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The intestinal microbiota among vertebrates is known to be one of the most complex ecosystems on this planet, outnumbering by far the cells and genes in the human body. The gastrointestinal tract is rapidly colonized by these microbiota upon birth, who aid in the food degradation processes of the hosts intestinal tract. Mainly anaerobic Bacteria and to a lesser extend also Archaea, Eukarya and their viruses are present within the intestinal tract, because of the harsh food degrading conditions inside. A protective layer of mucus covering the epithelial cells of the intestinal tract serves as the adherence surface for many host-microbe interactions and various bacteria developed mechanisms to use this mucus layer as a source for carbon and energy. Mucus-colonizing microbes are also suggested to be able to protect the host against pathogens by means of competitive exclusion. A good example is Lactobacillus rhamnosus, globally promoted as a probiotic, which carries pili that strongly bind to mucus thereby giving this strain a competitive advantage by outcompeting pathogens. The microbial community generally showed a marked resilience, despite possible pervasive effects due to changing environmental conditions. It is therefore assumed that the stability of the microbial community greatly contributes to the health of the host.
State of the art
With an immense diversity of microbiota, it is of great importance to identify the nature of host-microbe interactions and processes and relate them to the health status of the host. Currently, 'omics'-based techniques are being used to probe the microbial diversity and its functions. Analyzing metagenomic sequences of human microbiota led to the discovery of different networks, so-called enterotypes which are driven by groups of intestinal taxa. DNA-based approaches however, predict potential functions, but it is not known whether these genes are actually expressed and whether the DNA came from viable, dormant or dead cells. Metatranscriptome analyses could overcome these limitations by profiling gene expression and analyzing cDNA and RNA sequences. These results indicated that carbohydrate metabolism, energy production and synthesis of cellular components are the main functional roles of gut microbiota. Another approach, metaproteomics, studies all proteins recovered from the ecosystem and these results were in line with the predictions from meta- proteome and transcriptome analyses. Another technique is meta-bolomics, where metabolic profiling is used to study gut microbiota. Finally culturing is used to characterize isolates at the genomic and physiologic level to link metabolic traits to specific microbial lineages and predict their function and behavior. This is one of the greatest challenges scientists are facing today.
The suggested link between microbiota and the health of the host also encouraged research on this topic. Recent findings propose that intestinal tract microbiota are important contributors to the energy and metabolic homeostasis of its host. In germ free mice for instance, obesity resistance is observed and weight gain is stimulated upon gastro-intestinal (GI) tract colonization. However, studies in humans generated conflicting results, which may be explained by the heterogeneity among the human subjects. Human energy homeostasis varies greatly between individuals, as they differ in genotype, lifestyle and GI tract microbiota. It is suggested that the human host-genotype, especially immune system phenotype factors, greatly influences GI microbiota characteristics. Genotype however, is not taken into account as a determinant of the host phenotype in human microbiota studies. Minimizing genotypic influences by using monozygotic (MZ) twins could allow for pair-wise comparison studies within a fixed genotype.
Addressing the challenge of linking phylogeny information of microbiota to function has been demonstrated for Akkermansia municiphila, a member of the Verrucomicrobia isolated in 2004. 'Omics'-based techniques and culturing approaches were integrated to gain insight into the microbial structure and function in the intestine. This bacterium is a true symbiont of humans and one of the driving forces in two of the three discovered microbiome enterotypes, with presumably at least eight different species colonizing the intestine of humans. A. muciniphila has mucus-degrading abilities and the distribution along the gut suggest that the bacterium co-evolved with its host and its potential functionality. The host benefits from the ability of the bacterium to produce acetate and proprionate as a result of mucin degradation, and the presence of the products close to the epithelial cells makes them easily available for the host. A. muciniphila also could be associated with a protective role, because proprionate can signal to the hosts immune system via specific signaling pathways resulting in up regulation of genes involved in antigen presentation. However no inflammation developed, when germ-free mice were colonized with high numbers of the bacterium, suggesting that A. muciniphila induces immune tolerance. In short, A. muciniphila contributes to a healthy microbiota composition and serves as a buffer, because mucus degradation products attract other bacteria, thereby providing colonization resistance to pathogenic bacteria.
A study of Tims et al. (2012) investigated the differences in GI microbiota composition in MZ twin pairs concordant and disconcordant in BMI. The main objective was to define microbiota signatures that correlated directly with BMI differences, without the influence of host genotype and absolute BMI values. 40 MZ twin pairs contacted from the East Flanders Prospective Twin Study volunteered to donate fecal material. DNA was extracted and microbiota composition was analyzed with phylogenetic microarray from the Human Intestinal Tract Chip (HITChip). The cohort existed of 11 male and 29 female twin pairs who were previously recorded to differ more than 5 units in BMI. 20 age- and gender-matched twin pairs with no BMI difference were selected as controls.
First it was shown that both concordant and disconcordant twin paires had a significantly higher similarity in their GI microbiota, compared to random paired subjects. These results acknowledge the existence of a structural core in human GI microbiota, correlating with the genotype and shared environmental exposures in early life. Furthermore, it was evaluated whether different bacterial groups are associated to BMI. At the moment of sampling however, 15 of the selected discordant twin pairs differed less than 5 units in BMI and 6 twin pairs were between the BMI thresholds used to distinguish between concordant or disconcordant. These 6 twin pairs were not included and the latter was placed into two groups: higher and lower BMI. It was shown that no differences were observed in Bacteroides:Firmicutes ratio, but the Clostridium cluster IV diversity was significantly lower in diversity in the higher BMI siblings. This could indicate that Clostridium diversity decreases as BMI increases. Also specific microbial groups as Eubacterium ventrosium and Roseburia intestinalis were significantly more abundant in high BMI groups, while Oscillospira guillermondii was significantly more abundant in the lower BMI groups. Microbial groups more abundant in high BMI groups seem to belong to an ecological network, with butyrate producing species which are capable of degrading fibers themselves. These networks can visualize cooperation and competition between these groups. Oscillospira guillermondii belongs to a network which is specialized in degrading fibers into partially degraded oligosaccharides, acetate and lactate which can be used as substrates for butyrate producers. This theory was also assisted with the findings that after metabolic profiling higher levels of butyrate and valerate were present in higher BMI siblings, compared to lower BMI siblings.
Discussion and future directions
Despite the fact that for A. muciniphila, the relation between phylogeny and function has been analyzed, this information is still lacking for many other microorganisms. Although it is still hard to culture many microorganisms, knowledge on new techniques to analyze microbiota and their interactions has expanded enormously and in depth research will certainly be possible in the future. Linking the functions and interactions of the microbiota to the health status of the host is still one of the major challenges.
The MZ twin study of Tims et al. (2012) showed that human genotype and early life environmental factors strongly contribute to the structural composition of GI microbiota and these results contribute to the evidence for the existence of an imprinted structural core. However it remains speculative whether or not early life dietary influences also played a role. The study also showed that approximately half of the conserved 'core' genera within MZ twin pairs, were reported to be driving genera for the classification of the three enterotypes. This overlap adds to the debate whether GI microbiota truly can be classified into distinct enterotypes or that that they should be considered as a 'state' (a part of a continuum). The data from this research suggests that enterotypes can best be seen as distinct states, because the core genera have the capacity to form each enterotype. These assumptions deserve more attention in future studies.
The study also showed that two distinct ecological networks were found in lower and higher BMI siblings from monozygotic twins. The researchers hypothesize that host BMI increase is accompanied by changes in GI tract microbiota consequently generation a metabolic shift in butyrate production; from the production of fermentation products to fermenting fibers directly into butyrate. This could cause a shift in the hosts net energy production and affecting its energy harvest. However more information on dietary intake and fermentation products is needed to elucidate the mechanism between GI microbiota and the hosts energy homeostasis.