Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota

Abstract

The distal gut harbours ∼10(13) bacteria, representing the most densely populated ecosystem known. The functional diversity expressed by these communities is enormous and relatively unexplored. The past decade of research has unveiled the profound influence that the resident microbial populations bestow to host immunity and metabolism. The evolution of these communities from birth generates a highly adapted and highly personalized microbiota that is stable in healthy individuals. Immune homeostasis is achieved and maintained due in part to the extensive interplay between the gut microbiota and host mucosal immune system. Imbalances of gut microbiota may lead to a number of pathologies such as obesity, type I and type II diabetes, inflammatory bowel disease (IBD), colorectal cancer (CRC) and inflammaging/immunosenscence in the elderly. In-depth understanding of the underlying mechanisms that control homeostasis and dysbiosis of the gut microbiota represents an important step in our ability to reliably modulate the gut microbiota with positive clinical outcomes. The potential of microbiome-based therapeutics to treat epidemic human disease is of great interest. New therapeutic paradigms, including second-generation personalized probiotics, prebiotics, narrow spectrum antibiotic treatment and faecal microbiome transplantation, may provide safer and natural alternatives to traditional clinical interventions for chronic diseases. This review discusses host-microbiota homeostasis, consequences of its perturbation and the associated challenges in therapeutic developments that lie ahead.

Keywords: bacterial; host-pathogen interactions; inflammation; mucosa.

© 2014 British Society for Immunology.

Figures

Fig 1

The gut microbiota during the human lifespan. Over the first 2–3 years of life, the gut microbiota undergoes dynamic changes wherein highly adapted communities are established resulting in a healthy microbiome in a state of homeostasis. Environmental factors such as sustained intake of a high-fat, high-carbohydrate diet may drive the gut microbiota into a state of dysbiosis that may influence human diseases such as obesity, diabetes and colorectal cancer. Similarly, the elderly gut microbiota may degenerate into a state of dysbiosis resulting in chronic inflammation (inflammaging) and reduced immune function (immunosenescence).

Fig 2

Vaginal versus caesarean-section delivery. The pioneer microbial colonizers acquired vertically from first contact are distinct but microbial succession converges to become more similar over the first years of life. This illustrates that gut microbiota evolves over time to establish a state of homeostasis wherein resident species are highly adapted for survival in the highly competitive gut microenvironment.

Fig 3

Functional networks link the function of microbes and support community stability and resilience. Functional networks in the gut are extensive and imply that targeted modulation of the gut microbiota may have unexpected impact on the viability of off-target species. Left: low interconnectivity may render gut communities prone to change as the result of relatively small perturbation. Right: highly interconnected networks may be more robust and resistant to change.

Fig 4

Microbial stability landscape. A theoretical depiction of gut species and their response to perturbation. In some instances, a small perturbation may lead to a large change in the fitness of that species with low resilience, whereas other species may be equally impacted by a similar perturbation but display high resilience.

Fig 5

Stratification of the gut epithelium. In a healthy gut environment (left panel), goblet cells secrete mucin to establish a physical barrier excluding direct contact of the gut microbiota from the underlying epithelium. Paneth cells produce a number of anti-microbial defensins that are embedded in the mucin layer. Dendritic cells extend into the lumen to sample the commensal communities potentially as a means of determining self. During pathological conditions (right panel), mucin barrier is compromised which facilitates microbial invasion through the epithelium and leads to inflammation.