Functionalization of Bacteria by Surface Modification

The gut microbiota has been demonstrated to be an important regulator in human health. Disorders in the gut ecosystem have been implicated in various diseases, such as inflammatory bowel disease, diabetes, Alzheimer's disease, and cancers. Although fecal microbiota transplantation has demonstrated effective to positively modulate the gut microbiome, the implementation has been largely restricted by invasive operation and indeterminate composition, which inevitably result in low patient compliance and severe safety issues. Oral delivery of probiotic species to the gut microflora is an alternative to address these limitations, unfortunately, environmental complexity and a continuous flow within the gastrointestinal tract result in low oral bioavailability and limited intestinal colonization. Synthetic bioengineering is the most commonly used and feasible strategy to modify bacteria to tackle these challenges. However, the number of bacterial strains that can be genetically engineered is limited so far. Furthermore, many biomacromolecules especially eukaryotic proteins cannot be highly expressed and folded preciously and functionally by bacteria resulting from inefficient post-translational modifications, codon usage issues, and the formation of inclusion bodies that are not functional. Most importantly, engineered bacteria confront with potential risk of gene contamination via horizontal gene transfer, particularly with respect to in vivo applications. The focus of my research group is the use of biomaterials to modify or restructure the surface of bacteria to introduce exogenous functions that are naturally unachievable, which can increase bacterial survival and colonization in vivo following oral administration.<br/>For example, probiotics individually coated with a self-assembled lipid membrane exhibit significantly improved survival against environmental assaults (e.g., gastric acid, bile acid, antibiotics, etc.) and almost unchanged viability and bioactivity, demonstrating enhanced efficacies in oral delivery and treatment of intestinal mucositis. Moreover, probiotics wrapped with a yeast membrane-derived biomaterial can be delivered into lymphoid follicles after oral ingestion and promote robust mucosal immune responses and the production of secretory immunoglobulin A, which can prevent and treat gut barrier impairment. In addition, in-situ co-deposition with dopamine can generate a hybrid multifunctional coating, which can provide a dual protection and targeting ability to modified bacteria for locally modulating the gut microbiota around the inflamed tissue and enhancing the treatment of colitis. Also, oncolytic bacteria camouflaged with a cell membrane-derived biomaterial show a low inflammatory response, slow elimination by macrophages, increased accumulation in tumor tissue, and almost unchanged inherent bioactivities, which generate greatly enhanced antitumor efficacy under a safe dosage. Briefly, the main focus of my research is the development of functional coatings to modify bacteria, which can be endowed with various exogenous functions and applied as editable bacterial therapeutics for intervening gut microbiome imbalance and the associated diseases.