(27 February 2013) Although considerable progress has been made in determining the impact of the gut microbiota on the development of inflammatory bowel disease (IBD) and other gastrointestinal (GI) diseases, the detailed study and understanding of the composition and effects of this intestinal community still faces numerous methodological and empirical challenges. “Improvement of study design and sample collection, as well as a more precise understanding of the various genetic and environmental influences, are asked for,” says Professor Dirk Haller (Technical University Munich, Germany), who addressed some of the central issues that make up the agenda of future research. His talk was one of the topics presented at the 2nd World Summit “Gut Microbiota For Health” in Madrid, Spain. From 24 to 26 February 2013, internationally leading experts discussed the latest advances in gut microbiota research and its impact on health.
A challenge to establishing causal relationships between microbial dysbiosis (an imbalance in intestinal bacteria) and IBD is the fact that the gut microbiota presents itself as a permanently “moving target.” Earlier studies suggested that the gut microbiota composition of healthy adults was stable over time, but recent investigations using techniques with higher sensitivity have shown a surprising degree of variability within an individual’s faecal microbiota, even within days, with only a small core microbiota remaining unchanged in the long term. The medical significance of such shifts is still widely unclear. There is a lot of evidence that environmental influences such as diet, medications, mental conditions or GI infections, among others, affect the gut microbiota. But it is still fairly difficult to determine the precise effects of these dynamic factors.
Approaching the core
It has been suggested that there is a core microbiota to be found in the intestines of all individuals, but it remains unclear what its exact constituents might be. As there is undoubtedly an essential functionality of gut microbes that support human health and nutrition, it might be appropriate, instead, to define a set of core functions of the microbiota as the correct unifying concept. Evidence from recent studies supports this view: it shows that each individual has significant differences in the composition of their gut microbial communities, but these diverse communities share a majority of microbial genes with a presumed core functional capability and activity. Changes in this core set of functionally similar genes may well be responsible for different states of health and disease.
Given the dynamics and diversity of microbiota compositions, the concept of enterotypes — its merits notwithstanding — has certain limitations: this model has frequently been put into analogy with human blood groups, but the implications are misleading insofar as blood groups, unlike the microbiota enterotypes, are unchangeable and in no way subject to modifications of environmental conditions. Consequently, the notion of three clearly distinct enterotypes has been blurred recently, with some investigators now favouring the concept of a continuum of species functionality with only gradual distinctions, rather than discontinuous variation with segregated types. Recent examinations of the microbiota composition and associated health status in a large group of healthy, as well as frail, elderly individuals did not identify enterotypes as the strongest separation in the data. The composition of the microbiota of healthy elderly individuals was not radically different from that of younger controls; instead, the most marked distinctions were found in comparing the intestinal microbes of unhealthy, frail elderly subjects with healthy individuals of the same age.
How relevant is the faecal microbiota?
The empirical basis not only for defining the enterotypes, but also for the majority of gut microbiota investigations in general is the faecal microbiota, a fact that, according to Prof. Haller, also deserves scrutinising from a methodological point of view.
“The faecal microbiota is being preferred by many scientists as it is easy to acquire, inexpensive and does not require invasive procedures such as colonoscopy,” he says. “But the question arises whether this kind of microbiota is really representative of the resident microbiota of the distal GI tract. Many researchers believe — rightly in my opinion — that the microbial communities that are closely associated with the intestinal epithelium are biologically more relevant than planktonic microbes that exist in the lumen of the gut and, moreover, that the composition of faecal microbial communities may not accurately portray the mucosal microbiota. It turned out that rather than being a subset of the faecal microbiota, the mucosa-associated microbiota is compositionally distinct from that of stool.”
In view of the limitations connected with the study of stool bacteria, researchers have turned to mucosal biopsies of the GI tract collected by endoscopy. But this also has its downside, because fasting and colon cleansing are commonly required in advance of endoscopic biopsy collection, thus changing the microbial composition. Moreover, the tissue-associated mucosal bacteria themselves might be contaminated by luminal microbes in the process of endoscopic collection, as during colonoscopy; for example, biopsy forceps are advanced and then withdrawn via the same channel used to suction stool residue.
Refining the tools
Substantial progress in this area depends heavily on all sorts of highly developed tools and techniques, among which computer-based methods belong to the most important ones. In the past decade, highly advanced gene sequencing technologies have emerged that have increased the depth and speed of the gut microbiota’s analysis. But despite the enormous progress made in determining microbial community structures, there are still methodological gaps and insufficiencies. Certain gene sequencing techniques, though fast and efficient in categorising the intestinal microbes, provide no information about bacterial physiology and ecological significance, whereas others, while fulfilling this purpose, need large amounts of DNA and carry the risk of contaminating the microbial DNA with host DNA. “Currently, many microbial genes are identified, but so far we have not been able to assign a function to them,” says Prof. Haller.
The bioinformatic tools being used at present to unravel the interactions within the microbiota are mainly based on traditional statistical techniques that cannot cope sufficiently with the inherent complexity of biological systems, such as the gut microbiota, with its manifold and intertwined pathways and the permanent crosswise interactions the microbes are maintaining.
“The use of machine-learning algorithms, which are based on pattern recognition, including neural networks, support vector machines, and decision trees might help to make these complexities more transparent,” says Prof. Haller. Another problem facing investigators is the huge volume of data that gene sequencing generates, which might exceed available computing resources of an institution. Cloud computing, using the storage and processing capabilities of a network of remote servers hosted on the Internet, can resolve this problem.
About the Gut Microbiota & Health Section of ESNM
ESNM stands for the European Society of Neurogastroenterology and Motility, a member of United European Gastroenterology (UEG). The mission of the ESNM is to defend the interests of all professionals in Europe involved in the study of neurobiology and pathophysiology of gastrointestinal function. The Gut Microbiota & Health Section was set up to increase recognition of the links between the gut microbiota and human health, to spread knowledge and to raise interest in the subject. The Gut Microbiota & Health Section is open to professionals, researchers, and practitioners from all fields related to gut microbiota and health. www.esnm.eu/gut_health/gut_micro_health.php?navId=68
About the AGA
The American Gastroenterological Association is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include more than 16,000 members from around the globe who are involved in all aspects of the science, practice and advancement of gastroenterology. The AGA Institute administers the practice, research and educational programmes of the organisation. www.gastro.org
About Danone Dairy and Gut Microbiota For Health
Danone’s conviction is that food plays an essential role in human health namely through the impact that gut microbiota may have on health. That is why Danone Dairy supports the Gut Microbiota For Health World Summit and Experts Exchange web platform with the aim to encourage research and increase knowledge in this promising area, in line with its mission to “bring health through food to as many people as possible”.
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