Co-variation Analysis Of Human Gut Microbial Structure And Host Global Metabolism

Human beings can be considered as"superorganisms"as a result of their close symbiotic associations with the gut microbiota. Human metabolism involves integration of multiple indigenous metabolic processes which were encoded by the host genome with those of the microbiome. This results in extensive transgenomic co-metabolism of many substrates including those involved in host metabolic regulation. In health or disease, gut microbial variations would significantly modulate host physiology and pathology. Therefore, understanding the correlation between gut microbiome with host global metabolism relevant to chronic metabolic diseases, and identification of key functional members which modulate the host metabolism would provide new insights into potential contributions of gut microbiota to human health and disease.In the first part of this study, we analyzed the gut microbial composition and host global metabolic profiles of a healthy, four-generation, seven-membered Chinese family. A co-variation analysis method which linked the changes of gut microbiome and host metabolic phenotypes was developed to analyze the effects of key members of gut microbiota on host metabolism. Global gut microbiomic structure of the Chinese family was investigated by using bacterial universal 16S rRNA gene clone libraries. At the species level, there are clearly structural differences between the Chinese family gut microbiomes and those reported for American volunteers. In addition,the molecular diversity of Bacteroides spp., a prominent bacterial group in human intestinal microbiota, in the seven family members was also analyzed by using Bacteroides spp. group-specific 16S rRNA gene clone libraries. The diversity of Bacteroides spp. detected by the group-specific libraries was much higher than that of universal libraries,and most of Bacteroides species were uncharacterized. The analysis of the microbial DGGE fingerprints of the 16S rRNA gene V3 region for predominant bacteria and of regions for two specific groups, Bacteroides spp. and Clostridium leptum subgroup, showed a sex-related difference of gut microbial composition in this family cohort. And sex-related bacteria were indentified, e.g. Bacteroides thetaiotaomicron was higher in males of family members. The urinary NMR-based metabolic profiling of this family also showed significant sex-related differences, and 3-aminoisobutyrate was identified as a gender-related metabolite which was higher in the urine samples of male members. We applied a multivariate statistical analysis——OPLS to model the covariation between gut microbiomic structural patterns as reflected by community DGGE fingerprints and host metabotypes as defined by NMR spectroscopic urinary profiling, and pinpointed 10 key functional members of the microbiome that most significantly modulate host metabolism. For example, Faecalibacterium prausnitzii population variation is associated with eight urinary metabolites, indicating that this species is a highly functionally active member of the microbiome, influencing numerous host pathways. This study provides a methodological foundation for understanding the symbiotic metabolic relationship between gut microbiome and human host, and potential significance of gut microbiota in the development of metabolic diseases.To characterize the human gut microbial structure under various health conditions such as type 2 diabetes and obesity, and understand the potential correlation of gut microbial variation and chronic metabolic diseases, we used bar coded 454 pyrosequencing method to characterize the gut microbiomes of 316 human fecal samples from 140 newly diagnosed type 2 diabetic patients and 142 controls whom are 1:1 match in sex, age and geographical origin with diabetic patients. Totally 268,578 high-quality 16S rRNA gene V3 region sequences were obtained from all the samples. At the division level, there are 11 bacterial phyla in the Chinese human guts, dominated by Bacteroidetes and Firmicutes which account for more than 90% of total gut bacteria. At the species level, all the sequences were assigned into 2,136 operational taxonomic units (OTUs) with 97% identity cutoff. The diversity composition of gut microbiome of the Chinese human cohort at the species level exhibited remarkable inter-individual differences. No common OTU existed in 316 human fecal microbial samples, and 40% of total OTUs are host specific. The principle component analysis (PCA) of global gut microbial structure of Chinese human cohort exhibited a specific"branch-like structure". The individuals in each branch shared one or several predominant OTUs. However, the specific global structure of human gut microbiome seems not to be related with sex, age, geographical origin and health status, indicating that there would be some unknown factors which strongly influence human gut microbiome. Compared with control people, the global diversity of gut microbiota of diabetic and obese people was lower. And the proportions of several predominant bacterial groups were significantly different in two groups. For instance, the abundances of Bacteroidetes phylum, Bacteroidaceae family, Porphyromonadaceae family and Bacteroides genus were lower in diabetic people, whereas the proportions of Lachnospiraceae family which is the most predominant group in Firmicutes and Roseburia genus in this family were higher than those of control people. However, the UniFrac analysis, a phylogenetic method for comparing microbial communities based on the measurement of phylogenetic distance between sequences, showed no significant differences of gut microbiome in two groups of human cohort at species level. The gut microbial diversity composition of the Chinese human cohort revealed in this study provides reference data for"Human Metagenomic Project"; and the specific distribution of Chinese human gut microbiome provides insights into understanding the relationship of gut microbiota and impact factors, e.g. diet and disease.In summary, in this study, we developed a global analysis to correlate the gut microbial variation with human host global metabolism, showing that the key functional members of gut microbiome can modulate the host specific metabolic pathways; and we also analyzed the overall structure of gut microbiota of the Chinese human cohort with metabolic diseases and healthy controls. This study provides new insights for understanding the contributions of gut microbiota in human health and disease.