Engineering Gut Bacteria as Living Therapeutics

Microbes found in our intestines hold great promise as tools to treat human diseases. Genetically engineering gut bacteria is a unique strategy to design controlled and effective living therapeutics.

Microbes are emerging as a new a class of medicine to fight human diseases. However, this is not an entirely new concept. In the late 1800s, physicians in Germany and New York noticed that tumors regressed in some of their cancer patients who incidentally acquired a bacterial skin infection while in the hospital. Building on this observation, physicians tested the bold idea of administering the infectious bacteria to cancer patients as a potential cure. Some patients experienced dangerous side effects from the bacterial infections, but amazingly, other patients experienced tumor regression (1, 2).

A century later, the concept of using microbes to improve human health is changing our understanding of medicine. We are moving from viewing microbes only as agents that cause disease and need to be eliminated to seeing them as beneficial “living therapeutics.” Certain living micro-organisms can be used to prevent, treat, or cure diseases. In fact, many research labs and biotechnology companies are developing living therapeutics to treat diseases such as cancer, bacterial infections, autoimmune diseases, and metabolic diseases.

Over the past 15 years, technological advancements have enabled scientists to study the largest microbial community in humans, the gut microbiota. Multiple studies have shown that microbes in the gut interact intimately with the host. These interactions are associated with health, disease, and the efficacy of drugs (3, 4). To capitalize on this close association, researchers are exploring a promising new type of medicine by designing living therapeutics based on gut microbes. There have been some early clinical successes (5), but for such therapies to reach their full potential, it is crucial to achieve control of gut microbe behavior within the intestinal ecosystem. Genetically engineering microbes, and particularly commensal gut bacteria (i.e., bacteria that naturally reside in the gut and are beneficial for the host), will provide control over living therapeutics and propel their development to new heights.

This article discusses current strategies for using gut microbes as living therapeutics. It illustrates how genetically engineered commensal gut bacteria offer unique advantages over other strategies and how CRISPR-Cas9-based tools enable the engineering of those bacteria. Finally, it explores current challenges and the outlook for translating living gut bacteria into therapies.