Non-digestible food ingredients, colonic microbiota and the impact on gut health and immunity: a role for metabolomics.

Increasing health issues related to immune and gut function such as inflammatory disorders, resistance to infections and metabolic syndrome demand modern analytical approaches to accelerate nutritional research aimed at health promotion and disease prevention. Gut microbial-human mutualism endows the host 'superorganism' with a fitness advantage including nutritional, immune and intestinal health aspects. The gut microbiome enlarges our genome and enhances our metabolic potential. Dietary modulation can significantly alter the microbiota community and metabolic activity, and consequently impacts on nutrient bioavailability and host metabolism. Although in an early stage, microbial metabolites generated during colonic fermentation of food stuffs may have beneficial or deleterious effects on intestinal health and immunity, as summarized in this review. However, current evidence is largely based on in vitro and animal studies while substantiation in humans is lacking. The challenge to establish coherent links between the bioconversion of non-digestible food ingredients, their bioavailability and their downstream effects on the host metabolism may be achieved by metabolomics. In this review, metabolomics studies focusing on microbe-host mutualism have demonstrated that metabolomics is capable of detecting and tracking diverse microbial metabolites from different non-digestible food ingredients, of discriminating between phenotypes with different inherent microbiota and of potentially diagnosing infection and gastrointestinal diseases. Integrative approaches such as the combined analysis of the metabolome in different biofluids together with other -omics technologies will cover exogenous and endogenous effects and hence show promise to generate novel hypotheses for innovative functional foods impacting gut health and immunity.

[Physiological role of mucins in the colonic barrier integrity]. / Rôles physiologiques des mucines dans la barrière colique.

Colonic mucus is a key element of colonic barrier as it is located at the frontier between luminal microflora and colonic mucosa itself. Colonic mucus is mainly composed of high molecular weight glycoproteins called mucins that can be either secreted or membrane-linked. The expression of various colonic mucins is altered in colorectal cancers or inflammations. The aim of this review is to highlight the crucial role played by colonic mucins in the maintenance of colonic barrier integrity, both because they are part of the protective mucus layer, and because they individually exert specific functions involved in epithelial barrier, like cell growth and differentiation, immunomodulation, signal transduction or cell adhesion.

Environmental enteropathy: new targets for nutritional interventions.

In the developing world major public health issues such as malnutrition and compromised physical development are intimately linked to altered gut morphology and function with underlying chronic inflammatory responses. In these societies the downward spiral of malnutrition and infections does not seem to be remedied by well-informed nutritional interventions that supplement the identified nutrient deficiencies, suggesting that additional strategies are needed. The aim of this scientific opinion paper is to consider how a child from the developing world might benefit, separately and additively, from interventions targeted to impact hygiene, nutritional status, disease resistance and gut function, if successful interventions could be found. A failure to tackle environmental enteropathy (EE) may be a critical limiting factor that can explain the relative lack of success of interventions focussed on micronutrient supplementation so far. Therefore this paper starts with a summary of the aetiology and consequences of EE on child health and the current recommendations aimed at tackling this problem. Then a number of hypotheses will be considered in terms of research strategy to positively affect nutritional status, intestinal health and growth of children with EE, with the aim of inspiring future innovative strategies, for both the food industry and the public health sector, which could benefit millions of children.

Responders and non-responders to probiotic interventions: how can we improve the odds?

As with many clinical studies, trials using probiotics have shown clearly that some patients benefit from the treatment while others do not. For example if treatment with probiotics leads to 36% cure rate of diarrhea, why did the other 64% not have the same result? The issue is important for human and indeed experimental animal studies for two main reasons: (i) Would changing the design of the study result in more subjects responding to treatment? (ii) If a subject does not respond what are the mechanistic reasons? In order to tackle the issue of responders and non-responders to therapy, a workshop was held by the International Scientific Association for Probiotics and Prebiotics (ISAPP). The outcome was four recommendations. 1. Clearly define the end goal: this could be supporting a health claim or having the highest clinical effect and impact. 2. Design the study to maximize the chance of a positive response by identifying precise parameters and defining the level of response that will be tested. 3. Base the selection of the intervention on scientific investigations: which strain(s) and/or product formulation should be used and why. 4. Carefully select the study cohort: use biological or genetic markers when available to stratify the patient population before enrollment and decide at what point intervention will provide the best outcome (for example, in acute phase of disease, or during remission, with or without use of pharmaceutical agents). By following these recommendations and selecting an appropriate primary outcome, it is hoped that clinical data will emerge in the future that expands our knowledge of which probiotics benefits which subjects and by what mechanism.

The VSL# 3 probiotic mixture modifies microflora but does not heal chronic dextran-sodium sulfate-induced colitis or reinforce the mucus barrier in mice.

The mucus layer covering the epithelium is one of the main lines of defense of the colonic barrier. Both mucus gel and mucin expressions are altered during colonic inflammation and could be involved in epithelial repair. We postulated that modulating colonic mucus and mucins by probiotic supplementation could contribute to healing inflammatory mucosa. Our aim in this study was to determine whether probiotics could repair dextran-sodium sulfate (DSS)-induced chronic colitis in mice, and whether modifications of the colonic mucins could be involved. For that purpose, the VSL#3 probiotic mixture of 8 lactic acid bacteria probiotic strains was administered daily for 2 wk to mice with a mucosa impaired by a mild DSS treatment, and to mice with a normal mucosa. Probiotic strains survived in the gastrointestinal tract, increased the cecal concentrations of bifidobacteria, and modified cecal microflora metabolic activity in both DSS-treated and healthy mice. However, probiotic supplementation did not reverse the inflammation induced by DSS at either the macroscopic or histological level. Concurrently, probiotics did not modify the colonic mucus barrier, in terms of either mucin gene expression or adherent mucus layer thickness. In conclusion, the modification of microflora by supplementation with the VSL#3 probiotic mixture did not help to repair the colonic barrier breakdown caused by DSS treatment. The potential healing roles of mucins were neither confirmed nor invalidated by this study.

Butyrate regulation of glycosylation-related gene expression: evidence for galectin-1 upregulation in human intestinal epithelial goblet cells.

Glycosylation of mucins produced by human intestinal goblet cells plays a crucial role in their functions: mucus gel physico-chemical protective properties, host-bacteria interactions, cell-cell adhesion, cell migration, and cell signaling. Colonic mucin glycosylation can be modified by luminal metabolites of fiber fermentation like butyrate. Our aim was to assess the effect of butyrate on the expression of a large panel of glycosylation-related genes in human intestinal epithelial goblet cells HT29-Cl.16E. We found that only a very scarce group of genes: 9 out of 252 were evidenced by microarray screening, and only three had their modulation significantly confirmed by real time PCR quantification. The most striking effect of butyrate was its 8- to 18-fold increase of galectin-1 gene expression, which was confirmed at the protein level, specifically with a central and apical intracellular localization. Significant butyrate effects will be discussed in regard to their possible link with mucins expressed by HT29-Cl.16E cells.