Very interesting paper. The significance is very well summarized at the end of the paper
According to the 'hygiene hypothesis' put forth nearly two decades ago, reduced exposure to infections in early childhood—owing to diminishing family size and improvements in living standards and personal hygiene, for example—may increase the risk of allergic and autoimmune disease34. This concept is supported by epidemiological and clinical reports documenting increased incidences of IBD, colon cancer, asthma, type 1 diabetes and multiple sclerosis over the past 50 years in societies with improved medical care and hygiene (for example, Europe, the United States and Japan) but not in undeveloped countries35. However, the application of major interventions, including vaccination, sanitation, and antibacterial and antiviral therapies, often does not permit discrimination between infectious and non-infectious microorganisms and has undoubtedly led to changes in human association with the microbial world as a whole. The hygiene hypothesis does not address humanity's primary relationship with bacteria: the harbouring of multitudes of microbial species during commensalism. Our studies show that symbiotic bacteria residing in the mammalian gastrointestinal tract produce molecules that mediate healthy immune responses and protect the host from inflammatory disease. We propose that the mammalian genome does not encode for all functions required for immunological development but rather that mammals depend on critical interactions with their microbiome (the collective genomes of the microbiota) for health.
As mammals have harboured their commensal partners for millennia, adaptive co-evolution has formed an inextricable bond between microbe and host36. Imbalances in the microbiota may contribute to some human diseases, and altered composition of the gut bacteria has been implicated in obesity37. We show that B. fragilis protects its host from inflammatory disease caused by H. hepaticus in an animal model of experimental colitis. The implication that intestinal bacteria actively network with the host's immune system highlights the importance of the composition of the microbiota for overall health. If specific classes of bacteria have indeed evolved to promote the host's health, then disease may well result from the absence of these organisms and their beneficial molecules (for example, as a result of improved hygiene). Inflammation resulting from dysbiosis between symbionts and pathobionts may lay the molecular foundations for many intestinal—and perhaps non-intestinal—diseases. The exploration of probiotics (bacteria such as lactobacilli and bifidobacteria that promote health) has thus far failed to identify specific bacterial molecules or host mechanisms required for protection38. Here we present evidence that a single bacterial molecule can ameliorate inflammatory disease in animals. Our observations suggest that many other symbiosis factors—bacterial molecules that have evolved to promote human health—remain to be discovered. The finding that PSA from B. fragilis is a natural anti-inflammatory molecule that actively promotes mammalian health may provide a platform for the development of therapies based on the fundamental relationship between humans and their beneficial microbial partners.
F1000 reviews are pretty good as well.
Victor Nizet
University of California, San Diego, United States of America
MICROBIOLOGYThis elegant paper demonstrates how a member of the normal colonic microflora can regulate the cellular immune responses to a potential pathogen, thereby limiting inflammatory damage. Through detailed in vitro and in vivo analysis, the authors show the immunomodulatory effect is mediated through a single, unique polysaccharide antigen (PSA) of the commensal Bacteroides fragilis, which stimulates CD4+ T cell responses that produce the immunosuppressive cytokine interleukin-10. The manuscript reveals novel biological principles regarding the regulation of cellular immunity and mucosal inflammation, and provides proof of principle for a novel therapeutic strategy for inflammatory diseases -- namely, harnessing the natural immunomodulatory activities of PSA. No doubt this principle will be extended in the future to other bioactive molecules expressed by our normal microflora.
Christopher Thanos
Catalyst Biosciences, United States of America
CHEMICAL BIOLOGYTrust your gut: are we reliant on intestinal microbes to protect us from inflammatory disease? The authors show that symbiotic bacteria, which reside in the mammalian gut, secrete molecules that protect the host from inflammatory disease. In an elegant set of well controlled experiments, the authors demonstrated that polysaccharide A (PSA), from B.fragilis, protected mice from H.hepaticus mediated experimental colitis. The authors' work supports their theory that the mammalian genome alone does not fully encode all factors necessary for complete development of the immune system. Rather, the authors suggest that for proper health, we are reliant on our bacterial "partners" growing inside our gut. This work may spark new research in the development of therapeutics derived from commensal bacteria.
Here is the paper abstract:
Nature. 2008 May 29;453(7195):620-5.
A microbial symbiosis factor prevents intestinal inflammatory disease.Mazmanian SK, Round JL, Kasper DL.
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA. sarkis@caltech.edu
Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.
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