Researchers identify molecular link between gut bacteria and excitatory brain signaling in C. elegans

A new study published in Natural cellular biology by Mark Alkema, Ph.D., professor of neurobiology at the University of Massachusetts Chan Medical School, establishes an important molecular link between specific B12-producing bacteria in the gut of the roundworm C. elegans and the production of acetylcholine, a neurotransmitter important for memory and cognitive function.

Scientists increasingly recognize that diet and gut microbiota may play an important role in brain health. Changes in microbiome composition have been associated with neurological disorders such as anxiety, depression, migraines, and neurodegeneration. Yet determining the cause and effect of individual bacteria or nutrients on brain function has proven challenging.

“There are more bacteria in your gut than cells in your body,” said Woo Kyu Kang, Ph.D., a postdoctoral researcher in the Alkema lab and first author of the current study. “The complexity of the brain, the hundreds of bacterial species that make up the gut microbiome, and the diversity of metabolites make it almost impossible to understand the impact of bacteria on brain function.”

To isolate the impact of individual bacteria on specific brain functions, Dr. Kang fed a diet of a single bacterial species to worms carrying a mutation that causes an imbalance in excitatory/inhibitory signaling in the brain and leads to seizure-like behaviors. in the worm. A similar genetic mutation in humans causes migraines.

Kang fed these C. elegans mutants a diet of a single bacterial species and observed changes in seizure frequency. Of the 40 different bacterial diets he tested, 18 reduced the number of seizures. Further experiments showed that the common attribute among many of these bacteria was their ability to produce vitamin B12.

According to Dr. Alkema and Kang, B12 reduces choline levels in the body. Choline, a compound found in various foods and essential for fat metabolism in the liver, may be used in the vitamin B12-dependent methionine/S-adenosylmethionine (Met/SAM) cycle, a metabolic pathway that produces methionine ( an amino acid acquired by humans through diet essential for metabolism) in the intestine.

However, choline is also used to make the neurotransmitter acetylcholine in the nervous system. Too much acetylcholine results in an excitatory imbalance that causes seizure-like behavior in mutant worms.

When more B12 is present, more choline is used in the Met/SAM cycle, leaving less choline to produce acetylcholine. Reducing the amount of acetylcholine restores the excitatory/inhibitory balance in the nervous system and reduces seizure activity in C. elegans.

The researchers highlighted that the impact of “crosstalk” between the microbiome, vitamin B12, brain function and behavior only appears under conditions where the organism is stressed, either genetically or environmentally. B12 deficiency in humans has been associated with neurological disorders characterized by excitatory/inhibitory imbalance such as schizophrenia, depression, and migraines.

“It will be interesting to determine whether the molecular mechanisms discovered in the worm can also explain the impact of B12 on excitatory signaling in several human neurological disorders,” Alkema said.

By using other worm models for other human diseases and testing other metabolites and bacteria, Alkema and his colleagues hope to reveal other links between the gut microbiome and brain function that can also be used to improve the human health.

Provided by UMass Chan School of Medicine