that secrete mucus and line many body cavities and tubular organs including the gut. Furthermore this mucosal immune system provides three main functions; protection of the mucus membranes against infection, preventing any uptake of antigens, microorganisms and other foreign materials, and lastly moderating the organism’s immune responses to those potentially hazardous materials. Now the majority of these immunological active cells are present in tissues of the gastrointestinal tract, where there is a prevalence of immunogenic agents (including the food and components of the microbiota) is the greatest (Tlaskalova et. al 2011). The barrier function of the mucosal surfaces (especially of the intestine) is secured by complex interactive mechanisms involving the microbiota itself.
The microbiota acts as a natural barrier against pathogenic microorganisms. Moreover when the microbiota has an optimal composition, it further prevents the attachment and multiplication of pathogenic microorganims on these surfaces and thus also prevents invasions of these microorganisms into the epithelial cells and the circulation (Tlaskalova et. al 2011).
(Corthesy et. al 2007)
Above is a simplistic schematic representation of the multiple consequences of communication between probiotic bacteria (bacteria which stimulates the beneficial growth of microorganisms) and the intestinal mucosa. At the intestinal epithelial level, the bacteria may promote beneficial effects through transient colonization and/or release of specific bioactice compounds. The release of these compounds would further reinforce the intestinal barrier as well as direct modifications of epithelial cell functions (such as cytokine release). Translocation of bacteria to the lamina may affect adaptive immunity by also activating the production of cytokines by macrophages (Corthesy et. al 2007). An additional interaction to keep the gut flora “in check,” is the host barrier created by mucins (highly glycosylated macromolecules), which are situated between the gut contents and the epithelial cells, protecting them from direct contact with commensal bacteria and their components (Tlaskalova et. al 2011). Any changes in the amount and/or composition of the mucus would potentially lead to an inflammatory response and thus acts as a control mechanism against greedy bacteria.
INTESTINAL MICROFLORA OF NEWBORN INFANTS
The composition of the main bacterial population does not stabilize until after the first few years of life, during which the microbiota gradually colonizes the mucosal layer of the GI tract (along with the skin surfaces) of the neonate and exerts the greatest effect upon the development of the immune system (Wexler 2007). Due to its naturally closed system, fetuses are sterile in the womb, however beginning with the birth process (either vaginal delivery or via cesarean section) the infants are exposed to microbes that originate from the mother and the surrounding environment (including both breast milk or formula).
Of the four main phyla mentioned previously in the section on “The Basics of the Gut Flora,” the bacteroiodes are generally the first to become part of the human flora during the earliest stages of life (at least with a typical vaginal delivery). This is typically due to the mode of delivery and the fact that bacteroides may be passed from mother to child during a vaginal birth (Wexler 2007). During this natural delivery the infant tends to acquire additional flora by swallowing the vaginal fluid at the time of delivery. Furthermore since the vaginal flora and intestinal flora are similar, an infant’s flora may closely mimic the gut flora of the mother. While a normal vaginal delivery commonly permits the transfer of bacteria from the mother to the infant, during cesarean deliveries the transfer of bacteria is completely absent. Studies have shown that these infants are commonly colonized with flora from the hospital’s environment and therefore their flora may differ from maternal flora. More specifically infants delivered by cesarean section are more colonized with anaerobic bacteria than vaginally delivered infants. Thus, the mode of neonatal delivery is particularly important since the infants delivered by c-sections would lack the first input of maternal bacteria and therefore the development of the their intestinal microbiota differs significantly.
Furthermore the bacteria that initially colonize vary depending upon the food source of the infant. For instance in breast-fed infants’ gastrointestinal flora bifidobacteria account for more than 90% of the bacterial flora due to the high concentrations of protein in human milk. Breastfeeding is the best prevention for infections, morbidity and mortality rates in infants. Why you may ask? Because these infants develop an intestinal flora of gut bacteria that is dominated by bifidobacteria and lactobacilli. In addition they also possess less pathogenic bacteria compared to formula-fed infants. Breast-milk possesses human milk oligosaccharides (HMO)s which play an important role in the defense system, due to having both the prebiotic (occurring before the emergence of life) potential and the direct interaction with the immune cells (Arslanoglu 2007). Since many women are unable to breastfeed their infants, researchers have been searching for alternatives to mimic the prebiotic effect of HMO, which has both a huge diversity and a complex chemical structure. A prebiotic mixture of 90% short chain galactooligosaccharides (scGOS) and 10% long chain fructo-oligosaccharides (lcFOS). Companies developing and launching such infant formula mixtures include Immunofortis, Numico & BioGaia.
Although these oligosaccharides are not identical to HMO both the studies dealing with preterm and term infants have shown that a formula supplementation with this prebiotic mixture of scGOS/lcFOS results in an intestinal microbiota similar to that found in breast-fed infants (Arslanoglu 2007). This further demonstrates that there is a strong interaction between the composition of the intestinal microbiota and the post-natal development of the immune system. Thus it could be hypothesized that this highly complex and diverse prebiotic mixture might influence the immune system of formula-fed infants. The establishment of an intestinal microbial ecology is very variable at the beginning but will become a more stable system similar to the adult microflora by the end of the breastfeeding period. Other factors affecting the intestinal microflora of the infant include geographical differences (industrialized vs. developing countries) and administration of antibiotics in neonatal intensive care. Furthermore the usage of probiotics may be the most natural, safe way for keeping the balance of the intestinal ecosystem, as suggested by Jennifer Cherry (CEO of Everidis) in the following video.
(A conversation with Jennifer Cherry, CEO Everidis, on probiotics and BioGaia's Lactobacillus reuteri)
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