This post was written by Sean Kearney, a doctoral candidate in the Department of Biological Engineering at MIT.
Bacteria that live in the gut must cope with a rapidly changing host environment to survive. Any given day, an individual can eat dozens of different kinds of foods, which, at the molecular level, represent hundreds to thousands of different nutrient sources for a bacterium to eat. What to eat at any given time is a choice that gut bacteria make via molecular computation, asking the question: which food is the most abundant and which am I best at eating? The molecular machinery that underlies this decision-making process is a tool allowing control of a variety of processes within the bacterium. In a recent article published in Cell Systems, Tim Lu and colleagues report on re-engineering this tool to generate specific responses to different input signals in a gut bacterium, B. thetaiotaomicron (or B. theta). The ability to manipulate genetic pathways in this bacterium is significant for understanding associations between the microbiome and human health, as this bacterium is both an abundant and often encountered organism in the healthy human gut microbiota.
Though engineering bacteria to sense and respond to stimuli via molecular circuits is not new, this work is one of the first applications of this technology to an important member of the human gut microbiota. The authors engineered B. theta to sense and respond to three components commonly present in the human diet: lactose, rhamnose, and chondroitan, found in milk, plant foods, and animal tissues, respectively, and used induction of light as a way to measure the sensitivity of these organisms to the input of each component, designing circuits that could respond, in some cases, to a 10,000-fold difference in concentration of the input. Such a dynamic range suggests that the engineered bacteria is able to respond to varying levels of input in a graded way — that is, it may be possible to use B. theta as an exquisitely sensitive drug delivery device, targeted directly to the colon.
Beyond the fundamental scientific advance in regulating sensing behavior in B. theta, the authors upgraded the organisms’ memory capabilities, retooling it as a living environmental sensor. The authors reasoned that a historical log of a bacterium’s exposures to environmental changes could be created by recording each incident in the microbes own genome. This would ultimately allowing researchers to monitor host health vis-a-vis dietary or chemical exposures. In a clinical setting, this technique could eventually be used to monitor changes in the host gut before health concerns arise, perhaps as a way to predict the likelihood of a disease before it happens. B. theta species live primarily within the large intestine, and there is a wide range of conditions affecting the large intestine that could benefit from environmental monitoring by microbes living directly in situ, including diseases such as, irritable bowel syndrome, ulcerative colitis, and intestinal polyps. Recording the history of the resident gut microbes’ exposure to key environmental or dietary factors will provide a wealth of information for clinicians to inform the design of personalized treatments for each patient — reducing the amount of guessing that goes into diagnosis and treatment.
However, even more interesting and significant, may be the use of these organisms in limiting the spread of antibiotic resistance. Bacteroides species have long been recognized as a reservoir of antibiotic resistance genes, which presents a problem for treating pathogenic infections as the native microbiota might provide the genetic material for resistance. The authors used the powerful gene-editing technique, CRISPR, to silence genes specific for antibiotic resistance within B. theta. For a patient on a course of antibiotics, silencing these genes in B. theta could reduce the spread of antibiotic resistance genes and make the infection more likely to clear quickly. Aside from antibiotic resistance though, the ability to silence microbial processes could also reduce the spread of disease if deadly pathogens can be converted into harmless gut passengers just by turning off virulence factors or toxin production.
The gut microbiota has been implicated in conditions affecting nearly every aspect of human health, suggesting that engineering the gut ecosystem could have important consequences for positively impacting human health. This work in B. theta represents an advance in our capacity to engineer rational control over the activities of microorganisms living in our gut. The authors showed that these engineered bacteria could carry out their programmed functions in vivo, demonstrating that bacteria fed to mice responded to external stimuli and successfully recorded history of environmental exposures. Though the technology still requires considerable development before adopted for treatment and diagnostic use in humans, engineered bacteria may soon be a regular feature of our medicine cabinets.