The influence of diet on the gut microbiota.

Summary:  The gut‐associated lymphoid tissue is the largest immune organ in the body and is the primary route by which we are exposed to antigens. Tolerance induction is the default immune pathway in the gut, and the type of tolerance induced relates to the dose of antigen fed: anergy/deletion (high dose) or regulatory T‐cell (Treg) induction (low dose). Conditioning of gut dendritic cells (DCs) by gut epithelial cells and the gut flora, which itself has a major influence on gut immunity, induces CD103+ retinoic acid‐dependent DC that induces Tregs. A number of Tregs are induced at mucosal surfaces. Th3 type Tregs are transforming growth factor‐β dependent and express latency‐associated peptide (LAP) on their surface and were discovered in the context of oral tolerance. Tr1 type Tregs (interleukin‐10 dependent) are induced by nasal antigen and forkhead box protein 3+ iTregs are induced by oral antigen and by oral administration of aryl hydrocarbon receptor ligands. Oral or nasal antigen ameliorates autoimmune and inflammatory diseases in animal models by inducing Tregs. Furthermore, anti‐CD3 monoclonal antibody is active at mucosal surfaces and oral or nasal anti‐CD3 monoclonal antibody induces LAP+ Tregs that suppresses animal models (experimental autoimmune encephalitis, type 1 and type 2 diabetes, lupus, arthritis, atherosclerosis) and is being tested in humans. Although there is a large literature on treatment of animal models by mucosal tolerance and some positive results in humans, this approach has yet to be translated to the clinic. The successful translation will require defining responsive patient populations, validating biomarkers to measure immunologic effects, and using combination therapy and immune adjuvants to enhance Treg induction. A major avenue being investigated for the treatment of autoimmunity is the induction of Tregs and mucosal tolerance represents a non‐toxic, physiologic approach to reach this goal.

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Oral tolerance: Basic mechanisms and applications of oral tolerance

Growth kinetics, i.e., the relationship between specific growth rate and the concentration of a substrate, is one of the basic tools in microbiology. However, despite more than half a century of research, many fundamental questions about the validity and application of growth kinetics as observed in the laboratory to environmental growth conditions are still unanswered. For pure cultures growing with single substrates, enormous inconsistencies exist in the growth kinetic data reported. The low quality of experimental data has so far hampered the comparison and validation of the different growth models proposed, and only recently have data collected from nutrient-controlled chemostat cultures allowed us to compare different kinetic models on a statistical basis. The problems are mainly due to (i) the analytical difficulty in measuring substrates at growth-controlling concentrations and (ii) the fact that during a kinetic experiment, particularly in batch systems, microorganisms alter their kinetic properties because of adaptation to the changing environment. For example, for Escherichia coli growing with glucose, a physiological long-term adaptation results in a change in KS for glucose from some 5 mg liter−1 to ca. 30 μg liter−1. The data suggest that a dilemma exists, namely, that either “intrinsic” KS (under substrate-controlled conditions in chemostat culture) or μmax (under substrate-excess conditions in batch culture) can be measured but both cannot be determined at the same time. The above-described conventional growth kinetics derived from single-substrate-controlled laboratory experiments have invariably been used for describing both growth and substrate utilization in ecosystems. However, in nature, microbial cells are exposed to a wide spectrum of potential substrates, many of which they utilize simultaneously (in particular carbon sources). The kinetic data available to date for growth of pure cultures in carbon-controlled continuous culture with defined mixtures of two or more carbon sources (including pollutants) clearly demonstrate that simultaneous utilization results in lowered residual steady-state concentrations of all substrates. This should result in a competitive advantage of a cell capable of mixed-substrate growth because it can grow much faster at low substrate concentrations than one would expect from single-substrate kinetics. Additionally, the relevance of the kinetic principles obtained from defined culture systems with single, mixed, or multicomponent substrates to the kinetics of pollutant degradation as it occurs in the presence of alternative carbon sources in complex environmental systems is discussed. The presented overview indicates that many of the environmentally relevant apects in growth kinetics are still waiting to be discovered, established, and exploited.

Growth Kinetics of Suspended Microbial Cells: From Single-Substrate-Controlled Growth to Mixed-Substrate Kinetics

Accumulating epidemiologic evidence indicates that high consumption of red meat and of processed meat may increase the risk of colorectal cancer. We quantitatively assessed the association between red meat and processed meat consumption and the risk of colorectal cancer in a meta-analysis of prospective studies published through March 2006. Random-effects models were used to pool study results and to assess dose-response relationships. We identified 15 prospective studies on red meat (involving 7,367 cases) and 14 prospective studies on processed meat consumption (7,903 cases). The summary relative risks (RRs) of colorectal cancer for the highest vs. the lowest intake categories were 1.28 (95% confidence interval (CI) = 1.15-1.42) for red meat and 1.20 (95% CI = 1.11-1.31) for processed meat. The estimated summary RRs were 1.28 (95% CI = 1.18-1.39) for an increase of 120 g/day of red meat and 1.09 (95% CI = 1.05-1.13) for an increase of 30 g/day of processed meat. Consumption of red meat and processed meat was positively associated with risk of both colon and rectal cancer, although the association with red meat appeared to be stronger for rectal cancer. In 3 studies that reported results for subsites in the colon, high consumption of processed meat was associated with an increased risk of distal colon cancer but not of proximal colon cancer. The results of this meta-analysis of prospective studies support the hypothesis that high consumption of red meat and of processed meat is associated with an increased risk of colorectal cancer.

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Meat consumption and risk of colorectal cancer: a meta-analysis of prospective studies.

The gastrointestinal microbiota as a site for the biotransformation of drugs

In both health and disease, the colonic microbiota plays an important role in several areas of human physiology. This complex assemblage of microorganisms endows great metabolic potential on the large intestine, primarily through its degradative abilities. Many hundreds of different types of bacteria, varying widely in physiology and biochemistry, exist in a multitude of different microhabitats in the lumen of the large gut, the mucin layer and on mucosal surfaces. Both microbiota and host obtain clear benefits from association. For example, growth substrates from diet and body tissues, together with a relatively stable environment for bacteria to proliferate are provided by the host, which in turn has evolved to use butyrate, a bacterial fermentation product, as its principal source of energy for epithelial cells in the distal bowel. The main sources of carbon and energy for intestinal bacteria are complex carbohydrates (starches, non-starch polysaccharides). Carbohydrate metabolism is of great importance in the large intestine, since generically, and in terms of absolute numbers, the vast majority of culturable microorganisms are saccharolytic. The amounts and types of fermentation products formed by colonic bacteria depend on the relative amounts of each substrate available, their chemical structures and compositions, as well as the fermentation strategies (biochemical characteristics and catabolite regulatory mechanisms) of bacteria participating in depolymerization and fermentation of the substrates. Protein breakdown and dissimilatory amino acid metabolism result in the formation of a number of putatively toxic metabolites, including phenols, indoles and amines. Production of these substances is inhibited or repressed in many intestinal microorganisms by a fermentable source of carbohydrate. Owing to the anatomy and physiology of the colon, putrefactive processes become quantitatively more important in the distal bowel, where carbohydrate is more limiting.

S. Macfarlane

Papers

Human colonic microbiota: ecology, physiology and metabolic potential of intestinal bacteria.