Mechanisms controlling pathogen colonization of the gut
Section snippets
A word of caution
The mammalian gut is a highly complex ecosystem shaped by the host, a complex microbial community called microbiota and profoundly affected by interactions with the outside environment, for example, the intake of food or infection by pathogens [2]. This complexity has been an immense obstacle for mechanistic studies. Simplified model systems and recent advances in analytic methodology have fuelled significant progress. However, it should be kept in mind that no single study has so far been able
The composition of the gastrointestinal microbiota
The composition of the microbiota and its collective genome, the microbiome, has been intensely studied. Early cultivation based studies suggested that the human intestinal microbiota harbors at least 400 different, mostly obligate anaerobic bacterial species [3, 4]. This was confirmed by modern, culture-independent approaches estimating that an individual's microbiota comprises not more than 500 species [5•]. Two predominant phyla were observed, the Firmicutes and the Bacteroidetes. Other
General functions of the microbiota
In most cases the beneficial functions of the microbiota outweigh potentially harmful side effects. The microbiota provides digestive functions, modulates host metabolism and stimulates development of lymphatic tissue and the mucosal immune system. Moreover, it can efficiently limit infection of the gut by pathogenic bacteria. In fact, during pathogen infection, the microbiota may have at least three cardinal functions: (i) it may block growth of the pathogen and thus interfere with the
Mechanisms of CR
What do we know about the mechanisms underlying CR? Innate immunity, adaptive immunity and bacterial interactions are probably involved in modulating both the composition of the microbiota and the outcome of infections. To establish successful infection, all pathogens need to replicate in the gut lumen in order to reach a sufficient population density for causing disease. In the case of S. Typhimurium enterocolitis, this was demonstrated by infecting mice with defined mixtures of the wild-type
Environmental factors affecting the microbiota
The determinants influencing stability and composition of the microbiota are not completely understood. Besides antibiotics other factors are known that lead to alterations of intestinal bacterial communities and may, as a consequence, affect CR. The diet has a profound effect on the microbiota composition [48] as shown by next-generation deep sequencing analysis of the human microbiota [49, 50]. Both studies found that the microbiota can respond rapidly to changes in diet in as little as one
CR and intestinal inflammation
Mucosal inflammation has a profound effect on the host's mucosa, on the nutrient availability in the gut and on the microbiota composition. For practical reasons, we distinguish between chronic gut inflammation caused by effects of the commensal microbiota (IBD) and acute inflammation caused by enteric pathogens. Nevertheless, some functional principles might be common to both types of disease.
Work on acute Salmonella and Citrobacter infection models has revealed that enteropathogenic bacteria
Future directions
In the future, two developments will have a great impact on analyzing CR, simplified model systems and improved systems biology techniques (Box 2).
Gnotobiology has already contributed significantly to our current understanding of the microbiota–host cross-talk (Table 1). We will need to invest into improved GF and gnotobiotic animal models for analyzing particular strains (or combinations thereof). An increasing catalogue of sequenced microbial genomes and development of genetic tools for
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We are grateful to numerous colleagues for stimulating discussions and to Yvonne Lötscher for assisting with figure design. Work was supported by the Swiss National Science Foundation (310030-113623, 310030-132997 to WDH), the UBS foundation (1004/A, to WDH) and the BMBF Infektionsgenomik (to BS).
Glossary
- COG
- cluster of orthologous groups of proteins used for phylogenetic classification of proteins encoded in complete genomes
- Colonization resistance (CR)
- characteristic of the intestinal microbiota to block colonization of pathogens
- Defensin
- peptide with antimicrobial activity
- Gnotobiotic
- colonized with bacteria of known identity
- IBD
- inflammatory bowel disease (e.g. Crohn's disease and Ulcerative Colitis)
- Microbiome
- collective genome of all present bacteria
- Metagenome
- collective genome of all organisms
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