Sarkis Mazmanian Lab - Caltech

2014

 
 

Microbes dominate as the most abundant life form on Earth, occupying almost every terrestrial, aquatic, and biological ecosystem on our planet. Humans are no exception. Throughout our lives, we continuously encounter and provide residence to microorganisms that range from those essential for health, to those causing death. The human body is permanently colonized by microbial organisms on virtually all environmentally exposed surfaces (Figure 1). The vast majority of these microbes are harbored in the gastrointestinal (GI) tract where commensal bacteria can outnumber host cells by 10-fold (thus, we are all 90% bacteria on a cellular level). Many vital host functions are provided by the microbiota, including the synthesis of vitamins, digestion of complex polysaccharides, maintenance of the intestinal epithelial barrier, and resistance to pathogen colonization. Millions of years of co-evolution have inextricably linked the health of mammals to their microbiota.


Reflecting a growing medical crisis in Western societies, recent epidemiologic and clinical reports have revealed dramatic increases in the incidences of several immune disorders: inflammatory bowel disease, asthma, type 1 diabetes, and multiple sclerosis. The hygiene hypothesis proposed two decades ago speculated that these increases are the result of lifestyle changes and medical advances that reduce exposure to microbial pathogens. Microbial infections are, in fact, rare and opportunistic. Recent studies have launched a revolution in biology aimed at understanding how (and, more importantly, why) mammals harbor multitudes of symbiotic bacteria.


Our laboratory demonstrated for the first time that specific gut bacteria direct the development of the mammalian immune system and confer protection from intestinal diseases; thus fundamental aspects of health are absolutely dependent on microbial symbiosis. Astonishingly, the disorders whose incidences are increasing in Western countries involve a common immunologic defect found in the absence of intestinal bacteria. After eons of co-evolution with our microbial partners, have societal advances (including sanitation, ‘western’ diets, and antibiotics) paradoxically affected human health adversely by reducing our exposure to health-promoting bacteria?

We propose that the human genome does not encode all functions required for health but rather that humans depend on crucial interactions with products of the microbiome (the collective genomes of our intestinal bacterial species). Advances in the past few years now make it possible to mine this untapped reservoir for beneficial microbial molecules. Using advanced genomic, microbiologic, immunologic methods and animal models, our goal is to define the molecular processes evolved by symbiotic bacteria that mediate protection from inflammatory and autoimmune diseases.

Our laboratory has recently initiated research to understand the intriguing connections between gut bacteria and behavioral and neurodegenerative disorders. Investigating how the microbiome regulates the gut-immune-brain axis may lead to novel therapies for enigmatic neurological diseases. An understanding of the beneficial immune and nerological responses promoted by symbiotic gut bacteria may lead to the development of natural therapeutics based on entirely novel biological principles.

 

We All Live In A Microbial World

Humans co-evolved with bacteria. There are three parts of the human that continue to evolve through-out one’s lifetime: the brain, the immune system and the microbiota. We study how these three constantly evolving parts interact and influence health and disease.