Current Pharmaceutical Design - Volume 15, Issue 13, 2009

Each one of us exists in close symbiosis with a diverse and unique collection of microorganisms comprising the human microbiome. The colonic microbiota, representing the greater part of this microbiome, differs in species composition and relative population levels between individuals imparting great metabolic variability in the way our bodies respond to biologically active compounds which escape digestion or are shunted into the colon via bile secretions. Our microbial partners have co-evolved alongside humankind over the millennia, and are intimately involved in human health and disease. Recently there has been an upsurge of interest in gut microbiology, driven in part by ground breaking research employing metabonomic and metagenomic technologies which are providing novel and dramatic insights into the functioning of the gut microbiota, its interactions with human diet and xenobiotic metabolism, and in its interactions with host physiology and disease states. This issue of Current Pharmaceutical Design comprises a series of reviews by leading opinion formers, which present current understanding of the human microbiome, its role in chronic human disease, and which identify the gut microbiota as a putative therapeutic target discussing dietary means of modulating its activities. Saulnier et al. [1] describe in great detail the dichotomous nature of the human gut microbiota, at once being beneficial and essential for human wellbeing, as well as possessing the capacity to cause human disease. The authors go on to discuss how through dietary supplementation using probiotics, prebiotics and synbiotics, this balance between health promoting and deleterious activities may be modulated to improve host health. Putting probiotics, prebiotics and synbiotics into an historical and current market perspective, the authors provide a useful introduction to the proposed mechanisms underpinning these microbiota modulatory dietary tools and set the scene for concepts re-visited by others in this current issue. The authors also present a summary of culture independent molecular microbiological tools now being used to study the gut microbiota. This theme is taken up and expanded in Tuohy et al. [2], where we describe the recent application of metagenomics and metabonomics to study the human gut microbiota. Here, the notion of our co-evolved gut microbiota and its interaction with human diets past and present is discussed against the back-drop of high resolution “-omics” based techniques and the challenges facing gut microbial ecology in assigning biological function to novel gut bacteria, the vast majority of which resist cultivation under laboratory conditions.

Gut bacteria can be categorised as being either beneficial or potentially pathogenic due to their metabolic activities and fermentation end-products. Health-promoting effects of the microflora may include immunostimulation, improved digestion and absorption, vitamin synthesis, inhibition of the growth of potential pathogens and lowering of gas distension. Detrimental effects are carcinogen production, intestinal putrefaction, toxin production, diarrhoea/constipation and intestinal infections. Certain indigenous bacteria such as bifidobacteria and lactobacilli are considered to be examples of health-promoting constituents of the microflora. They may aid digestion of lactose in lactose-intolerant individuals, reduce diarrhoea, help resist infections and assist in inflammatory conditions. Probiotics, prebiotics and synbiotics are functional foods that fortify the lactate producing microflora of the human or animal gut.

The human gut microbiota comprises a diverse microbial consortium closely co-evolved with the human genome and diet. The importance of the gut microbiota in regulating human health and disease has however been largely overlooked due to the inaccessibility of the intestinal habitat, the complexity of the gut microbiota itself and the fact that many of its members resist cultivation and are in fact new to science. However, with the emergence of 16S rRNA molecular tools and “post-genomics” high resolution technologies for examining microorganisms as they occur in nature without the need for prior laboratory culture, this limited view of the gut microbiota is rapidly changing. This review will discuss the application of molecular microbiological tools to study the human gut microbiota in a culture independent manner. Genomics or metagenomics approaches have a tremendous capability to generate compositional data and to measure the metabolic potential encoded by the combined genomes of the gut microbiota. Another post-genomics approach, metabonomics, has the capacity to measure the metabolic kinetic or flux of metabolites through an ecosystem at a particular point in time or over a time course. Metabonomics thus derives data on the function of the gut microbiota in situ and how it responds to different environmental stimuli e.g. substrates like prebiotics, antibiotics and other drugs and in response to disease. Recently these two culture independent, high resolution approaches have been combined into a single “transgenomic” approach which allows correlation of changes in metabolite profiles within human biofluids with microbiota compositional metagenomic data. Such approaches are providing novel insight into the composition, function and evolution of our gut microbiota.

A number of studies have been performed examining the influence of various probiotic organisms, either alone or in combination, on immune parameters, infectious outcomes, and inflammatory conditions in humans. Some components of the immune response, including phagocytosis, natural killer cell activity and mucosal immunoglobulin A production (especially in children), can be improved by some probiotic bacteria. Other components, including lymphocyte proliferation, the production of cytokines and of antibodies other than immunoglobulin A appear less sensitive to probiotics. Probiotics, including lactobacilli and bifidobacteria, administered to children can reduce incidence and duration of diarrhoea, but the precise effects depend upon the nature of the condition. Probiotic supplementation can reduce the risk of travellers' diarrhoea in adults, but does not affect duration. The effect of probiotics on other infectious outcomes is less clear. Probiotics may benefit children and adults with irritable bowel syndrome and adults with ulcerative colitis; studies in Crohn's Disease are less clear. Probiotics have little effect in rheumatoid arthritis. Probiotic supplementation, especially with lactobacilli and bifidobacteria, can reduce risk and severity of allergic disease, particular atopic dermatitis; early supplementation appears to be effective. Overall, the picture that emerges from studies of probiotics on immune, infectious and inflammatory outcomes in humans is mixed and there appear to be large species and strain differences in effects seen. Other reasons for differences in effects seen will include dose of probiotic organism used, duration of supplementation, characteristics of the subjects studied, sample size, and technical differences in how the measurements were made.

Higher organisms such as mammals exist in a symbiotic relationship with their gut microbiota, formed from a diverse and highly metabolically active consortium of species. The gut microbiota, in addition to their ability to process dietary derived material, are also capable of performing a range of biotransformations on xenobiotics, such as drugs and their metabolites, in ways that can affect absorption and bioavailability. The potential for the gut microflora to influence drug metabolism and toxicity in unexpected ways is discussed.

Both environmental and genetic factors contribute to cancers of the gastrointestinal tract including, the stomach, colon and rectum. The mechanisms associated with gastrointestinal cancer causation and prevention are largely unknown and the subject of much research. Many of the proposed mechanisms implicate the metabolic activities of the bacterial biota normally resident in the gastrointestinal tract. This review examines both the adverse and beneficial consequences of bacterial activity of the gastrointestinal tract focusing, in particularly on the stomach and large intestine. Studies on the role of the bacterial biota in colon carcinogenesis have also resulted in several useful biomarkers for use in human.

Crohn's disease and ulcerative colitis are the two principal forms of inflammatory bowel disease (IBD). The root causes of these chronic and acute immunological disorders are unclear, but intestinal microorganisms are known to play a key role in the initiation and maintenance of disease. However, at present, there is no clear evidence for a single transmissible agent being involved in IBD aetiology. Although marked alterations occur in faecal and mucosal bacterial communities in IBD, it is unclear whether they are responsible for causing disease, or are due to changes in the gut environment that result from inflammatory reactions and extensive tissue destruction. Despite the involvement of microorganisms in inflammatory processes, antibiotic therapy has generally been unsuccessful in IBD. However, recent studies involving the use of probiotics, prebiotics and synbiotics suggest that there is potential for controlling these diseases through manipulation of the composition of the gut microbiota, and direct interactions with the gut immune system.

The ‘gut origin of sepsis’ concept describes the role of the intestine in the development of sepsis and the postoperative Multi Organ Dysfunction Syndrome (MODS). Translocation of the microbiota from the gut into the systemic milieu is thought to be integral to this process. However, advances in molecular biology have demonstrated numerous mechanisms of interkingdom signalling within the gut and evidence suggests that the gut microbiota may directly influence the mammalian phenotype. The gut ecosystem fluctuates significantly in response to exogenous and surgical trauma yet until recently it has not been possible to study this non invasively and thus it is not known how current perioperative infection control strategies influence the microbiome and the consequences of this intervention for the host. However, novel analytical techniques such as metabonomics and metagenomics are permitting the in vivo analysis of the gut microbiome and are creating new avenues of research that have significant surgical applications. Furthermore, the protective mechanisms of commensal biota are increasingly being recognised, suggesting that perioperative modulation of the gut microbiome with pre, pro and synbiotics may beneficially influence surgical outcome. This paper reviews the role of the gut microbiome in determining surgical outcome, and highlights research into the mammalian microbial symbiotic axis which is leading to novel therapeutic interventions in surgery.

Obesity is now classically characterized by a cluster of several metabolic disorders, and by a low grade inflammation. The evidence that the gut microbiota composition can be different between healthy and or obese and type 2 diabetic patients has led to the study of this environmental factor as a key link between the pathophysiology of metabolic diseases and the gut microbiota. Several mechanisms are proposed linking events occurring in the colon and the regulation of energy metabolism, such as i.e. the energy harvest from the diet, the synthesis of gut peptides involved in energy homeostasis (GLP-1, PYY…), and the regulation of fat storage. Moreover, the development of obesity and metabolic disorders following a high-fat diet may be associated to the innate immune system. Indeed, high-fat diet feeding triggers the development of obesity, inflammation, insulin resistance, type 2 diabetes and atherosclerosis by mechanisms dependent of the LPS and/or the fatty acids activation of the CD14/TLR4 receptor complex. Importantly, fat feeding is also associated with the development of metabolic endotoxemia in human subjects and participates in the low-grade inflammation, a mechanism associated with the development of atherogenic markers. Finally, data obtained in experimental models and human subjects are in favour of the fact that changing the gut microbiota (with prebiotics and/or probiotics) may participate in the control of the development of metabolic diseases associated with obesity. Thus, it would be useful to find specific strategies for modifying gut microbiota to impact on the occurrence of metabolic diseases.