by Jess Kanwal
figures by Shannon McArdel
Would you be willing to pop “freeze-dried-poop” pills for a chance to slim down? While this weight-loss strategy certainly doesn’t sound appetizing, scientists are currently embarking on a clinical trial to find out whether such a method could be a new treatment for obesity.
Researchers are collecting fecal samples from lean, healthy donors, freeze-drying their stool and packaging a few grams of it into capsules, which are then given to 20 obese patients. Elaine Yu, an assistant professor and clinical researcher at Massachusetts General Hospital, is leading the study and plans to monitor the weight and health of the patients over the course of a year.
Why would poop-packaged pills help obese patients?
There are over 10 trillion microbes that inhabit the human body, collectively called the microbiome. Most of them live in the gut and intestines, where they help us to digest food, synthesize vitamins, and fight off infection (Figure 1). Recent work has also suggested that these microbes may play a role in regulating body weight.
Jeffery Gordon of Washington University, St. Louis and his team raised genetically identical rodents in a germ-free environment so that they would be free of any bacteria. They then populated the guts of these mice either with human intestinal microbes from an obese woman or from her lean twin sister. The mice that received microbes from the obese twin became chubby and had more body fat than the ones that received microbes from the thin twin.
Mice from both groups were fed exactly the same diet and ate the same amount of food. Furthermore, Gordon and his colleagues showed that the microbial community from a lean human could infiltrate and displace that from an obese person, preventing mice from gaining weight as long as they were on a healthy diet. These experiments demonstrate that human gut microbes “transmitted” to mice can shape physical traits such as obesity and leanness in the mice. We will have to wait for results from further studies, such as the one led by Elaine Yu, to find out whether the same is true for human to human microbe transfer. Specifically, she’s asking whether transferring intestinal microbes from a slim person may help an obese person lose weight.
Obesity is a disorder of energy balance, as it occurs when we consume more calories in our food than we burn through physical activities and exercise. Normally, the brain responds to signals from within our body and the external environment to decide when we should and should not eat. A brain region called the hypothalamus integrates a variety of cues, such as hormone levels and the smell of food in our surroundings, to regulate our hunger and metabolism levels. It was previously thought that the brain is solely responsible for regulating body weight, since it controls peripheral organs such as the gut. However, in light of studies like that led by Jeffery Gordon, scientists now think that the gut-brain communication pathway could be bidirectional.
How could microbes in the gut send messages to the brain?
Researchers think there may be three major ways that gut microbes could send signals to the brain, a communication pathway termed the gut-brain-axis (Figure 2). One method hypothesizes that microbes may signal the brain through the vagus nerve, which connects networks of nerves in the gut to various brain regions such as the hypothalamus. Nerve cells are activated or suppressed by chemical signals called neurotransmitters. One such example of a neurotransmitter is serotonin, which is thought to largely regulate appetite and mood. Researchers have found that certain gut microbe species can directly produce serotonin. Serotonin release from the gut can then stimulate the vagus nerve. Thus, researchers speculate that when gut microbes prompt the release of serotonin and stimulate the vagus nerve, it may in turn alter activity in the hypothalamus and other brain regions and affect hunger levels (Figure 3). Although such pathways exist, it remains unknown how altered serotonin levels in the gut influence brain activity. Several research labs, such as that of Dr. Elain Hsaio at UCLA, are trying to understand the connection between gut microbe serotonin production and brain activity.
The second hypothesized method of gut-brain communication proposes that gut microbes may stimulate immune cells, which could then signal the brain. For example, gut microbes can prompt immune cells to produce and release small proteins called cytokines. Cytokines may then travel through the bloodstream to the brain, where they can influence the maturation and activation of microglia. Microglia are the primary immune cells in the brain and when activated perform functions such as removing damaged cells at a site of injury. Researchers speculate that the proper functioning of microglia in brain regions such as the hypothalamus is critical for maintaining the health of those cells so that they can continue to integrate hunger-related information and regulate metabolism.
The third method of communication is proposed to be through metabolites, molecules produced by microbes in the gut. For example, a recent study found that certain gut-microbe-derived fatty acids, such as butyrate and tyramine, signal to cells that line the digestive tract to increase serotonin production. The increased serotonin could then stimulate vagal nerves or enter the bloodstream and travel to the brain. In relation to hunger, it is possible that serotonin or other nutrients that reach the brain through blood vessels may affect local neuron activity in the hypothalamus and modulate hunger. However, the effect of serotonin traveling in the bloodstream on brain activity is still largely speculation and remains to be explored.
Although correlation studies show that microbes have an affect on the brain, neuroscientists are still at the early stages of uncovering the molecular cascades of events that explain exactly how gut microbes communicate with the brain. A recent effort to describe such processes in detail led to the discovery of one way in which the gut microbiome affects obesity levels in organisms.
In a study led by Gerald Schulman from Yale University, researchers placed mice on a high-fat diet. They found that the gut microbes present after an animal was on such a diet produced more acetate, a short-chain fatty acid. That acetate spread throughout the rodents’ bodies and into their brains where it activated a network of nerve pathways that regulate the body’s unconscious actions, such as digestion and excretion. Activation of this nerve network then led certain brain regions to send a signal through the vagus nerve down to the pancreas to increase insulin production. Insulin tells fat cells to store more energy. More insulin caused fat to build up and this in turn lead to obese mice. The acetate also increased levels of a hunger-promoting hormone called ghrelin, which is thought to have led the animals to eat even more.
We are just at the beginning of discovering methods by which the gut-brain axis modulates obesity, but this communication pathway is likely not just for regulating hunger. Studies have correlated the gut microbiome to changes in brain development, psychiatric and neurodevelopment disorders, as well as stress, anxiety, and mood.
The quest is on to study and understand the function and role of each microbe present in the human body. Ideally, future treatments will comprise of supplementing one’s diet with the specific missing microbe species that could, for instance, alleviate depression or cause weight loss. For now, we will have to wait and see whether poop pills, and the tiny creatures in them, have the potential to alter our bodies and minds.
Jessleen K. Kanwal is a Ph.D. candidate in the Program in Neuroscience at Harvard University.
For more information:
To learn more about how the gut communicates to the brain, check out these links:
To learn more about how microbe acetate production affects obesity, check out these links:
Perry, R., Peng, L., Barry, N., Cline, G., et al. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature. June 2016.
To learn more about how microbes affect the brain through immune cells, check out this link:
Rea, K., Dinan, T., Cryan, J. The microbiome: A key regulator of stress and neuroinflammation. Neurobiology of Stress. March 2016.
To learn more about how gut microbes mediate serotonin production, check out these links:
Yano, J., Yu, K., Donaldson, G., Shastri, G., et al. Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis. Cell. April 2015.