Joshi presently is a core faculty member of the Wyss Institute and associate professor at Harvard’s Paulson School of Engineering and Applied Sciences (SEAS), and will shortly be appointed as a professor at Northeastern University in Boston.
In previous work
, Joshi’s group demonstrated that self-regenerating bacterial hydrogels firmly attached to mucosal surfaces ex vivo
, and, when orally given to mice, withstood the harsh pH and digestive conditions of the stomach and small intestine without affecting the animals’ health. To fabricate them, his team programmed a laboratory E. coli
strain to synthesize and secrete a modified CsgA protein, which as part of E. coli
’s “curli” system assembles into long nanofibers at the outer surface of the bacteria. “To enable mucus adhesion, we fused CsgA to the mucus-binding domain of different human trefoil factors (TFFs), proteins that occur naturally in the intestinal mucosa and bind to mucins, the major mucus proteins present there. The secreted fusion proteins form a water-storing mesh with tunable hydrogel properties,” said co-author Anna Duraj-Thatte
, a postdoctoral fellow working with Joshi. “This turned out to be a simple and robust strategy to produce self-renewing, mucoadhesive materials with long residence times in the mouse intestinal tract.”
In their new study, the team further built on these findings by introducing the machinery for producing one of the mucoadhesive hydrogels based on TFF3 into an E. coli
Nissle strain that is a normal gut bacterium that can thrive in the colon and cecum sections of the intestinal tract affected by IBD, and is currently sold in many commercial probiotic formulations. “We found that the newly engineered Nissle bacteria, when given orally, also populated and resided in the intestinal tract, and that their curli fibers integrated with the intestinal mucus layer,” said first author Pichet Praveschotinunt
, who is a graduate student mentored by Joshi.
“When we induced colitis in the colons of mice by orally administering the chemical dextran sodium sulfate, animals that had received the PATCH-generating E. coli Nissle strain by daily rectal administration starting three days prior to chemical treatment had significantly faster healing and lower inflammatory responses, which caused them to lose much less weight and recover faster compared to control animals,” said Praveschotinunt. “Their colon epithelial mucosa displayed a more normal morphology and lower numbers of infiltrating immune cells.”
Joshi and his team think that their approach could be developed as a companion therapy to existing anti-inflammatory, immuno-suppressant, and antibiotic therapies to help minimize patients’ exposure to the drugs and potentially provide protection against IBD relapses.
Additional authors on the study are Wyss Institute researchers Ilia Gelfat, Franziska Bahl, and David B. Chou.
The study was supported by a grant from the National Institutes of Health, funds from Harvard’s Wyss Institute for Biologically Inspired Engineering and the Blavatnik Biomedical Accelerator, and a royal Thai government scholarship.