Commensal bacteria have long had branding issues. First there was an awareness problem – “Wait, these things are inside us?” Then there was an image problem – “Germs! Bad! Kill!” They even had a Pluto moment, when it turned out a whole bunch of them weren’t even bacteria at all.
Despite these difficulties, the word “probiotic” has helped the bacterial brand tremendously through its association with the deliciousness of yogurt and cheese. Since we now realize how beneficial bacteria can be, scientists have been wondering if we can make them even better by mixing the right species or designing them to treat particular diseases.
Recent work has shown that transplanting a healthy microbiome (don’t ask) can help treat inflammatory bowel diseases, as can bacteria engineered to secrete anti-inflammatory molecules. Bacteria have also been engineered to treat autoimmune disorders, cancers, infections, and even obesity.
We here at EpiGenie have seen a batch of cool microbiome-hacking papers come through recently, and we wanted to give a quick run-down.
Yogurt-Based Cancer Screening
It turns out that bacteria tend to colonize tumors. Noting this, lead authors Tal Danino and Arthur Prindle at UCSD and MIT modified a common probiotic, E. coli Nissle, to express the reporter genes luciferase and lacZ, and then fed it to mice. The luciferase signal showed that the bacteria specifically colonized liver tumors in the mice but left healthy tissue alone.
In the clever bit, they then fed the mice harmless molecules that are easily detected when cleaved by lacZ. When mice had liver tumors, they were colonized by lacZ-expressing probiotics, which converted test molecules into detectable signals that were excreted in urine. So for these mice, at least, cancer screening was as easy as take two and call me if your pee changes color.
Selecting a Designer Microbiome to Treat Hyperammonemia
Another liver-related problem occurs when the liver fails to remove ammonia from the blood. Most ammonia is produced by gut bacteria breaking down urea, but not all bacteria have urease genes, so another pair of lead authors, Ting-Chin David Shen and Lindsey Albenberg at U. Penn, found a low-urease community of 8 species and tried transplanting them into liver-damaged mice.
This new low-urease microbiome helped the mice keep their ammonia levels low, thus extending their lifespans and avoiding the brain damage usually caused by hyperammonemia. Interestingly, this protection lasted several months to a year, even though the new community evolved over time.
Programmed Bacteria Reprogram Intestinal Cells, Treating Diabetes
Moving away from the liver just a bit, the focus for Franklin Duan in the lab of John March at Cornell was type 1 diabetes, which is caused when insulin-secreting cells in the pancreas die off. A potential treatment was found when it was discovered that intestinal cells, even though not in the pancreas, can differentiate into insulin-secreting cells if they are exposed to GLP-1. The catch is, GLP-1 only sticks around in the body for a few minutes, making it nearly impossible to give the target cells a high enough dose.
Unless, that is, we had some source that would hang out in the intestine and provide a continuous stream of GLP-1 in just the right place… oh, wait, bacteria! This lab had previously made GLP-1-secreting Lactobacillus gasseri and shown that they could induce differentiation in a cultured cell line. In the new paper, they fed the engineered Lactobacilli to diabetic rats. The probiotic-fed rats still had defective pancreases, but they regained the ability to produce insulin – just from their intestines instead.
Check out these papers (and a review, as a bonus) over a big bowl of yogurt and a fizzy glass of kombucha at:
- Programmable probiotics for detection of cancer in urine, Science Translational Medicine
- Engineering the gut microbiota to treat hyperammonemia, J. Clinical Investigation
- Engineered Commensal Bacteria Reprogram Intestinal Cells Into Glucose-Responsive Insulin-Secreting Cells for the Treatment of Diabetes, Diabetes
- Engineered bacteria as therapeutic agents, Current Opinion Biotechnology