Deciphering the niche adaptations of a gut commensal involved in educating the host immune system

Project Information

NICHEADAPT

Grant agreement ID: 866222

DOI

10.3030/866222

EC signature date 17 February 2020

Start date 1 June 2021

End date 31 May 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 999 948,00

EU contribution

€ 1 999 948,00

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 2 - NICHEADAPT (Deciphering the niche adaptations of a gut commensal involved in educating the host immune system)

Reporting period: 2022-12-01 to 2024-05-31

Summary of the context and overall objectives of the project

Over the past decade, the important role of the gut microbiome in health and disease has become increasingly clear. While the gut microbiome is composed of hundreds of different bacteria, a few bacterial species have unique effects on the host. One species, Segmented filamentous bacteria (SFB), have been shown to play an outsized role in the education of the host immune system during early life and has been linked to increased colonization resistance against pathogens both in and outside of the gut. Conversely, due the potent immunostimulatory potential of SFB and its pleiotropic effect on the host immune system, SFB has been linked to the exacerbation of disease phenotypes in a number of mouse models while also ameliorating disease in other instances. Understanding the interaction of this unusual bacterium with the host is therefore important for both health and disease but remains largely uncharacterised due to the only limited ability to propagate this fastidious anaerobe outside of its host. While SFB appears to be a ubiquitous bacterium in vertebrates, its colonization is host species-specific. Colonization of SFB involves its intimate attachment to the host epithelium, a pathogenic pattern generally absent in commensal bacteria. While this attachment to the epithelial surface is a prerequisite for its immunostimulatory effect on the host, little is known about this unusual feature and how SFB has evolved to colonize this specific niche at the intestinal surface. A better understanding of this interaction is therefore integral to elucidating how SFB mediates its protective role against pathogens and how it influences disease progression. The EU-funded NicheAdapt project aims to elucidate this host-bacterial interaction in more detail and to uncover the adaptations of this bacterium that allow it to colonize its unique replicative niche. Using a combination of comparative genomics approaches as well as high resolution microscopy and gnotobiology models, we are addressing the genetic variability between SFB from phylogenetically distant hosts and are working to identify structural features and molecular details that are involved in this unique host-bacterial interaction and in the immunological stimulation of the host.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Results obtained through a comparative genomics approach have revealed a number of interesting and unique niche adaptations in the genomes of SFB from phylogenetically distant hosts. These adaptations relate to how this bacterium can survive the hostile environment of the epithelial surface and its strategy for nutrient acquisition, pointing towards potential host-specific physiological and nutritional differences. Phylogenetic analysis also has revealed a surprising genomic sequence divergence of SFB within individual host species that has important implications for the molecular detection of this low abundance bacterial species. In-depth characterization of structural features involved in the host-bacterial interaction has furthermore allowed us to identify a previously unknown temporal transition in the development of the bacterium, shedding light on how this bacterium protects itself from environmental harm and how it colonizes the host epithelium. At the same time, we have gained a better understanding of the molecular factors involved and signaling pathways activated in the immunological response of the host to SFB colonization. This work sets the groundwork for a more detailed analysis of the novel SFB-host interaction and its stimulatory potential.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

SFB remains a largely enigmatic bacterium for which nearly no molecular details are known and whose life-cycle remains to be fully characterized. This is largely due to the difficulties encountered in working with this bacterium, such as its low abundance, its fastidious growth requirements and its tolerance of only very low oxygen levels. While the description of the life cycle of this bacterium is largely based electron microscopy work from the 1970s, our recent morphological analysis has revealed new details in the development of its unusual life-cycle that provide insights into how this bacterium mediates its interaction with the host and thereby adds to the description of its novel growth strategy. The extent of SFB prevalence in animals also remains elusive as this bacterium is only a minor, albeit very important, member of the gut microbiota. New insights gained through our comparative genomics approach now allows us to address the question of SFB prevalence in a more systematic manner and will lead to a greater understanding of its distribution. In addition, identification of the novel morphological features and immunological pathways activated in the host now opens the way to link more molecular details to these findings. Overall, this work should achieve a more comprehensive view of this intriguing host-bacterial interaction and how broadly SFB contributes to immune development in different species.