A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals.

BACKGROUND: The gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Intérieur Consortium, a total of 1000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20-69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. RESULTS: Among 110 demographic, clinical, and environmental factors, 11 were identified as significantly correlated with α-diversity, ß-diversity, or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between > 5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. CONCLUSION: In a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01699893

EVOLUTION OF ANTIGEN BINDING RECEPTORS

This review addresses issues related to the evolution of the complex multigene families of antigen binding receptors that function in adaptive immunity. Advances in molecular genetic technology now permit the study of immunoglobulin (Ig) and T cell receptor (TCR) genes in many species that are not commonly studied yet represent critical branch points in vertebrate phylogeny. Both Ig and TCR genes have been defined in most of the major lineages of jawed vertebrates, including the cartilaginous fishes, which represent the most phylogenetically divergent jawed vertebrate group relative to the mammals. Ig genes in cartilaginous fish are encoded by multiple individual loci that each contain rearranging segmental elements and constant regions. In some loci, segmental elements are joined in the germline, i.e. they do not undergo genetic rearrangement. Other major differences in Ig gene organization and the mechanisms of somatic diversification have occurred throughout vertebrate evolution. However, relating these changes to adaptive immune function in lower vertebrates is challenging. TCR genes exhibit greater sequence diversity in individual segmental elements than is found in Ig genes but have undergone fewer changes in gene organization, isotype diversity, and mechanisms of diversification. As of yet, homologous forms of antigen binding receptors have not been identified in jawless vertebrates; however, acquisition of large amounts of structural data for the antigen binding receptors that are found in a variety of jawed vertebrates has defined shared characteristics that provide unique insight into the distant origins of the rearranging gene systems and their relationships to both adaptive and innate recognition processes

Approche épidémiologique de l’étude du microbiote intestinal humain - Associations avec le métabolisme systémique et l’alimentation usuelle de l’hôte et relations entre la consommation de fibres et la santé de l’hôte

Il est désormais admis que le microbiote intestinal joue un rôle prépondérant dans la santé de son hôte humain. Le co-métabolisme hôte-microbiote produit un très grand nombre de biomolécules intégrées au sein d’axes métaboliques complexes. De ce fait, le microbiote intestinal est considéré comme un organe endocrine à part entière. Bien que de nombreuses études se soient attachées à la caractérisation fonctionnelle spécifique de certaines molécules, les études envisageant plus globalement les relations métaboliques entre l’hôte et son microbiote intestinal restent rares. Parmi les nombreux facteurs influençant la composition et l’activité métabolique du microbiote intestinal, l’alimentation joue un rôle prépondérant. Toutefois, les relations entre l’alimentation usuelle et le microbiote intestinal n’ont pas été complètement élucidées. La compréhension des facteurs modulant le microbiote intestinal est un enjeu majeur des recherches actuelles, car des liens entre le microbiote intestinal et de nombreuses pathologies (troubles gastro-intestinaux, cardio-métaboliques, neuropsychiatriques, etc.) ont été suggérés. Dans ce contexte, nous avons utilisé une approche épidémiologique pour caractériser les associations entre la composition du microbiote intestinal d’une part et le métabolisme systémique et l’alimentation usuelle de l’hôte d’autre part, au sein de la population Milieu Intérieur (N=1 000). Enfin, dans la cohorte prospective NutriNet-Santé (N≈160 000), nous avons analysé les associations entre la consommation de fibres d’une part et le risque de maladies chroniques et le microbiote intestinal d’autre part.Nos résultats décrivent des associations spécifiques entre les caractéristiques du microbiote intestinal et certaines composantes du métabolisme de l’hôte, et suggèrent un rôle important de l’axe intestin-rein. De plus, des associations inverses entre la diversité du microbiote intestinal et la consommation d’aliments caractéristiques du régime occidental ont été détectées. Enfin, nos travaux confirment que la consommation de fibres est associée à une réduction du risque de maladies chroniques, dans un contexte où un nombre croissant d’études suggère une implication du microbiote intestinal dans de tels effets.It is now admitted that the gut microbiota plays a key role in the health status of its human host. It is indeed fully recognized as an endocrine organ producing biologically active molecules which are integrated within human metabolism. However, comprehensive studies characterizing host-gut microbial metabolic relationships remain scarce. Numerous factors have been shown to exert a modulatory impact on the gut microbiota. Notably, diet is supposed to be a major driver, but the relationships between usual diet and the gut microbiota are not fully elucidated yet. Furthermore, many studies have suggested the implication of the gut microbiota in a wide range of disease states, such as gastrointestinal, cardio-metabolic, neuropsychiatric, etc. disorders. Thus, understanding the factors influencing the gut microbiota constitutes an active area of research. In this context, we adopted an epidemiological approach to investigate one of the largest population-based samples so far (Milieu Intérieur population, N=1,000). We notably assessed the associations between gut microbiota composition on one hand and the systemic metabolism and the usual diet of the host on the other. Finally, in the NutriNet-Santé cohort (N≈160,000), we investigated the associations between the intake of dietary fibers and the risk of a variety of chronic diseases, and described how dietary fibers are associated with the gut microbiota.Overall, our results suggest that gut bacterial features are specifically associated with certain components of the systemic metabolism of the host, and we hypothesize a substantial role of the gut-kidney axis. Besides, negative associations between food items for which a limited consumption is generally recommended (i.e. processed foods) and gut microbial features were detected. Additionally, we confirm robust inverse associations between the consumption of dietary fibers and several major chronic diseases. Mounting evidence suggests that such effects could be mediated by the gut microbiota

Dietary iron and breast cancer risk - modulation by an antioxidant supplementation in the SU.VI.MAX randomized controlled trial

National audiencePurpose: Epidemiological evidence suggested that red and processed meat intake may be associated with increased breast cancer risk. Recent experimental studies showed that, among the pro-carcinogenic compounds found in red/processed meat, heme iron may be particularly involved in the initiation of carcinogenesis, through lipid peroxidation. Thus, it could be hypothesized that iron intake may all the more increase cancer risk as diet has a low antioxidant potential and a high lipid content. Our objectives were to prospectively investigate the association between dietary iron intake and breast cancer risk, and its potential modulation by antioxidant supplementation and lipid intake. Methods: The SU.VI.MAX study was a randomized, double-blind, placebo-controlled trial (1994-2002) in which participants received low-dose antioxidants or a placebo. This prospective study included 4646 women. 188 incident breast cancers were diagnosed (median follow-up=12.6y). Dietary iron intakes were assessed using repeated 24h dietary records. Associations were characterized by multivariate Cox proportional hazards models. Results: Dietary iron intake was associated with an increased breast cancer risk (HRT3vs.T1=1.67 (1.02-2.71), P- trend=0.04). This association was more specifically observed in the placebo group of the SU.VI.MAX trial (HRT3vs.T1=2.80 (1.42-5.54), P-trend=0.003), but not in the antioxidant-supplemented group (P-trend=0.7, P- interaction=0.1). Besides, in the placebo group, increased breast cancer risk associated with iron intake tended to be more specifically observed in women with higher lipid intake (HRT3vs.T1=2.57 (0.86-7.69), P- trend=0.046). Conclusions: In this prospective study, dietary iron intake was associated with an increased breast cancer risk. This association was modified by an antioxidant supplementation and by lipid intake. Dietary iron intake was associated with breast cancer risk in the women not supplemented with antioxidants and in women with higher lipid intakes. These epidemiological findings support the experimental results suggesting that heme iron may increase breast cancer risk through lipid peroxidation

Dietary iron intake and breast cancer risk: modulation by an antioxidant supplementation

Experimental results suggested that iron-induced lipid peroxidation may explain the direct associations observed between red/processed meat intakes and colorectal and breast cancer risk. However, epidemiological evidence is lacking. Thus, we investigated the association between dietary iron intake and breast cancer risk, and its potential modulation by an antioxidant supplementation and lipid intake. This prospective study included 4646 women from the SU. VI. MAX trial (daily lowdose antioxidants vs. placebo). 188 incident breast cancers were diagnosed (median follow-up= 12.6y). Dietary iron intake was assessed using repeated 24h dietary records. Multivariable Cox proportional hazards models were computed. Dietary iron intake was associated with an increased breast cancer risk (HRT3vs. T1= 1.67 (1.022.71), P-trend= 0.04). This association was observed in the placebo group (HRT3vs. (T1)= 2.80 (1.42-5.54), P-trend= 0.003), but not in the antioxidant-supplemented group (P-trend= 0.7, P-interaction= 0.1). Besides, in the placebo group, the increased breast cancer risk associated with dietary iron intake was more specifically observed in women with higher lipid intake (P-trend= 0.046). These findings suggest that dietary iron intake may be associated with an increased breast cancer risk, especially in women who did not received antioxidants during the trial and who consumed more lipids. This supports the experimental results suggesting that breast cancer risk may be increased by iron-induced lipid peroxidation