The Prospect of Engineering Better Gut Bacteria

Scientists are finding that gut bacteria have some influence on natural variations in longevity; not as much as exercise or calorie intake - though they they may mediate some of those benefits - but enough to be interesting to the research community. The distribution of species changes with age, for example, and gut bacteria interact with the immune system to produce inflammation and other effects. A range of other specific mechanisms will probably emerge in the years ahead as more research teams join the investigation. I suspect that this is one of those parts of the field that will diminish in importance as rejuvenation therapies after the SENS model take off: the size of the effects are just not all that interesting in a world in which it becomes possible to reliably add ten or more healthy years with treatments to clear senescent cells, remove glucosepane cross-links, and so forth. Still, I think you'll have to agree that the prospect of engineering better, more beneficial gut bacteria, as outlined here, is certainly interesting from a technical and future scope of options perspective, setting aside the question of the size of likely near-term benefits for a moment.

We have a symbiotic relationship with the trillions of bacteria that live in our bodies - they help us, we help them. It turns out that they even speak the same language. And new research suggests these newly discovered commonalities may open the door to "engineered" gut flora who can have therapeutically beneficial effects on disease. In a double-barreled discovery, researchers found that gut bacteria and human cells, though different in many ways, speak what is basically the same chemical language, based on molecules called ligands. Building on that, they developed a method to genetically engineer the bacteria to produce molecules that have the potential to treat certain disorders by altering human metabolism. In a test of their system on mice, the introduction of modified gut bacteria led to reduced blood glucose levels and other metabolic changes in the animals.

The method involves the lock-and-key relationship of ligands, which bind to receptors on the membranes of human cells to produce specific biological effects. In this case, the bacteria-derived molecules are mimicking human ligands that bind to a class of receptors known as GPCRs, for G-protein-coupled receptors. Many of the GPCRs are implicated in metabolic diseases and are the most common targets of drug therapy. And they're conveniently present in the gastrointestinal tract, where the gut bacteria are also found. The researchers engineered gut bacteria to produce specific ligands, N-acyl amides, that bind with a specific human receptor, GPR 119, that is known to be involved in the regulation of glucose and appetite, and has previously been a therapeutic target for the treatment of diabetes and obesity. The bacterial ligands they created turned out to be almost identical structurally to the human ligands.

Among the advantages of working with bacteria is that their genes are easier to manipulate than human genes and much is already known about them. "All the genes for all the bacteria inside of us have been sequenced at some point. The biggest change in thought in this field over the last 20 years is that our relationship with these bacteria isn't antagonistic. They are a part of our physiology. What we're doing is tapping into the native system and manipulating it to our advantage. This is a first step in what we hope is a larger-scale, functional interrogation of what the molecules derived from microbes can do."



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