Gut microbiome-host interactions in health and disease

Kinross et al. Genome Medicine 2011, 3:14 http://genomemedicine.com/content/3/3/14 REVIEW Gut microbiome-host interactions in health and disease James M Kinross1, Ara W Darzi1 and Jeremy K Nicholson*2 Abstract The gut microbiome is the term given to describe the vast collection of symbiotic microorganisms in the human gastrointestinal system and their collective interacting genomes. Recent studies have suggested that the gut microbiome performs numerous important biochemical functions for the host, and disorders of the microbiome are associated with many and diverse human disease processes. Systems biology approaches based on next generation ‘omics’ technologies are now able to describe the gut microbiome at a detailed genetic and functional (transcriptomic, proteomic and metabolic) level, providing new insights into the importance of the gut microbiome in human health, and they are able to map microbiome variability between species, individuals and populations. This has established the importance of the gut microbiome in the disease pathogenesis for numerous systemic disease states, such as obesity and cardiovascular disease, and in intestinal conditions, such as inflammatory bowel disease. Thus, understanding microbiome activity is essential to the development of future personalized strategies of healthcare, as well as potentially providing new targets for drug development. Here, we review recent metagenomic and metabonomic approaches that have enabled advances in understanding gut microbiome activity in relation to human health, and gut microbial modulation for the treatment of disease. We also describe possible avenues of research in this rapidly growing field with respect to future personalized healthcare strategies. *Correspondence: 2 Section of Bimolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, The Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK Full list of author information is available at the end of the article © 2010 BioMed Central Ltd © 2011 BioMed Central Ltd The medical importance of the human microbiome The human intestine carries a vast and diverse microbial ecosystem that has co-evolved with our species and is essential for human health [1,2]. Mammals possess an ‘extended genome’ of millions of microbial genes located in the intestine: the microbiome [3]. This multigenomic symbiosis is expressed at the proteomic and metabolic levels in the host and it has therefore been proposed that humans represent a vastly complex biological ‘superorganism’ in which part of the responsibility for host metabolic regulation is devolved to the microbial symbionts [4]. Modern interpretation of the gut microbiome is based on a culture-independent, molecular view of the intestine provided by high-throughput genomic screening technologies [5,6]. Also, the gut microbiome has been directly implicated in the etiopathogenesis of a number of pathological states as diverse as obesity [7], circulatory disease [8], inflammatory bowel diseases (IBDs) [9] and autism [10] (Figure 1). The gut microbiota also influence drug metabolism and toxicity [11], dietary calorific bioavailability [12], immune system conditioning and response [13], and post-surgical recovery [14]. The implication is that quantitative analysis of the gut microbiome and its activities is essential for the generation of future personalized healthcare strategies [15] and that the gut microbiome represents a fertile ground for the development of the next generation of therapeutic drug targets. It also implies that the gut microbiome may be directly modulated for the benefit of the host organism. The gut microbiota therefore perform a large number of important roles that define the physiology of the host, such as immune system maturation [16], the intestinal response to epithelial cell injury [17], and xenobiotic [18] and energy metabolism [7]. In most mammals, the gut microbiome is dominated by four bacterial phyla that perform these tasks: Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria [19]. The phylotype composition can be specific and stable in an individual [20], and in a 2-year interval an individual conserves over 60% of phylotypes of the gut microbiome [21]. This implies that each host has a unique biological relationship with its gut microbiota [22,23], and by definition that this influences an individual’s risk of disease. The gut microbiome varies Kinross et al. Genome Medicine 2011, 3:14 http://genomemedicine.com/content/3/3/14 Page 2 of 12 Gut-brain hypothesis 1. Autism C. bolteae / clostridia spores Mechanism unkown 2. Mood: depression, anxiety Asthma / atopy Hygiene hypothesis: Exagerrated innate immune response Upregulation of regulatory T cells after capture of Ags by DCs Bifidobacteria, Gram +ve organisms Clostridia Diet high in red meat and animal fat Low SCFA / butyrate High fecal fats Low vitamin absorption  7α dehydroxylating bacteria: Colon cancer cholic aciddeoxycholic acid (co-carcinogen) Low in H2S metabolizing bacteria Hypertension / ischemic heart disease Biliary disease Altered enterohepatic circulation of bile Altered xenobiotic / drug metabolism e.g. Paracetamol metabolism:  predose urinary p-cresol sulfate leads to  postdose urinary acetaminophen sulfate : acetaminophen glucuronide. Bacterially mediated p-cresol generation and competitive o-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Obesity / metabolic syndrome Bacteroidetes and Actinobacteria in obese Peripheral vascular disease Altered energy / lipid metabolism Higher relative abundance of glycoside hydrolases, carbohydrate-binding modules, glycosyltransferases, polysaccharide lyases, and carbohydrate esterases in the Bacteroidetes TLR mediated Result of metabolic syndrome Altered lipid deposition / metabolism Inflammatory bowel disease Hygiene hypothesis Altered immune response: TLR signaling Less microbial diversity Activation of specific species: for example, Escherichia Figure 1. Diseases influenced by gut microbial metabolism. The variety of systemic diseases that are directly influenced by gut microbial metabolism and its influence on other mammalian pathways, such as the innate immune system, are shown. Specifically highlighted are the metabolic pathways involved in drug metabolism and obesity that are directly influenced by the gut microbial content. Ags, antigens; C. bolteae, Clostridium bolteae; DCs; dendritic cells; SCFA, short-chain fatty acid; TLR, Toll-like receptor. between species and, as a result, in vivo models utilizing gnotobiotic rodents or pigs conventionalized with human baby flora (HBF) have been adopted to permit more accurate modeling of the human gut [24]. Future experimental models must also accurately replicate the metabolic function of the gut microbiome [25]. For this to occur, the ‘healthy’ intestinal microbiome must first be understood; (...truncated)