|Year : 2017 | Volume
| Issue : 3 | Page : 133-139
Changes in Gut Microbiota During Lifespan
Fernanda de Pace
Medical Clinic Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
|Date of Web Publication||24-Oct-2017|
Fernanda de Pace
Tessália Vieira de Camargo Street, 126, 13083887 Campinas, São Paulo
Source of Support: None, Conflict of Interest: None
Being able to communicate and modulate host metabolism, the tens of trillions of bacteria that inhabit our gut have been shown to affect traits, which vary from host’s gene expression to behavior, being responsible for maintaining health and exerting influence on the development of a number of diseases. This review shows the changes that occur in the gut microbiota composition along the lifespan, and how the communication with the immune system and central nervous system can be modified as years go by. These changes, most of the times, favor the appearance of inflammatory signals (in older adults), and may contribute to the development of neurodegenerative diseases. Finally, there is a consideration of manipulating the gut microbiota with probiotic therapy as an important option to prevent and treat diseases related to gut microbiota modifications.
Keywords: Central nervous system, gut microbiota, immune system, lifespan, probiotics
|How to cite this article:|
de Pace F. Changes in Gut Microbiota During Lifespan. MAMC J Med Sci 2017;3:133-9
| Introduction|| |
Our present model of life on Earth would not be able to exist without the presence of bacteria. Despite the great number of pathogenic microorganisms, most bacteria are harmless and beneficial to their host’s survival. Our skin, mucous, mouth, entire digestive tract, and placenta have a myriad of bacterial groups that exert a key role in regulating the development and maintenance of the metabolism as a whole.
Recently, some research groups characterized microbiome niches found in meconium,, placental tissue,, the umbilical cord, amniotic fluid,,, and fetal membranes from newborns that did not present any sign of infection or inflammation. But how can these microbes get access to this highly immune-protected area? Although this process is not yet fully understood, it has been suggested that bacteria reach the placenta via the bloodstream from translocation through the gut epithelium. Dendritic cells can penetrate the gut barrier, shuttle microbes across the epithelium and, as they migrate to lymphoid organs, they transport these live microorganisms to the placenta and to maternal mammary glands during lactation, which explains why the composition of the babies’ gut microbiota resemble their mothers.,, It has been shown that there is a maternal microbial transmission from fetuses during the pregnancy and that physiological bacterial translocation is highly increased during pregnancy and during lactation in animal models. From these data, it is reasonable to assume that bacteria from microbiota would have a role in epigenetic processes, exerting some influence in fetus development.
During early infancy, the composition of the gut microbiota shows high fluctuation and low diversity, and the reasons of this instability would be centered on the mode of delivery (vaginal or caesarian section), feeding (formula or breastfeed), the use of antibiotics or other drugs, and the hygiene condition of the environment that the baby is raised in: there are generally higher levels of Enterobacteriaceae, Enterococci spp., and Lactobacilli spp. observed where the sanitation is poor.
Babies born by caesarian section tend to have lower bacterial counts in the first weeks of life, with a predominance of Enterobacteria such as Klebsiella spp. and Enterobacter spp., and present delayed colonization by Bifidobacterium spp. and Escherichia coli spp.,
Despite the oligosaccharides and probiotics present in baby’s formula resembling the constitution of human milk, the microbiota of formula-fed babies present some variations with higher levels of E. coli, Bacteroides spp., Lactobacillus spp., and Clostridium difficile, and lower levels of Bifidobacterium spp. Additionally, as well as containing beneficial bacteria which help colonize the gut of new born babies, human milk presents molecular characteristics that favor the growth of these bacteria. It is also easily digested which prevents intestinal problems, and among a multitude of other benefits, it has immunoglobulins, which actively prevent diseases.
Although extremely variable, bacterial colonization generally follows a set course. After birth, the first bacterial colonizers of the mammalian guts are frequently facultative anaerobes, such as E. coli and Enterococcus spp. These facultative anaerobes that initially dominate the gut environment consume the available oxygen, produce carbon dioxide, promotes pH changes, and modify the structure of the gut, providing additional sites for bacterial adhesion., Furthermore, these “pioneering species” produce nutrients and lower the redox potential, that is, acts by reducing the oxygen concentration, creating an environment that favors the growth of obligate anaerobes, such as species of Clostridium, Bacteroides, and Bifidobacterium., The level of Bifidobacterium spp. proved to be significantly higher in babies in comparison with adults. This group of bacteria protects babies against pathogens, eliminates unwanted bacteria, prevents allergic manifestations, contributes to good digestive health, and protects the baby from excess weight gain in the future.,,, Regarding weight gain, Kalliomäki et al. showed that although presenting a remarkable inter-individual variation at all ages, the microbiota of a 6-month-old infant can predict obesity in childhood. Children who became obese presented fewer Bifidobacterium spp. and higher Staphylococcus aureus levels, indicating a possible link between early life microbiota composition and obesity, reinforcing the importance of breastfeeding.
The bacterial diversity in gut microbiota progressively increases such as an ecological succession, where bacterial communities go through successive compositional and functional changes after initial colonization until it reaches a relative stability by 3 years of life when the child presents a microbiota composition and diversity that quite resembles that of an adult.,,, The gut microbiota is then inhabited by 1013–1014 microorganisms, 100 times more genes than we have in our genome and over 1000 species (and more than 7000 strains), influencing the host metabolism as a whole. There are predominantly four phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria,, which are likely to face variations in percentages of different taxonomic levels (class, order, family, genus, species) due to variations of lifestyle, diet, drugs, and age. Although the existence of a vast inter-individual and intra-individual variation of the composition, the predominance of four phyla lead the researchers to consider the existence of a “core microbiota,” which would play essential roles in host metabolism and would be common and relatively persistent in a large portion of the world’s population. Although this topic is frequent in a large amount of microbiota articles, there is no consensus about which characteristics need to be considered to establish the composition of this core or of which fundamental bacteria this core would be composed. However, the inter-individual differences in the composition of the gut microbiota are remarkable, and to define a dominant core in the majority of people (which would play indispensable physiological roles) is a great challenge.
As the individual gets older, the stability of gut microbiota is no longer maintained, coinciding with the appearance of metabolic and neural disorders, frailty, and cognitive impairment.
Studies involving older people have reported an alteration in the relative proportions of the two major phyla, namely an increase of Bacteroidetes and decrease of Firmicutes., A decrease in groups such as Bifidobacterium spp., Bacteroides spp., and Clostridium cluster IV has also been observed.
In addition to the decrease of Firmicutes as we get older, there is a group of bacteria (e.g., Escherichia spp., Streptococcus spp., Veillonella spp., Clostridium spp., and Enterococcus spp.), that increases. This group has a role in protein degradation, which leads to NH3, H2S, amines, and phenol production, compounds linked to aging and putrefaction.,
Changes in the composition of the gut microbiota through the years has a direct influence on bacterial and host gene expression and the metabolites produced by these bacteria, exerting a direct influence on the host’s metabolism. This communication between microbiota and their host comprises a multitude of metabolic signals; therefore, the study of this conversation is extremely important to understand the development of related diseases and to find novel targets to prevent and treat disorders.
| Host–Gut Microbiota Communication With Immune System|| |
Comprising over 100 trillion microbial cells, the intestine is capable of maintaining tolerance to this legion of antigens, establishing a symbiotic relationship with gut microbiota, and at the same time triggering inflammatory responses to self-defense against pathogens. As part of gut epithelium, paneth cells synthesize and secrete antibacterial molecules such as α-defensins, C-type lectins, lysozymes, and phospholipase A2.
In a healthy gut, homeostasis is maintained by the balance of microbes and the immune recognition generated in response to the microbial surface antigens. These antigens and the metabolism of the gut microbiota are essential for the maturation of immune tissues and the adjustment of the proper immune responses. The Toll-like receptors (transmembrane proteins that act as innate immune sensors and are expressed in a number of cell types, including intestinal epithelial cells) play important roles in maintaining the homeostasis of gut microbiota and promote a network between the microorganisms of gut microbiota, intestinal epithelial cells, and the immune system, being responsible for recognizing and generating immune responses properly.,, They are able to identify microbial structures known as microbial-associated molecular patterns, activating specific signaling pathways resulting in the production of cytokines, chemokines, and expression of other genes which are important for the development of the immune system and immune responses.,,
As mentioned before, recent works have shown that there are bacteria that inhabit the gut of fetuses, and although the intrauterine roles of this microbiota are still largely unknown, it would be plausible to consider that the development of the immune system might initiate even before birth. However, what is currently well defined is that the development of the immune system begins at birth and the mode of delivery influences the colonization, and therefore the immune system development of neonates. Microbiota contributes to immune system development, and on the other hand, the immune system influences the composition of microbiota. The crosstalk between microbes and the immune system occurs through a multitude of molecular signals and biochemical interactions between microbes and the host, which modulates metabolic reactions. Among these reactions are the bacterial production of bile acids and short chain fatty acids (SCFAs), which are important metabolites to promote metabolism homeostasis. The SCFAs are the end product of bacterial fermentation of undigested complex carbohydrates, and among others, are comprised of acetic,, butyric, and propionic acids. These acids act as major energy sources of colonocytes, nourishing the colonic mucosa and are fundamental for the maintenance of mucosal immunity by increasing tight junctional protein expression. Therefore, they contribute to intestinal epithelial cell barrier function, which helps in the prevention of a vast array of disorders and diseases;,,, and finally, they are essential for modulating immune responses through different ways. SCFAs are inhibitors of histone deacetylases (HDACs − enzymes that remove acetyl groups from histones, allowing this protein to wrap the DNA more tightly, which controls DNA expression), contributing to promote tolerogenic and anti-inflammatory cell effects, which are essential to maintaining immune homeostasis. Among these anti-inflammatory effects are the inactivation of NF-kB, downregulation of necrose tumor factor, dendritic cells, and macrophages,,,,, which reinforce the observation that the inhibition of HDAC by SCFA is essential in regulating innate immune responses and that the gut microbiota also play a role in epigenetic regulation.
Throughout adulthood, the composition of the core microbiota is relatively stable. But as the years go by when old age arrives, changes in gut microbiota composition consequently influence the immune system, influencing its functioning. Although there is an extreme inter-individual variation in the gut microbiota composition, a decrease of Bifidobacterium spp. (genus that promotes anti-inflammatory effects) is frequently observed, corresponding with altered physiological traits and with the time the immune system starts to decline in its “protection” functions. It is associated with older adults as part of the immunosenescence process (a low level of systemic inflammation) as a result of an imbalance of gut microbiota which play an important role in the modulation of the inflammatory and anti-inflammatory networks of the host.,,, These changes observed in microbiota are associated with an increase in the abundance of genes of the microbiome related to aromatic amino acid metabolism, a decrease of genes involved in SCFAs production, an expansion of opportunistic bacteria and changes in levels of metabolites produced by bacteria. This all contributes to promoting the typically low level of inflammatory state found in older people, which is associated with a high range of metabolic disorders common in this stage of life., Additionally, aging is also associated with an increase of LPS in gut microbiota and LPS-binding proteins in the host,,, which activates the NF-kB (associated with immunosenescence), among other cytokines.,,
The inflammation observed in older people is also related to several changes in physical and cognitive abilities,, and although mediated by immune factors and cells (such as NF-kB and T-cells), it is modulated by polymorphisms in a vast array of immune system genes related to the development of some age-related diseases.,,
All these microbiota and metabolic changes lead to disorders and diseases that are frequent in older adults. Aging is accompanied by a decline of motor abilities, cognitive functions, and favors the emergence of other disorders associated with the communication existing between the intestinal bacteria and central nervous system (CNS), such as Alzheimer’s and Parkinson’s diseases., The relation of some neural disorders with metabolites produced by intestinal bacteria and their possible prevention associated with probiotics therapy is attracting the attention of researchers in the neuroscience field.
| Microbiome–Gut–Brain Axis|| |
It is becoming increasingly clear that gut bacteria can synthesize metabolites, which act on the peripheral and CNS. In addition to the immune system, recent works have shown that gut microbiota is also able to communicate and modulate the CNS through secretion of metabolites, hormone-like molecules, and immune pathway.
Since the fetus is colonized by microbes, it is reasonable to consider that this communication would start inside the uterus, and that gut bacteria would help the development and act on the epigenetic process of the CNS. The microbiome–gut–brain axis (the bidirectional communication between brain and bacteria in the gut) is composed of the CNS, hypothalamus–pituitary–adrenal (HPA) axis, the sympathetic–parasympathetic autonomic nervous system, the enteric nervous system (ENS), and finally, the gut and its microbiota.,
The development of cells and metabolites that compose the CNS occurs concomitantly with the shaping of the microbiota, and it is being demonstrated that the set of events which occur during early infancy (involving genes expression, colonization pattern of the gut microbiota and secretion of metabolites, and some environmental influences) would contribute to the general CNS health across the lifespan. Perturbation of the microbial–host interaction during critical stages of life as in the prenatal, postnatal, and adolescent periods can lead to neurodevelopmental disorders.,,
A few weeks after birth, the gut microbiota is formed by a community, which prevails with anaerobes, and it coincides with the activation of the HPA axis. This has an important role on the ENS, which innervates the gastrointestinal tract. The HPA axis which compounds the limbic system (part of the brain that is involved in memory and emotion) coordinates adaptive responses to stressors.
Across the lifespan, there is constant communication between the gut and CNS, which determines proper neurodevelopment and is strongly associated with cognitive and neurological health. In the gut, microbial products communicate with a number of enteroendocrine cells (such as K cell, L cell, I cell, enterochromaffin, N cell, and S cell), regulating their expression. In response to bacterial stimuli, these cells secrete peptides or hormones (depending on the type of the enteroendocrine cell), such as neurotensin, cholecystokinin, somatostatin, histamine, γ-aminobutyric acid (GABA), and serotonin, which end up acting and affecting the CNS functions, mostly through enteric neurons projected in the mucosa., Thus, it is reasonable to conclude that neurobehavioral health depends on proper composition and functionality of the gut microbiota.
As an individual gets older, an imbalance of the gut microbiota is observed, and its imbalance, in turn, may affect the proper functions of CNS, which could lead to neurodegenerative diseases. The relationship of some neurodegenerative diseases such as Parkinson’s, Alzheimer’s, schizophrenia, and multiple sclerosis with changes in gut microbiota is already well established in the literature.,,,,,,, The modifications observed in the gut microbiota of older people and their consequent effects such as neuroinflammation (and the associated cellular response of microglia) are a frequent characteristic of this stage of life. In addition to neurodegenerative diseases, a decline in other cognitive functions and frailty are frequently observed during aging, which are also associated with changes in gut composition, and more specifically with a decline in Bifidobacterium spp. So, it is becoming clear that it is crucial to maintain a balanced microbiota composition across the lifespan to maintain the brain and complete metabolic health.
| Conclusion and Future Perspectives|| |
It is well established that microbiota play an extremely important role in our metabolism as a whole, across our entire existence. To use this knowledge to improve our health during the lifespan, different studies consisting of the use of germ-free animals, probiotics, prebiotics, and antibiotics have been conducted.
It has been shown that manipulations of the microbiome with probiotics can have important effects. For instance, Bifidobacterium infantis has been shown to elevate plasma tryptophan levels (serotonin precursor), while Enterococcus spp., Streptococcus spp., and Escherichia spp. can produce serotonin, with all of them influencing 5-HT levels.,, The strains of Bifidobacterium spp. and Lactobacillus spp. have been shown to produce the neurotransmitter GABA and have been extensively studied for their anti-inflammatory characteristics and for treating cancer, diabetes, allergies, inflammatory bowel disease, Crohn’s disease, obesity, diarrhea due to infections, preventing hypertension, and a decline of the mucus barrier in older people, along with several other disorders.,,, It has been also demonstrated that probiotics can even improve cognition and prevent neurodegenerative diseases in older people. The majority of the results, although very promising, have been found using animal models, it is necessary more translational research.
Hopefully, in the near future, some metabolic and neurodegenerative diseases will be prevented by manipulating the gut microbiome (e.g., using probiotics, metabolites produced by commensal bacteria and fecal transplantation), raising new possibilities for the prevention and treatment of related diseases.
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Conflicts of interest
There are no conflicts of interest.
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