Hello my name is Søren Sørensen and I am professor at the University of Copenhagen at Section of Microbiology. In this lecture I will talk about the Human Gut Microbiome. The human intestinal system faces an extremely difficult task. The gut is - similar to the skin - exposed externally and is therefore also a non-sterile environment. Several mechanisms of the skin, such as the secretion of acidic sweat, are intended to prevent alien organisms from utilizing and colonizing it. Unlike the skin, though, the gut must also be highly efficient in actively absorbing molecules and serving in fluid and electrolyte secretion as part of maintaining whole-organism homeostasis. To perform this task, the gut has a combined surface area about 200 times larger than that of the skin. This, together with the abundance of available nutrients from ingested food, makes the job - of trying to prevent microbial presence - impossible. In fact, with a surface area of up to 300 m2 in adults, the digestive track is an ideal setting for microbial biofilm formation; It can be considered as a huge bioreactor with constant temperature around 37°C, high humidity, and regular supply of food and removal of waste. These are all ideal conditions for microbial growth. It’s therefore not surprising that the human gut host an extremely dense microbiota, up to 1014 bacterial cells in adults, and several hundreds of different bacterial species. Therefore, as an alternative strategy, the digestive tract has evolved to exist in symbiosis with its microbial inhabitants instead of trying to eliminate them. The human host actually benefits quite considerably from this co-existence. The bacteria of the gut serve multiple beneficial functions: • They enhance the recovery of energy by breaking down macromolecules that would otherwise have been in-digestible. • They participate in the biosynthesis of vitamin such as vitamin B and vitamin K. • They can degrade potentially harmful substances • And, they can provide protection from pathogens by competing for available space and nutrients. All these advantages of the commensal gut bacteria are a logical consequence of bacterial growth and activity. However, recent research has shown that our bacterial partners also influence several other aspects of human health. According to the “hygiene hypothesis” our relatively newly acquired “sterile” life-style has brought imbalance to the pattern and diversity of microbes that we are normally exposed to; and this is the causative factor behind the increased incidence of diseases such as diabetes, obesity and asthma and possible many others. This idea implies that the microorganisms within us are able to modulate immune-responses against other antigens. This modulation or priming is believed to occur very early in life. At birth the baby is initially equipped with a so called type 2 T-helper cell orientated immune system, resembling that of individuals suffering from allergic diseases. Exposure of microbes to the Gut Associated Lymphoid Tissue in babies is thought to mediate a shift towards a type 1 T-helper cell phenotype – common in healthy adults – thereby providing protection against allergic reactions later in life. However, unlike originally argued by in “hygiene hypothesis”, we now know that it is not just a lack of expositor to microbes in general, which are causing these problems. It is also important which microbes we are exposed to and when. Almost one hundred years ago, Elie Metchnikoff, a Russian Nobel prize laureate, first used the term dysbiosis in order to describe an imbalance in the composition and distribution of the microbiota. It has been suggested that a dysbiotic microbiota is causing insufficient activation of healthy immune responses early in life, which will leads to systemic immunological deviations and possible disease. Accordingly, the gut microbiota of infants who would later develop allergy has been shown to harbor less Enterococcus and Bacteriodes and higher amounts of Clostridia compared to healthy infants. In addition, allergic children have been shown to harbor a microbiota that differs in composition from the microbiota in healthy children. Studies have shown that allergic individuals are less often colonized with Bifido-bacterium and Lacto-bacillus in the gut and more often with Staphylo-coccus than healthy subjects. A general reduction in the microbial diversity in the gut during early childhood has also been shown to be associated with allergy development. These findings, whether species specific, or based on diversity, support the general hypothesis that an imbalance of the human gut microbiome in early childhood, enhances the risk of development of asthma and other aller-genic disease. Also lifestyle illnesses such as diabetes and obesity have been shown to correlate with such dysbioses. The establishment of a balanced gut microbiota is therefore apparently vital for many aspects of human health, and abnormal intestinal colonization during the first weeks of life, may alter both the nutritional, the immunological, and the protection functions of the host microbiota. Thus, the first bacteria, that the infant is exposed to, are likely to become the ones priming the process of healthy gut microbiota maturation. Several different factors, such as mode of delivery, diet, and environment, influence bacterial colonization of the infant gut, but their specific contribution remains unclear. The gastro-intestinal system has traditionally been considered sterile until birth, during which it becomes rapidly colonized with vaginal and fecal bacteria from the mother and microorganisms from the surrounding environment. However, some data suggest that gut colonization may even start before birth through an internal transfer of maternal bacteria to the fetal digestive tract. But the mechanism for this pre-birth bacterial transfer remains to be substantiated. Whether or not it happens before or after birth, the transfer of bacteria from mother to child is a type of heritance of the maternal microbiota and factors, which determine the microbiome of pregnant mothers may, therefore, also influences whether the offspring will develop allergy or not. Facultative anaerobes, such as Entero-bacter, Entero-coccus, Lacto-bacillus, and Strepto-coccus species, are the first bacteria to establish. As these bacterial populations expand during the first days, they consume the oxygen in the infant gut, thus creating an anaerobic environment, favoring the growth of strictly anaerobic bacteria, including Bacte-roides, Bifido-bacterium, Fuso-bacterium, and Clostridium species. With time, more and more anaerobic species are able to establish and expand in the infant gut, thus replacing some of the facultative bacteria. Within the first year of life, and typically after the introduction of solid food, the microbial community generally stabilizes and resembles that of an adult with the majority of the microbial species belonging to the phyla Firmicutes and Bacteriodetes. Interestingly, the intestinal microbiota of babies delivered by caesarean section has been reported to differ from that of babies delivered vby normal birth, both in the timing of colonization and in the species composition of the microbiota. Children born by caesarean section show delayed and less frequent colonization with Bifido-bacterium, Lacto-bacillus and Bacteriodes species and more frequently colonized by opportunistic pathogens typically found on human skin and in hospitals, such as Staph. aureus, Klebsiella, and Clostridium difficile. Furthermore, the total microbial diversity of gut microbiota in vaginal-delivered babies is significantly higher than caesarean-delivered ones, and this effect can still be detected during the first 2 to 3 years of life. In this connection, it is very striking that it has been shown that children delivered by caesarean section have a two-fold increased risk of developing asthma and other allergic diseases. Other factors can also have an effect. Evidence suggests that consumption of probiotics and antibiotics by mothers during pregnancy leads to specific changes in the gut bacteria in new borns. Since probiotics and antibiotics have been shown to alter the composition of the intestinal and vaginal microbiota, these data demonstrate that the specific composition and diversity of the mothers’ microbiota during pregnancy play an important role in colonization of the infant gut. The first 1000 days of life (starting from interception) is considered as the most important period in any individual’s life; providing the foundation for health and later development of illnesses, and the establishment of a natural and diverse gut microbiome seems to be a very important factor here. A huge research effort has, therefore, been put into understanding the factors that lead to a dysbiotic gut microbiota in early life. The main influence on early gut colonization is believed to be the mothers’ microbiota but several other factors could possibly contribute. Gut colonization patterns have also been shown to be influenced by lifestyle factors such as feeding methods, diet and family structure, this includes number of siblings and household pets. Among these are also differential exposures to microbes during childhood as a consequence of the use of antibiotics. The uncontrolled use of antibiotics represents an immense interference with the natural environment, potentially influencing maintenance for a diverse gut microbiota and elimination of important beneficial bacteria. As I have described in this presentation, consequences of such alteration in the gut microbiome have many potential negatives effects, including providing opportunities for colonization of pathogenic bacteria and impairing a healthy human nutrition. The recent acceleration of prominent changes to our life-style might have significantly altered the composition of the human gut microbiota, thereby compromising normal health and well being. In order to firmly establish causal correlation, more research is needed, but accumulating evidence suggests that our microbial partners do play a significant role in maintaining a healthy body and avoiding diseases such as allergy and diabetes.
