Qiang Feng:
Metagenomics study on the polymorphism of gut microbiota and their function on human health

Date: 18-09-2015    Supervisor: Jun Wang & Karsten Kristiansen

As the key component of the human micro-ecosystem, intestinal microorganisms transfer energies and exchange information with the human body. While they play essential roles in maintaining homeostasis in our bodies, until recently, we have had very limited understanding of the extent of taxonomic diversity and functional complexity of the gut microbiome. Facilitated by the Next Generation Sequencing (NGS) technologies and the progress of bioinformatics in the past decade, we have acquired substantial achievements in metagenomic studies on human gut microbiome and established the fundamentals of our understanding of the interactions between gut microbes and human body, and also the importance of this interaction on human health. As one of the milestones, the first integrated gene catalog in the human gut microbiome was constructed in 2010 in the scheme of the Metagenomics of Human Intestinal Tract (MetaHIT) Project, which was conducted by BGI and other research institutes under the 7th FP program of European Commission. This gene catalog contains 3.3 million non-redundant reference genes. By estimation, each individual harbors approximately 1,000 to 1,500 microbial species and on average 160 ‘core species’ are shared in the population. These microorganisms participate in various metabolic pathways and activities of the immune system and the nervous system of our bodies,and have fundamental impacts on our health. For example, an association study between gut microbiome and type 2 diabetes (T2D) highlighted a series of microbial gene markers possibly related to this disease and among them, 50 markers showed great potential for diagnosis.

Based on previous work, we further collected 1,267 samples of gut metagenomes data from 1,070 individuals living in three continents (North America, Europe and Asia) and constructed a 9.9 M non-redundant high-quality gene catalog representing the gut microbiome feature of about 5% of populations around the globe. Following the same principle, a 2.6 M gene catalog of the mice gut microbiome was constructed and a canonical animal gut model was built. A comparison to the human gut catalog revealed that only 4% of the genes were shared by the human counterpart, highlighting the significant difference between these two gut microbiome datasets.

To understand the establishing process of gut microbiome during the first year of life after birth, fecal samples from 98 infants and their mothers were collected and analyzed after parturition. In this study, we found that delivery methods (vaginally- or C-section-delivered) and feeding regime (breast-feeding or mixed feeding) had significant impacts on the gut microbiome of the infants.

Moreover, metagenome-wide association studies (MGWAS) were conducted to investigate the potential relationship between gut microbiome and diseases such as colorectal adenoma (CRA) and carcinoma (CRC), rheumatoid arthritis (RA) and coronary heart disease (CHD). Compared to the healthy individuals, CRA and CRC patients exhibited an enrichment of specificly low abundannce microbes in their gut, which were positively related to the red meat intake, while taxa associated with fruit and vegetable intake were depleted. Abundance changes in certain bacteria, such as Fusobacterium nucleatum and Parvimonas micra, were correlated with the different stages during CRC development. Four genes were selected as reliable markers to identify CRC patients in Chinese, Danish and Austrian populations, which holds promising implications in non-invasive diagnosis in the future.

In the study of the gut and oral microbiomes abnormalities in RA patients, Haemophilus sp. was found depleted, which was negatively correlated to the concentration of RA immune antibodies, while Lactobacillus salivarius was significantly enriched in the feces, dental plaque and saliva of the RA patients, and was positively related to the order of severity of the disease.

The comparison between the gut microbiome of atherosclerosis CHD patients and healthy controls showed significant differences between the two groups. Further more, by integratively analyzing the urine metabolites and fecal microbiota, we demonstrated that gut microbiome dysbiosis was closely correlated with the metabolic abnormality in CHD patients.

The extended integrated gene catalog of the human gut microbiome and the following association studies in a series of complex diseases highlight the strong connection between intestinal microorganisms and human health. These studies also shows a great potential of using microbiome-based approaches for early diagnostics, and also in therapy and prevention of common diseases such as T2D, CRC, RA, and CHD.