Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 15, Number 13, 2009

Contents

The Human Microbiome - A Therapeutic Target for Prevention and Treatment of Chronic Disease
Executive Editor: Kieran Tuohy


Editorial: Pp. 1401-1402


Microbiology of the Human Intestinal Tract and Approaches for Its Dietary Modulation Pp. 1403-1414
D.M. Saulnier, S. Kolida and G.R. Gibson
[Abstract] [Purchase Article] [PMID: 19442165 PubMed - indexed for MEDLINE]


Studying the Human Gut Microbiota in the Trans-Omics Era - Focus on Metagenomics and Metabonomics Pp. 1415-1427
K.M. Tuohy, C. Gougoulias, Q. Shen, G. Walton, F. Fava and P. Ramnani
[Abstract] [Purchase Article] [PMID: 19442166 PubMed - indexed for MEDLINE]


Probiotics, Immune Function, Infection and Inflammation: A Review of the Evidence from Studies Conducted in Humans Pp. 1428-1518
A.R. Lomax and P.C. Calder
[Abstract] [Purchase Article] [PMID: 19442167 PubMed - indexed for MEDLINE]


The Role of Gut Microbiota in Drug Response Pp. 1519-1523
I.D. Wilson and J.K. Nicholson
[Abstract] [Purchase Article] [PMID: 19442168 PubMed - indexed for MEDLINE]


The Role of the Gastrointestinal Microbiota in Colorectal Cancer Pp. 1524-1527
I.R. Rowland
[Abstract] [Purchase Article] [PMID: 19442169 PubMed - indexed for MEDLINE]


The Gut Microbiota in Inflammatory Bowel Disease Pp. 1528-1536
G.T. Macfarlane, K.L. Blackett, T. Nakayama, H. Steed and S. Macfarlane
[Abstract] [Purchase Article] [PMID: 19442170 PubMed - indexed for MEDLINE]


The Gut Microbiota as a Target for Improved Surgical Outcome and Improved Patient Care Pp. 1537-1545
J. Kinross, A.C. von Roon, N. Penney, E. Holmes, D. Silk, J.K. Nicholson and A. Darzi
[Abstract] [Purchase Article] [PMID: 19442171 PubMed - indexed for MEDLINE]


The Role of the Gut Microbiota in Energy Metabolism and Metabolic Disease Pp. 1546-1558
P.D. Cani and N.M. Delzenne
[Abstract] [Full Text Article] [PMID: 19442172 PubMed - indexed for MEDLINE]




Abstracts


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Editorial: The Human Microbiome - A Therapeutic Target for Prevention and Treatment of Chronic Disease

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.

Lomax and Calder [3] present a comprehensive and detailed review of human studies examining the efficacy of probiotic microorganisms in modulating immune function, protecting against infections and reducing inflammation. The authors concluded that although certain immune responses including phagocytosis, natural killer cell activity and mucosal immunoglobulin A secretion appear to be augmented by probiotics, other data are equivocal, and there appears to be much species and strain difference in terms of probiotic:immune system interactions.

Wilson and Nicholson [4] examining more closely the symbiotic relationship between humans and their gut microbiota have focused on microbiota mediated xenobiotic transformations in the colon, key processes effecting drug absorption and bioavailability as well as the hosts metabolic response to drug side-effects. They identify the individuality of the gut microbiota as a confounding factor in the development of personalised medicine highlighting the important role of extra-genomic environmental/microbiotal contributors to the human metabonome.

Rowland [5] examines both the adverse and beneficial consequences of bacterial activity within the gastrointestinal tract focusing in particular on the large bowel. He describes the involvement of the gut microbiota both in the production of carcinogens and in eliciting anti-carcinogenic activities, identifying the gut microbiota as a target for modulation using probiotics and prebiotics. Rowland also discusses the usefulness of metabonomics in identifying profiles of metabolites associated with increased cancer risk and the potential of cell based model systems for the development of relevant biomarkers of colon cancer risk.

Macfarlane et al. [6] describes the key role played by the gut microbiota in the initiation and maintenance of inflammatory bowel disease (IBD). With recent data showing that the microbiota (both faecal and mucosal) of IBD patients differs from that of healthy individuals, the authors discuss the potential of microbiota modulation and immune interactions using probiotics, prebiotics and synbiotics in controlling these diseases. Kinross et al. [7] focus on the perceived role of the gut microbiota in influencing post-operative outcome and highlight future avenues where the intestinal microbiome is likely to be increasingly important in the care of surgical patients. The authors illustrate clearly how metabonomics is proving an invaluable tool in studying the surgical microbiome and review studies using probiotics, prebiotics and synbiotics to improve patient care.

Cani and Delzenne [8] review recent data from metagenomics based studies highlighting the important role of the gut microbiota in human energy metabolism, obesity and the diseases of obesity. They discuss the impact of the gut microbiota on energy harvested from the diet, synthesis of gut peptides involved in energy homeostasis, regulation of fat storage and in providing the inflammatory trigger for the chronic low grade inflammation characteristic of the obese state. The authors go on to describe how prebiotics in particular are proving successful in reducing body weight and treating the diseases of obesity.

I would like to sincerely thank all the authors for their contributions which have given a comprehensive and detailed insight into the role of the gut microbiota in human health and disease.

References

[1] Saulnier DM, Kolida S, Gibson GR. Microbiology of the human intestinal tract and approaches for its dietary modulation. Curr Pharm Des 2009; 15(13): 1403-1414.

[2] Tuohy KM, Gougoulias C, Shen Q, Walton G, Fava F, Ramnani P. Studying the human gut microbiota in the trans-omics era – focus on metagenomics and metabonomics. Curr Pharm Des 2009; 15(13): 1415-1427.

[3] Lomax AR, Calder PC. Probiotics, immune function, infection and inflammation: a review of the evidence from studies conducted in humans. Curr Pharm Des 2009; 15(13): 1428-1518.

[4] Wilson ID, Nicholson JK.The role of gut microbiota in drug response. Curr Pharm Des 2009; 15(13): 1519-1523.

[5] Rowland IR. The role of the gastrointestinal microflora in colorectal cancer. Curr Pharm Des 2009; 15(13): 1524-1527.

[6] Macfarlane GT, Blackett KL, Nakayama T, Steed H, Macfarlane S. The gut microbiota in inflammatory bowel disease. Curr Pharm Des 2009; 15(13): 1528-1536.

[7] Kinross J, von Roon AC, Penney N, Holmes E, Silk D, Nicholson JK, Darzi A. The gut microbiota as a target for improved surgical outcome and improved patient care. Curr Pharm Des 2009; 15(13): 1537-1545.

[8] Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 2009; 15(13): 1546-1558.


Kieran Tuohy
Department of Food Biosciences
School of Chemistry, Food Biosciences and Pharmacy
The University of Reading
UK
E-mail: k.m.tuohy@reading.ac.uk


[Back to top] [Purchase Article] [PMID: 19442165 PubMed - indexed for MEDLINE]
Microbiology of the Human Intestinal Tract and Approaches for Its Dietary Modulation
D.M. Saulnier, S. Kolida and G.R. Gibson

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.


[Back to top] [Purchase Article] [PMID: 19442166 PubMed - indexed for MEDLINE]
Studying the Human Gut Microbiota in the Trans-Omics Era - Focus on Metagenomics and Metabonomics
K.M. Tuohy, C. Gougoulias, Q. Shen, G. Walton, F. Fava and P. Ramnani

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 “trans-genomic” 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.


[Back to top] [Purchase Article] [PMID: 19442167 PubMed - indexed for MEDLINE]
Probiotics, Immune Function, Infection and Inflammation: A Review of the Evidence from Studies Conducted in Humans
A.R. Lomax and P.C. Calder

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 pro-liferation, 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.


[Back to top] [Purchase Article] [PMID: 19442168 PubMed - indexed for MEDLINE]
The Role of Gut Microbiota in Drug Response
I.D. Wilson and J.K. Nicholson

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.


[Back to top] [Purchase Article] [PMID: 19442169 PubMed - indexed for MEDLINE]
The Role of the Gastrointestinal Microbiota in Colorectal Cancer
I.R. Rowland

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.


[Back to top] [Purchase Article] [PMID: 19442170 PubMed - indexed for MEDLINE]
The Gut Microbiota in Inflammatory Bowel Disease
G.T. Macfarlane, K.L. Blackett, T. Nakayama, H. Steed and S. Macfarlane

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.


[Back to top] [Purchase Article] [PMID: 19442171 PubMed - indexed for MEDLINE]
The Gut Microbiota as a Target for Improved Surgical Outcome and Improved Patient Care
J. Kinross, A.C. von Roon, N. Penney, E. Holmes, D. Silk, J.K. Nicholson and A. Darzi

The ‘gut origin of sepsis’ concept describes the role of the intestine in the development of sepsis and the post-operative 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.


[Back to top] [Full Text Article] [PMID: 19442172 PubMed - indexed for MEDLINE]
The Role of the Gut Microbiota in Energy Metabolism and Metabolic Disease
P.D. Cani and N.M. Delzenne

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.