Research shows how colanic acid extends longevity in C. elegans

Meng Wang, a researcher at Baylor College of Medicine, had already shown that bacteria that produce a metabolite called colanic acid (CA) could extend the life of worms in its laboratory by as much as 50%, but her collaboration with Rice University synthetic biologist Jeffrey Tabor provides tools to answer the larger question of how the metabolite provides longer life.

In a study published in eLife, Wang, Tabor and colleagues showed that they could use different colors of light to turn gut bacteria genes on and off while the bacteria were in the intestines of worms. The work was made possible by an optogenetic control system that Tabor has been developing for more than a decade.

The Meng group found that the CA fertilizer could extend life but could not say for sure whether this was a dietary ingredient digested in the stomach or a metabolite produced by bacteria in the stomach. . We were able to limit CA production to the cleavage and show that it had a beneficial effect on cells in the abdomen. “

Tabor, Associate Professor of Bioengineering and Biological Sciences, Rice University

For the experiments, Tabor’s laboratory engineered strains of E. coli to produce CA when exposed to green light, but not red. To make sure the bacteria worked properly, the team applied genes to produce different colors of fluorescent proteins that would show up clearly under a microscope. One color was always present, to make it easy to see where the bacteria were inside the worms, and a second color was made only when the bacteria were making CA.

In collaboration with Wang’s laboratory, Tabor’s laboratory kept the bacteria under red light and fed them worms, a species known as Caenorhabditis elegans (C. elegans) that is commonly used in life sciences. Researchers monitored the progress of the bacterium through the digestive tract and turned on the green light when they made it to the abdomen.

“When exposed to green light, worms carrying this E. coli strain also lived longer. The stronger the light, the longer it lasts,” said Wang, Chairman of Robert C’s Endowment .Fyfe on Aging, professor of molecular and human genetics at Baylor’s Huffington Center for Aging and Howard Hughes Medical Institute researcher.

In C. elegans cells and other higher order life, from humans to yeast, specific organelles called mitochondria supply most of the energy. Thousands of mitochondria work around the clock in each cell and maintain a dynamic balance between uniformity and fusion, but become less efficient over time. As humans and other organisms grow, a lack of mitochondria leads to a decline in function in their cells.

In prior experiments with C. elegans, Wang and colleagues showed that CA can regulate the balance between mitochondrial fission and fusion in both intestinal and muscle cells to improve longevity. The worms usually live around three weeks, but Wang’s lab has shown that CA can extend their life to 4.5 weeks – 50% longer than normal.

Tabor said this raises a number of questions. For example, if CA is excreted in the gut, do intestinal cells benefit first? Is the beneficial effect of CA related to its level? And most importantly, do the mitochondrial benefits spread throughout the body from within?

in the eLife study, the researchers found that CA production in the gut significantly improved mitochondrial function in intestinal cells. They found no evidence of such direct, short-term mitochondrial benefits in worm muscle cells. Thus, the longevity effect of CA starts from the cleavage and then spreads into other fissures over time.

“With our technology, we can use light to turn on CA production and watch the impact travel through the worm,” Tabor said.

He said the accuracy of the optogenetic technology could allow researchers to ask fundamental questions about gut metabolism.

“If you can control the time and place of metabolite production with precision, you can think of an experimental design that demonstrates cause and effect,” he said.

A key achievement is to show that gut bacteria have a direct impact on health or disease.

“We know that gut bacteria affect many processes in our bodies,” Tabor said. “They have been linked to obesity, diabetes, anxiety, cancers, autoimmune diseases, heart disease and kidney disease. There has been a study to measure what bacteria you have when you have this or that illness, and it shows all sorts of corrections. “

But there is a big difference between showing correlation and causation, Tabor said.

“The goal, what you really want, is gut bacteria that you can eat that will improve health or treat disease,” he said.

But researchers find it difficult to prove that molecules produced by gut bacteria cause disease or health. That’s partly because it’s difficult to get into experimentally, and it’s especially difficult to design experiments that show what’s going on in specific places within the slit.

“The gut is a difficult place to get into, especially in large mammals,” Tabor said. “Our intestines are 28 feet long, and they’re very heterogeneous. The pH changes all over and the bacteria changes a lot along the way. So do the figs and what they do, like the molecules they separate.

“To answer questions about how gut bacteria affect our health, you need to be able to turn on genes in certain places and at certain times, such as when an animal is young or when an animal wakes up in the morning. , “he said.” You need that level of control to examine trails on their own turf, where they occur and how they occur. “

Because it uses light to stimulate genes, optogenetics offers that level of control, Tabor said.

“So far, light is actually the only signal that has enough precision to turn bacterial genes on the small scale against the large intestine, for example, or during the day but not at night, “he said.

Tabor said he and Wang have considered many ways in which they could use optogenetics to study age.

“She has discovered two dozen bacterial genes that can extend life in C. elegans, and we don’t know how most of them work,” Tabor said. “The colanic acid genes are very interesting, but there are many more that we would like to turn on with light in the worm to find out how they work. We can reveal the exact invention In this paper we can also use them to study the new genes.And other people who study the microbome can also use it.It is a powerful tool for studying how bacteria infect benefit our health. “