Understanding the beneficial role and antimicrobial potential of novel human gut bacteria

The study of the human gut microbiome has emerged as a new frontier of biomedical research. With the advent of high-throughput DNA sequencing, a strong link between the human gut microbiome composition and various aspects of human health is being increasingly recognized. However, thousands of bacterial species in the human gut microbiome remain recalcitrant to cultivation (that is, they have not yet been isolated nor grown under laboratory conditions). This technical limitation represents a major hurdle to understanding the biological mechanisms and beneficial role of human gut bacteria in host health.

The most remarkable example of one such large uncultured group is the bacterial order referred to as Christensenellales. Christensenellales is a highly prevalent and globally distributed clade that is gaining increasing attention as a promising player in the maintenance of human health. Multiple independent observations suggest Christensenellales bacteria have a beneficial role in metabolic health, inflammatory bowel disease and even longevity. In fact, my preliminary data also indicates Christensenellales species may have underappreciated antimicrobial properties, particularly against opportunistic pathogens in urgent need of new treatments. In my recent work, I have expanded by almost 100-fold the number of Christensenellales genomes available (from 89 to 8,585 genome sequences), while showing that at least 98% of the bacterial species belonging to this clade remain uncultured.

The vast body of evidence from both my own preliminary analyses and previous studies raises the hypothesis that Christensenellales bacteria have a multifaceted role in human health with promising antimicrobial properties. Therefore, this opens a number of important questions:

- Which functions enable Christensenellales to successfully colonize the human gut?
- What is the role of Christensenellales in maintaining or promoting health?
- How can we selectively culture Christensenellales bacteria in vitro to test their mechanistic roles?
- Do Christensenellales bacteria have an antimicrobial effect against intestinal pathogens?

With this in mind, I will apply a holistic, cross-disciplinary approach leveraging my unique expertise, datasets and methods to understand the biological role of Christensenellales bacteria and explore their antimicrobial properties. I will: (i) investigate the functional potential, health-associated features and gut adaptation of Christensenellales at a genomic level with an unprecedented detail and resolution; (ii) develop new methods to culture Christensenellales bacteria and enable mechanistic investigations; and (iii) evaluate the antimicrobial activity of Christensenellales and test new compounds with promising antibiotic potential.

By providing an integrated view of the physiology and functions of Christensenellales, I will improve our understanding of the role of the gut microbiome in human health and open new avenues of research to develop innovative therapeutic applications. The core principles and methodologies here established will open opportunities to explore other uncultured bacteria of relevance to health and disease.

In this multidisciplinary project, I will uncover the biological roles of novel Christensenellales bacteria belonging to the human gut microbiome. The importance of Christensenellales in diverse aspects of human health is becoming increasingly recognized, but there have been a number of challenges and limitations preventing further progress in the field.

Until recently, the mere existence of most of Christensenellales species colonizing the human gut was unknown, as previous studies have lacked sufficient resolution due to their reliance on the analysis of the 16S rRNA gene and the lack of reference genomes. I have now massively expanded the number of Christensenellales species and genomes currently known, which will transform our understanding of the functional capacity, host adaptation and beneficial role of Christensenellales in health.

Isolating and culturing new Christensenellales species will enable me to understand their biology while opening opportunities to explore their utility as next-generation probiotics. This represents a potentially ground-breaking undertaking, as currently >98% of Christensenellales species remain uncultured and inaccessible to experimental testing. In addition, the rationale in developing these new culturing strategies may be extended to other important gut bacteria.

Given my promising preliminary data, I will also test new antimicrobial peptides that may be active against multidrug-resistant pathogens. Identifying new ways to treat pathogenic bacteria causing high rates of morbidity and mortality worldwide will have a wide-reaching clinical, social and economic impact. Furthermore, the discovery of new bioactive compounds affecting the growth of gut bacteria may inform new strategies to engineer the human gut microbiome composition for improved health.