The vast complexity of the intestinal microbiome is difficult to fathom. The densest collection of bacteria on the planet arguably resides within the gut! We simplify this system using gnotobiotic animals maintained in isolators. This allows us to colonize mice with a known group of bacteria that model the broad functions of the microbiota.

The Gnoto-It-All project investigates host-microbe interactions over the lifespan of the mouse to answer the following questions:

How does the host monitor its commensals? What happens during periods of acute stress, like infection or dietary deprivation? How do commensals respond? What are the long-term impacts to the host-microbe relationship?

As our diets and lifestyles rapidly change, it is crucial that we consider the impact to our gut commensals. Gnoto-It-All establishes a framework for understanding host-microbe dynamics in a volatile world.

Toll-like receptors (TLRs) detect microbial products and activate immune responses. TLR signaling is tightly controlled: too little can lead to infection while too much can end in death. Furthermore, TLRs bridge the innate and adaptive arms of the immune response, exerting long-lasting impacts on host-microbe interactions.

TLR5 responds to flagellins, proteins produced by both pathogens and commensals in the gut that enable motility. Flagellins are remarkably diverse in their ability to activate TLR5. Clasen et al. describes how some commensals evade host immunity by producing “silent flagellins” that bind but weakly activate TLR5. This discovery revealed huge gaps in our understanding of TLR5’s signaling mechanism.

How do flagellins tune TLR5 signaling?

We study TLR5s from diverse species using a combination of molecular and structural techniques to gain insight into TLR5’s activation mechanism.

Crohn’s disease (CD) is a chronic inflammatory condition that occurs when the immune system targets gut commensals. While the cause of CD remains unknown, its prevalence in industrialized countries, including the US, is increasing. Treatments are costly and work by suppressing the immune response, which can lead to dangerous side effects.

Elevated serum antibodies against commensal flagellins are a diagnostic marker of CD; however, the role of these antibodies in the pathogenesis of CD is unclear.

We investigate the function of these antibodies using cell-culture and mouse models with the long-term goal of developing precision medicine-based therapies to treat CD.