Optogenetics Give Gut Bacteria the Green Light to Promote Longevity

Once thought to solely play a role in the digestion of food and synthesis of certain vitamins, the bacteria that live in our guts are now known to do so much more. With numbers topping 100 trillion, this collection of bacteria is known as the gut microbiome. In addition to its predictable role of benefiting intestinal health, research has also found the microbiome to play a role in immunity, inflammation, mental health, obesity, metabolism, brain function, and — most recently — aging.

These gut microbes also produce various bacterial metabolites that modulate health and longevity, which researchers from Baylor College of Medicine and Rice University have targeted in a recent study. Published in eLife in December 2020, Hartsough and colleagues investigated the impact of a certain bacterial metabolite on the aging process in worms, using green light exposure to control the activity of genetically engineered bacteria  — also known as optogenetics.

Channeling light to choreograph gene activity

First described in 2005, optogenetics is an innovative method that uses light to control gene levels and activity. Although the field of optogenetics is relatively recent, certain species of green algae have been intuitively practicing it for billions of years. The behavior of algae led to the discovery of optogenetics, as these single-celled organisms use proteins called opsins to move towards light sources, creating the energy it needs to survive through photosynthesis. 

Over the past 15 years, optogenetics has not only revolutionized the field of neuroscience, as the method is most often used to precisely control neuron activity, but it has also has shown promise in treating conditions related to the heart, eyes, and muscles. Now, Hartsough and colleagues show how optogenetics can be used to manipulate gene activity and bacterial metabolism in the gut microbiome.

Genetic modifications worm their way in 

Previous research from the same team found that 29 mutants of the bacteria Escherichia coli (E. coli) — meaning, versions of E. coli with a gene deleted — increased lifespan in the worm Caenorhabditis elegans (C. elegans) by up to 40 percent. 

From there, the researchers narrowed it down to five bacterial mutants that promote longevity through increased secretion of a type of sugar found on the exterior of many gut microbes called colanic acid. Specifically, one of the E. coli bacterial mutants deleted a gene called Lon, which encodes for a protein that reduces colanic acid levels; worms without Lon were found to have significantly longer lifespans. 

Piggybacking off of this previous study, Hartsough and colleagues aimed to extend the lifespan of C. elegans by feeding them a genetically engineered strain of E. coli that increases the secretion of colanic acid when exposed to green light.

Bringing bacteria to light 

Using fluorescent reporter proteins that respond to specific colors, the researchers engineered a strain of E. coli to increase colanic acid production when exposed to green light and deactivate when exposed to red light. After feeding the bacteria to the worms, shining green light on the transparent C. elegans increased their colanic acid production and significantly improved several aspects of the worms’ lives, including the overall lifespan and function of their intestinal mitochondria — also known as the energy powerhouses of the cell. 

When exposed to a low exposure of green light, the worms containing this colanic acid-boosting E. coli strain lived to approximately 12 days, compared to 11 days when the worms were exposed to red light. When the intensity of the green light was increased, the lifespan was extended to about 14 days. This indicates that the additional colanic acid produced after green light exposure benefits lifespan in a dose-dependent manner — meaning, the more intense the green light exposure, the longer the life. If these results were to affect humans in the same way, humans would live 8 to 24 years longer, assuming the average human lives to be 79. Although we can’t directly extrapolate this research to humans — and no human research has been done yet — it suggests that increasing colanic acid production in this way may lead to longer lifespans.

Colanic acid also protected the intestinal mitochondria from stress-induced fragmentation, also known as mitochondrial fission. As mitochondria are highly dynamic parts of the cell, they frequently fuse together and fragment apart. While mitochondrial fragmentation can be a protective response — it can segregate and clear damaged mitochondria — too much of this process negatively impacts overall mitochondrial function. As mitochondrial dysfunction is implicated in accelerated aging, studies in yeast and worms have found that inhibiting this fragmentation is linked to increased longevity. 

After inducing stressful conditions, green light exposure significantly suppressed the mitochondrial hyper-fragmentation that arose in these worms’ intestinal tracts. The researchers believe that this protective effect on intestinal cells is due to the overproduction of colanic acid in their guts. 

Although this research addressed aging, it didn’t tackle any specific diseases. The team hypothesizes that engineering gut bacteria to make more colanic acid could soon be used for the treatment of many other age-related disorders. Additionally, they are hopeful that optogenetics will uncover other ways to positively impact human health by studying different gut bacteria metabolites. That gets a green light from us. 

References: 

Han B, Sivaramakrishnan P, Lin CJ, et al. Microbial Genetic Composition Tunes Host Longevity.  Cell. 2017;169(7):1249-1262.e13. doi:10.1016/j.cell.2017.05.036

Hartsough LA, Park M, Kotlajich MV, et al. Optogenetic control of gut bacterial metabolism to promote longevity. Elife. 2020;9:e56849. Published 2020 Dec 16. doi:10.7554/eLife.56849