A probiotic-based therapeutic approach, where gut bacteria were genetically engineered to produce a patch, enhanced intestinal wound healing in a mouse model of inflammatory bowel disease (IBD), a study reports.
The study, “Engineered E.coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut,” was published in the journal Nature Communications.
The cause of IBD is not yet fully understood but multiple factors seem to play a role, including environmental factors and an overactive immune system against the body’s own gut microbes.
This dysregulated immune system leads to the destruction of the intestinal barrier between the inside of the gut and the rest of the body, leading to an increase in the amount of bacteria and other harmful materials that enhance inflammation. This barrier is known as a mucosal layer, where certain cells produce mucus (a thick fluid) which acts to protect against pathogens. The recovery of this barrier is essential for treating IBD symptoms.
Anti-inflammatory therapies are used to decrease inflammation, and antibiotics to treat the infections in IBD. However, anti-inflammatory therapies have side effects, and antibiotics can also harm the microbiome. Currently, no therapies are available that can be directly applied to the inflamed lesions.
The potential involvement of gut microbes in IBD has led researchers to attempt to use living bacteria, or probiotics, as therapeutics with the hope that these would decrease the side effects of systemic (whole-body) therapies.
Microbes genetically engineered to release protective molecules (e.g. interleukin-10 or anti-tumor necrosis factor) locally in the gut have shown promising results in animal models. However, these have failed to produce significant improvements in clinical studies, likely due to difficulties in achieving meaningful concentrations at the site of the disease.
Researchers at Wyss Institute for Biologically Inspired Engineering at Harvard University have now engineered a type of E.coli Nissle gut bacteria to function as a locally acting probiotic, a strategy they named Probiotic Associated Therapeutic Curli Hybrids or PATCH.
These bacteria synthesize a network of small fibers which bind to mucus, allowing a patch to form over the inflamed areas in the gut to shield the cells from gut microbes and environmental factors.
“With this ‘living therapeutics’ approach, we created multivalent biomaterials that are secreted by resident engineered bacteria on-site and attach to many mucus proteins at a time — firmly adhering to the viscous and otherwise moving mucus layer, which is a challenging thing to do,” Neel Joshi, PhD, associate professor at Harvard’s Paulson School of Engineering and Applied Sciences (SEAS), and the study’s lead author, said in a press release.
The PATCH approach “creates a biocompatible, muco-adhesive coating that functions as a stable, self-regenerating Band-Aid and provides biological cues for mucosal healing,” he added.
E.coli Nissle bacteria are a normal gut bacterium, well-studied and relatively easy to manipulate genetically. Furthermore, they are safe in humans, and often included in commercial probiotic formulations for general gastrointestinal disorders. The bacteria are mainly located in the colon, particularly in regions that are damaged in many types of IBD.
The PATCH approach was based on work by the same team in a previous study.
“To enable mucus adhesion, we fused CsgA [a modified bacterial protein] 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 Anna Duraj-Thatte, PhD, a study author.
“This turned out to be a simple and robust strategy to produce self-renewing, muco-adhesive materials with long residence times in the mouse intestinal tract,” she added.
When these bacterial hydrogels were provided orally to mice, they didn’t affect the animals’ health, and were able to withstand the harsh conditions in the stomach and small intestine. In addition, the bacteria showed persistent colonization of the mouse intestinal tracts, and were seen throughout the gut lumen including the mucus layers closest to the surface.
In this new study, the scientists inserted the hydrogels into the E.coli Nissle bacteria.
“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 Pichet Praveschotinunt, the study’s first author.
The effects of the bacteria were then tested in a mouse model of colitis, one of the two major forms of IBD, which was induced by the chemical dextran sodium sulfate (DSS). The mice received the bacteria rectally for three days before DSS treatment, during the five days of DSS exposure, and during the five-day recovery period.
DSS treatment in mice that had not received the bacteria caused intestinal inflammation, as indicated by weight loss and increased disease activity index (which includes factors such as weight loss, diarrhea, and rectal bleeding).
The effects on mice administered the bacteria, when treated with DSS, were markedly lessened. These mice almost returned to the same conditions as mice not treated with DSS, following the recovery period.
DSS-induced inflammation normally decreases colon length. However, the colon length was similar between the bacteria-treated mice and the healthy controls. In addition, the mice that received the bacteria had reduced levels of certain inflammatory molecules.
The researchers believe that their approach could be used in combination with existing anti-inflammatory, immuno-suppressant, and antibiotic therapies to help reduce patients’ need for the therapies and to help prevent IBD relapses.
“This powerful and simple approach could potentially impact the lives of thousands of patients with IBD for whom there is no disease-specific cure available. It also is a testament to the creativity and vision of the Wyss Institute’s ‘Living Cellular Devices’ initiative that engineers living cells to perform key therapeutic and diagnostic tasks in our bodies,” said Donald Ingber, MD, PhD, professor of vascular biology at Harvard Medical School and bioengineering at SEAS.
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