Host mechanisms of gut colonization by commensal bacteria that affect lifespan

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Project Summary Gut bacteria associate with host tissues and alter host physiology, impacting lifespan and aging. Some types of bacteria, such as Lactobacilli, benefit health while others degrade it. A key gap in our knowledge is how the host constructs microenvironments that coordinate colonization by specific bacteria. In particular, which host cells (Aim 1), genes, and molecules (Aim 2) promote colonization by specific bacteria? As an important step forward, this proposal aims to investigate host mechanisms of bacterial colonization in Drosophila melanogaster using recently isolated bacterial strains of Lactobacillus plantarum and Acetobacter from a wild D. melanogaster, which are found to colonize a tightly-defined physical space in the fly gut. L. plantarum, is a probiotic in humans, and the fly provides unique and powerful genetic resources to study homologs of human disease genes. This proposal harnesses several unique assays developed to identify host mechanisms that mediate commensal strain specificity, including the host cell types, genes and molecules that recruit and maintain commensal bacteria. The central hypothesis is that specific cell types in the fly foregut produce a "commensal niche": a specialized chemical and physical microenvironment that facilitates adhesion and proliferation of specific bacteria that may benefit the host. The proposal aims to (i) use single cell RNA sequencing to identify the specific host cell types and genes that create this specialized microenvironment. This will enable the use of Drosophila genetics to (ii) probe the mechanisms of host tissue maintainance through cell turnover and localized secretion of a defined extracellular matrix. As a critical test of the hypothesis, the proposal will examine the L. plantarum population kinetics that enable its association with the commensal niche. By studying commensal niche construction in the Drosophila gut, this research will establish a new paradigm that enables interrogation of the conserved molecular and cellular interactions between hosts and their commensals that influence host health. The proposal holds translational potential for developing tools to drive these beneficial interactions.