Gut Bacteria Injection Systems Mediating Human-Microbe Interactions
Abstract
Gut Bacteria Injection Systems Mediating Human-Microbe InteractionsThe balance of human gut microbes like Bacteroidales is correlated with human physical andmental fitness. A long-term goal of the microbiome field is to characterize the factors produced by microbiome bacteria that directly affect host functions~knowledge that would significantlypromote our ability to promote warfighter brain performance and body physiology. However, asignificant gap in knowledge remains in our understanding of bacterial factors that promote these physical and mental capabilities. Knowledge of these bacterial factors could mitigate dysbiosis related diseases (e.g. IBD, Chron~s disease) that warfighters often face during active deployment. We recently discovered a syringe-like injection system that bacteria use to naturally interact withanimal hosts (tubeworms, insects and mice; Shikuma et al. Science 2014, Rocchi et al. CellReports 2019, Ericson et al. eLife 2019). This secretion system is one of a unique class ofContractile Injection System (CIS) that allow bacteria to deliver protein effectors into animal cells.We now have new data showing that Bacteroidales from the human gut naturally produce aclosely related, yet previously undescribed CIS (we term Bacteroidales Injection System, BIS).Based on microbiome data mining, we found that the majority (99%) of human adults carryBacteroidales that produce these newly described CIS (Rojas et al. submitted).Hypothesis and Aims. Our central hypothesis is that BIS are naturally produced in response tothe host environment and elicit their effect by binding and injecting proteins into host epithelialcells. Based on our discovery of a new CIS, our expertise with lab-based model interactions(tubeworms and human epithelial cell lines) and our preliminary results, we are ideally positioned to test this hypothesis with the following specific aims.Specific Aim 1. To Identify conditions and genetic factors that stimulate BIS production,we will grow bacteria in conditions that mimic the host environment and employ forward geneticscreens and reporter strains that provide a clear readout for BIS production.Specific Aim 2. To observe and analyze the outcome of the production of BIS withinsimplified bacteria-host interaction models, we will directly observe the interaction of BIS with human gut epithelial cell lines in flow-cell systems and organoid models usingimmunofluorescence microscopy, cytokine profiling, metabolomic and transcriptomic analyses.Determining the conditions that promote BIS production and observing the interactions and effects of BIS on human cells and organoids will provide a deeper understanding of how the human microbiome promotes host body and brain function. Such knowledge could form the basis for research tools employing Bacteroidales and their BIS to understand the role of microbiome in gut-brain and gut-immune system axis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 11, 2020
- Source ID
- N000142012120
Entities
People
- Nicholas J Shikuma
Organizations
- Office of Naval Research
- Salk Institute for Biological Studies
- United States Navy