New biological principles governing the fitness of beneficial GUT bacteria

The National Institute of General Medical Sciences awarded Yale University $462,114 on August 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate stress response mechanisms in beneficial gut bacteria, specifically how Bacteroides thetaiotaomicron uses carbon starvation as a regulatory signal to promote gut fitness factors.

The research spans five years (through May 31, 2031) and focuses on establishing novel biological principles governing bacterial survival in mammalian hosts. The laboratory will examine how the target bacterium responds to nutrient limitation by supporting energy-efficient protein synthesis and altering gut fitness factor activity through phase separation. The work encompasses solving protein and RNA functions, revealing novel activities in conserved factors such as the chaperone HSP70, and investigating how newly discovered mechanisms contribute to bacterial survival and proliferation in animal hosts. The ultimate goal is to generate biological knowledge that enables rational engineering of probiotics with direct health applications.

Performance occurs in New Haven, Connecticut. This is a Project Grant, the assistance type under which NIGMS funds investigator-initiated biomedical research designed to generate fundamental scientific discoveries.

Abstract

My laboratory investigates how bacteria survive stress conditions faced inside and outside mammalian hosts. We identify specific stress signals and their sensors, solve the mechanisms bacteria use to convert stress signals into cellular responses, and reveal the biochemical functions of the proteins and rnas that help bacteria cope with various stresses. We aim to establish novel biological principles of broad significance. My laboratory discovered the first MG2+ sensor, first FE3+ sensor, first cation-sensing riboswitch, first riboswitch controlled by the essential transcription termination factor RHO, first and only example of a translation factor that functions without hydrolyzing GTP, and first example of phase separation governing bacteria-host interactions. During the next five years, we will explore how a prevalent beneficial bacterium uses carbon starvation - a condition all GUT bacteria face daily - as a key regulatory signal that promotes the abundance and activity of GUT fitness factors. We will examine how bacteroides thetaiotaomicron responds to nutrient limitation by supporting energy- efficient protein synthesis, the most energy-demanding activity in all living cells, and by altering the activity of GUT fitness factors by phase separation. Our research program is deliberately designed to discover new biology. We succeed by: 1) solving the functions of proteins and rnas; 2) revealing novel activities for well- studied factors, as we recently established for the highly conserved and widely distributed chaperone HSP70; and 3) investigating how newly discovered mechanisms contribute to the survival and proliferation of bacteria in animal hosts. Such novel biological principles are critical for the rational engineering of unique probiotics that directly advance human health.