The role of microbiota in infectious disease

The intestine harbors an ecosystem composed of the intestinal mucosa and the commensal microbiota. The microbiota fosters development, aids digestion and protects host cells from pathogens – a function referred to as colonization resistance. Little is known about the molecular basis of colonization resistance and how it can be overcome by enteropathogenic bacteria. Recently, studies on inflammatory bowel diseases and on animal models for enteric infection have provided new insights into colonization resistance. Gut inflammation changes microbiota composition, disrupts colonization resistance and enhances pathogen growth. Thus, some pathogens can benefit from inflammatory defenses. This new paradigm will enable the study of host factors enhancing or inhibiting bacterial growth in health and disease.

Introduction

Most bacterial pathogens infect their hosts via mucosal surfaces of the respiratory, urogenital or gastrointestinal tracts. Mucosal surfaces are protected against infection by several mechanical and immunological barriers, which have recently been reviewed elsewhere 1, 2. Here, we focus on an additional protective mechanism – colonization resistance – which is characteristic of the heavily colonized intestinal mucosa (Box 1). Colonization resistance describes the failure of most pathogenic bacteria to colonize the normal gut and cause enteric disease (Box 2). It results from the presence of a dense (10¹² organisms per ml) microbial community called the microbiota (see Glossary). In the normal gut the relationship between the microbiota and the host is mutually beneficial. The microbiota is provided with steady growth conditions and a (somewhat limited) nutrient supply. In return, the microbiota contributes to the host's nutrition, immune system development, angiogenesis and fat storage 1, 3, 4, 5, 6, 7, 8, 9. This complex network of interactions is thought to stabilize the population structure of the microbiota and to prohibit colonization by intruding pathogens. The molecular basis of colonization resistance is still poorly understood.

In spite of colonization resistance and numerous other defenses, some pathogens are still capable of infecting the gut. The mechanisms that pathogens use to overcome these barriers, to compete against the intrinsic microbiota and to guarantee successful infection also remain elusive. One such mechanism has recently been shown in studies on the enteropathogenic bacteria Citrobacter rodentium and Salmonella enterica spp. I serovar Typhimurium (S. Typhimurium) 10, 11. Remarkably, both enteropathogens were shown to rely on the inflammatory host response, which they evoke in the gut: inflammation changed the composition of the commensal gut microbiota and concurrently fostered pathogen growth. Similar observations were made in patients and animal models for inflammatory bowel diseases (IBD). In this case, the gut inflammation also coincided with altered population structure of the microbiota 11, 12, 13, 14. These findings identify a shared mechanism of gut ecosystem intrusion by enteropathogens: that is, triggering the host's inflammatory response to overcome colonization resistance. The molecular basis of this strategy is still unclear and might involve different molecular mechanisms. The inflamed gut might offer altered conditions such as changes in the available nutrients and adhesion sites that can be exploited by the pathogen but not by the microbiota (the ‘food hypothesis’). Alternatively, changes in antimicrobial compounds such as lectins and defensins released by the inflamed tissue might be detrimental for the microbiota but not for the pathogen (the ‘differential killing hypothesis’).

In this review, we describe the ‘classical’ observations linking a disturbed gut microbiota to increased susceptibility to gut infections. We then discuss how inflammation might alleviate colonization resistance and how these basic findings can be extended to help elucidate the interactions between bacteria and the gut mucosa in health and disease.