Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era

Abstract

Studies of metagenomics and the human microbiome will tremendously expand our knowledge of the composition of microbial communities in the human body. As our understanding of microbial variation and corresponding genetic parameters is refined, this information can be applied to rational remodeling or "tailoring" of human-associated microbial communities and their associated functions. Physiologic features such as the development of innate and adaptive immunity, relative susceptibilities to infections, immune tolerance, bioavailability of nutrients, and intestinal barrier function may be modified by changing the composition and functions of the microbial communities. The specialty of gastroenterology will be affected profoundly by the ability to modify the gastrointestinal microbiota through the rational deployment of antibiotics, probiotics, and prebiotics. Antibiotics might be used to remove or suppress undesirable components of the human microbiome. Probiotics can introduce missing microbial components with known beneficial functions for the human host. Prebiotics can enhance the proliferation of beneficial microbes or probiotics, to maximize sustainable changes in the human microbiome. Combinations of these approaches might provide synergistic and effective therapies for specific disorders. The human microbiome could be manipulated by such "smart" strategies to prevent and treat acute gastroenteritis, antibiotic-associated diarrhea and colitis, inflammatory bowel disease, irritable bowel syndrome, necrotizing enterocolitis, and a variety of other disorders.

Figure 1

The gut microbiome as a therapeutic target: the “drug the extended” genome strategy. Perturbed metagenomic or metabonomic profiles associated with complex disease states can be restored to homeostasis with rationally selected antibiotic, probiotic, prebiotic, or combination treatment strategies. Adapted with permission from Macmillan Publishers Ltd: Nature Reviews Drug Discovery, copyright 2008. http://www.nature.com/nrd/.

Figure 2

A super-organismal view of the human microbiome. Core and variable components of the human microbiome could have important implications for human health, including nutrient responsiveness, innate and adaptive immunity, and development. As the microbiome affects multiple aspects of human health and disease, host biology influences the composition and function of the commensal microbiota. A subset of microbial genes may be found in most healthy human beings (core microbiome), whereas variable components are present only in specific ethnic groups, age groups, geographic locations, or associated with specific dietary patterns or disease states. Manipulation of either the core or the variable parts of the human microbiome can affect human physiology, overall health status, and disease susceptibilities. Adapted with permission from Macmillan Publishers Ltd: Nature, copyright 2007. http://www.nature.com/nature/.

Figure 3

Microbial manipulation strategies and effects on intestinal biology. (A) The composition and aggregate functions of mixed microbial communities are dramatically altered by antibiotics. Various functions affected include gastrointestinal physiology and innate and adaptive immunity, resulting in increased host susceptibility to human disease. (B) Manipulation of the microbiota with rationally selected prebiotics or probiotics can inhibit pathogens, strengthen epithelial barrier function, and supply the host with key nutrients, including short-chain fatty acids (SCFAs) and vitamins. (C) Specific microbes modulate mucosal immunity by secreted factors and by direct interactions with immune cells and the intestinal epithelium. Anti-inflammatory responses are mediated by TGF-β production by epithelial cells and IL-10 from mononuclear cells. Immunostimulatory responses occur as a result of a wide variety of proinflammatory cytokines from stimulated epithelial cells, mononuclear cells, and lymphocytes, in addition to IgA production from B lymphocytes. FOS, fructo-oligosaccharides or oligo-fructose.

Figure 4

Selection of microbes for probiotics-based strategies. As emerging metagenomics approaches improve our understanding of the fundamental biology underlying probiosis, this knowledge will facilitate probiotic engineering and rational selection of natural strains to prevent and treat a variety of gastrointestinal diseases. Natural strains may be useful in functional foods, and recombinant probiotics might be used to target specific gastrointestinal disorders.