Mechanisms controlling pathogen colonization of the gut

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The intestinal microbiota can protect efficiently against colonization by many enteric pathogens (‘colonization resistance’, CR). This phenomenon has been known for decades, but the mechanistic basis of CR is incompletely defined. At least three mechanisms seem to contribute, that is direct inhibition of pathogen growth by microbiota-derived substances, nutrient depletion by microbiota growth and microbiota-induced stimulation of innate and adaptive immune responses. In spite of CR, intestinal infections are well known to occur. In these cases, the multi-faceted interactions between the microbiota, the host and the pathogen are shifted in favor of the pathogen. We are discussing recent progress in deciphering the underlying molecular mechanisms in health and disease.

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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