Recent studies suggest that animals and people alike have close and complex relationships with the bacteria around and within them. The human gut microbiome, for instance, has been associated with both depression and Parkinson's disease. To go beyond association toward understanding of the actual mechanisms that enable the bacterial microbiome to influence brain function, a new study by neuroscientists in The Picower Institute for Learning and Memory at MIT examines the mechanisms at work in a model "bacterial specialist," the nematode C. elegans.
In the new study in Current Biology, the team led by postdoctoral Picower Fellow Cassi Estrem in the Picower Institute lab of Associate Professor Steven Flavell identifies the specific chemicals that a key neuron in C. elegans senses both in the bacteria that it eats as well as in the bacteria that it needs to avoid ingesting.
"In our bodies, our own cells are outnumbered by the bacterial cells living in and on us. There's an increasing recognition that this has a profound impact on human health," said Flavell, an investigator of the Howard Hughes Medical Institute and faculty member of MIT's Brain and Cognitive Sciences Department. "It's been clear that there are links for some time. Our study aimed to identify the hard mechanisms of how a host nervous system is affected by bacteria in the alimentary canal."
Achieving a fundamental mechanistic understanding of how neurons interact with bacteria could help improve attempts to intervene in or manipulate those interactions with therapeutic drugs or supplements, Flavell said.
Mmm…sugar
Flavell calls C. elegans a "bacterial specialist" because the tiny, transparent worm has evolved to eat bacteria as its diet, while also needing to avoid pathogenic bacteria that can prove to be its undoing. This has led it to develop a nervous system especially well attuned to sorting out what is food and what is foe. In 2019, the lab discovered that the neuron NSM, which projects into the worm's alimentary canal, employs two "acid sensing ion channels" (ASICs) to detect when certain bacteria have been ingested. Notably, those ion channels are analogous to ones found in neurons in humans. When NSM detects yummy bacteria, it releases serotonin that causes the worm to increase its feeding rate and slow its slithering so that it can stay to dine on the surrounding meal.
To really understand how this works, Flavell and Estrem realized they needed to know exactly what the ion channels are detecting in the bacteria. To get started, they exposed worms to 20 different kinds of bacteria the worms are known to encounter and found that they all activated NSM activity to varying extents. Then they broke the bacteria down into more and more specific chemical components to see which one or ones triggered NSM. The experiments ruled out many components, including DNA, lipids, proteins, and simple sugars, and instead found that it's specifically the polysaccharide sugars that coat many bacteria that drive NSM activation. In particular, in gram-positive bacteria, a chemical called peptidoglycan activated NSM. In gram-negative bacteria, a different polysaccharide was apparently in play.
Estrem and Flavell's team also ran experiments showing that polysaccharides from bacteria in general and peptidoglycan in particular not only trigger NSM electrical activity but actually promote the feeding and slowing behaviors. They also showed that genetically knocking out the ASICs abolished these responses. In all, they demonstrated that polysaccharide and peptidoglycan detection are sufficient to trigger the worm's behaviors and requires the ASICs.
Better not eat this
Having shown what exactly triggers the worms to recognize their bacterial food, the researchers wondered whether they could also pinpoint a danger sign the worm finds in harmful bacteria. For these experiments, they carefully used Serratia marcescens, a bacterium that's also infectious for humans. Some strains of the bacteria have a red color while others do not. The red ones, which have a pigment called prodigiosin, tend to be much more lethal for worms. In their testing, the researchers found that when NSM detected the non-pigmented bacteria, the neuron still activated and the worms still ingested the bacteria, but when prodigiosin was present, NSM did not activate and the worm did not pump it in or slow down to eat.
Adding prodigiosin to normally yummy bacteria also suppressed NSM's usual response. In other words, the worms have evolved their digestive behavior (and the detectors within NSM) to avoid ingesting a chemical specifically associated with danger.
Flavell says it's likely that some of the fundamental mechanisms highlighted in the new paper will inform studies of similar mechanisms in other animals.
"We developed a way of identifying these pathways by studying this organism that specializes in bacterial detection and displays robust responses," Flavell said. "But there's no reason these pathways should be limited to C. elegans. The molecular players we identified are found in many species, including mammals."
In addition to Estrem and Flavell, the paper's other authors are Malvika Dua, Colby Fees, Greg Hoeprich, Matthew Au, Bruce Goode, and Lingyi Deng.
The National Institutes of Health, the McKnight Foundation, the Alfred P. Sloan Foundation, the Howard Hughes Medical Institute, and The Freedom Together Foundation provided support for the study.
