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Friday, September 22, 2017

The Brain in Your Gut

I know a lot of people with gastroparesis have memory issues, myself included. So, what causes this? How does our brain chemistry change when you have gastroparesis? Sleep deprivation, malnutrition, and medication can play a big part in altering our brain chemistry but I wanted to dig a bit deeper to see what else can change our body's brain chemistry, and why it affects us so harshly.


According to Cal Tech,

"Although serotonin is well known as a brain neurotransmitter, it is estimated that 90 percent of the body's serotonin is made in the digestive tract. In fact, altered levels of this peripheral serotonin have been linked to diseases such as irritable bowel syndrome, cardiovascular disease, and osteoporosis.

'More and more studies are showing that mice or other model organisms with changes in their gut microbes exhibit altered behaviors,' explains Elaine Hsiao, research assistant professor of biology and biological engineering and senior author of the study. 'We are interested in how microbes communicate with the nervous system. To start, we explored the idea that normal gut microbes could influence levels of neurotransmitters in their hosts.'

Peripheral serotonin is produced in the digestive tract by enterochromaffin (EC) cells and also by particular types of immune cells and neurons. Hsiao and her colleagues first wanted to know if gut microbes have any effect on serotonin production in the gut and, if so, in which types of cells. They began by measuring peripheral serotonin levels in mice with normal populations of gut bacteria and also in germ-free mice that lack these resident microbes.

The researchers found that the EC cells from germ-free mice produced approximately 60 percent less serotonin than did their peers with conventional bacterial colonies. When these germ-free mice were recolonized with normal gut microbes, the serotonin levels went back up—showing that the deficit in serotonin can be reversed.

'EC cells are rich sources of serotonin in the gut. What we saw in this experiment is that they appear to depend on microbes to make serotonin—or at least a large portion of it,' says Jessica Yano, first author on the paper and a research technician working with Hsiao.

The researchers next wanted to find out whether specific species of bacteria, out of the diverse pool of microbes that inhabit the gut, are interacting with EC cells to make serotonin.

After testing several different single species and groups of known gut microbes, Yano, Hsiao, and colleagues observed that one condition—the presence of a group of approximately 20 species of spore-forming bacteria—elevated serotonin levels in germ-free mice. The mice treated with this group also showed an increase in gastrointestinal motility compared to their germ-free counterparts, and changes in the activation of blood platelets, which are known to use serotonin to promote clotting.

Wanting to home in on mechanisms that could be involved in this interesting collaboration between microbe and host, the researchers began looking for molecules that might be key. They identified several particular metabolites—products of the microbes' metabolism—that were regulated by spore-forming bacteria and that elevated serotonin from EC cells in culture. Furthermore, increasing these metabolites in germ-free mice increased their serotonin levels.

Previous work in the field indicated that some bacteria can make serotonin all by themselves. However, this new study suggests that much of the body's serotonin relies on particular bacteria that interact with the host to produce serotonin, says Yano. 'Our work demonstrates that microbes normally present in the gut stimulate host intestinal cells to produce serotonin,' she explains.

'While the connections between the microbiome and the immune and metabolic systems are well appreciated, research into the role gut microbes play in shaping the nervous system is an exciting frontier in the biological sciences,' says Sarkis K. Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and a coauthor on the study. 'This work elegantly extends previous seminal research from Caltech in this emerging field'.

Additional coauthor Rustem Ismagilov, the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering, adds, 'This work illustrates both the richness of chemical interactions between the hosts and their microbial communities, and Dr. Hsiao's scientific breadth and acumen in leading this work.'

Serotonin is important for many aspects of human health
, but Hsiao cautions that much more research is needed before any of these findings can be translated to the clinic.

'We identified a group of bacteria that, aside from increasing serotonin, likely has other effects yet to be explored,' she says. 'Also, there are conditions where an excess of peripheral serotonin appears to be detrimental.'

Although this study was limited to serotonin in the gut, Hsiao and her team are now investigating how this mechanism might also be important for the developing brain. 'Serotonin is an important neurotransmitter and hormone that is involved in a variety of biological processes. The finding that gut microbes modulate serotonin levels raises the interesting prospect of using them to drive changes in biology,' says Hsiao.

The work was published in an article titled 'Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis.' In addition to Hsiao, Yano, Mazmanian, and Ismagilov, other Caltech coauthors include undergraduates Kristie Yu, Gauri Shastri, and Phoebe Ann; graduate student Gregory Donaldson; postdoctoral scholar Liang Ma. Additional coauthor Cathryn Nagler is from the University of Chicago."

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This is an interesting study considering that Gastroparesis/DTP is slow to little to no motility, depending on how severe it is in each person affected with it. If 90 percent of serotonin is produced in the stomach, what happens to that serotonin when the motility is limited or the stomach is removed? Could that be a link to depression in people with Gastroparesis? Scientific American believes that psychiatry may have to readjust to consider just that in the years to come as discussed below.

According to Scientific American,

"As Olympians go for the gold in Vancouver, even the steeliest are likely to experience that familiar feeling of 'butterflies' in the stomach. Underlying this sensation is an often-overlooked network of neurons lining our guts that is so extensive some scientists have nicknamed it our 'second brain'.

A deeper understanding of this mass of neural tissue, filled with important neurotransmitters, is revealing that it does much more than merely handle digestion or inflict the occasional nervous pang. The little brain in our innards, in connection with the big one in our skulls, partly determines our mental state and plays key roles in certain diseases throughout the body.

Although its influence is far-reaching, the second brain is not the seat of any conscious thoughts or decision-making.

'The second brain doesn't help with the great thought processes…religion, philosophy and poetry is left to the brain in the head,' says Michael Gershon, chairman of the Department of Anatomy and Cell Biology at New York–Presbyterian Hospital/Columbia University Medical Center, an expert in the nascent field of neurogastroenterology and author of the 1998 book The Second Brain (HarperCollins).

Technically known as the enteric nervous system, the second brain consists of sheaths of neurons embedded in the walls of the long tube of our gut, or alimentary canal, which measures about nine meters end to end from the esophagus to the anus. The second brain contains some 100 million neurons, more than in either the spinal cord or the peripheral nervous system, Gershon says.

This multitude of neurons in the enteric nervous system enables us to 'feel' the inner world of our gut and its contents. Much of this neural firepower comes to bear in the elaborate daily grind of digestion. Breaking down food, absorbing nutrients, and expelling of waste requires chemical processing, mechanical mixing and rhythmic muscle contractions that move everything on down the line.

Thus equipped with its own reflexes and senses, the second brain can control gut behavior independently of the brain, Gershon says. We likely evolved this intricate web of nerves to perform digestion and excretion 'on site,' rather than remotely from our brains through the middleman of the spinal cord. 'The brain in the head doesn't need to get its hands dirty with the messy business of digestion, which is delegated to the brain in the gut,' Gershon says. He and other researchers explain, however, that the second brain's complexity likely cannot be interpreted through this process alone.

'The system is way too complicated to have evolved only to make sure things move out of your colon,' says Emeran Mayer, professor of physiology, psychiatry and biobehavioral sciences at the David Geffen School of Medicine at the University of California, Los Angeles (U.C.L.A.). For example, scientists were shocked to learn that about 90 percent of the fibers in the primary visceral nerve, the vagus, carry information from the gut to the brain and not the other way around. "Some of that info is decidedly unpleasant," Gershon says.

The second brain informs our state of mind in other more obscure ways, as well. 'A big part of our emotions are probably influenced by the nerves in our gut,' Mayer says. Butterflies in the stomach—signaling in the gut as part of our physiological stress response, Gershon says—is but one example. Although gastrointestinal (GI) turmoil can sour one's moods, everyday emotional well-being may rely on messages from the brain below to the brain above. For example, electrical stimulation of the vagus nerve—a useful treatment for depression—may mimic these signals, Gershon says.

Given the two brains' commonalities, other depression treatments that target the mind can unintentionally impact the gut. The enteric nervous system uses more than 30 neurotransmitters, just like the brain, and in fact 95 percent of the body's serotonin is found in the bowels. Because antidepressant medications called selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels, it's little wonder that meds meant to cause chemical changes in the mind often provoke GI issues as a side effect. Irritable bowel syndrome—which afflicts more than two million Americans—also arises in part from too much serotonin in our entrails, and could perhaps be regarded as a "mental illness" of the second brain.

Scientists are learning that the serotonin made by the enteric nervous system might also play a role in more surprising diseases: In a new Nature Medicine study published online February 7, a drug that inhibited the release of serotonin from the gut counteracted the bone-deteriorating disease osteoporosis in postmenopausal rodents. (Scientific American is part of Nature Publishing Group.) 'It was totally unexpected that the gut would regulate bone mass to the extent that one could use this regulation to cure—at least in rodents—osteoporosis,' says Gerard Karsenty, lead author of the study and chair of the Department of Genetics and Development at Columbia University Medical Center.

Serotonin seeping from the second brain might even play some part in autism, the developmental disorder often first noticed in early childhood. Gershon has discovered that the same genes involved in synapse formation between neurons in the brain are involved in the alimentary synapse formation. 'If these genes are affected in autism,' he says, 'it could explain why so many kids with autism have GI motor abnormalities' in addition to elevated levels of gut-produced serotonin in their blood.

Down the road, the blossoming field of neurogastroenterology will likely offer some new insight into the workings of the second brain—and its impact on the body and mind. 'We have never systematically looked at [the enteric nervous system] in relating lesions in it to diseases like they have for the' central nervous system, Gershon says. One day, perhaps there will be well-known connections between diseases and lesions in the gut's nervous system as some in the brain and spinal cord today indicate multiple sclerosis.

Cutting-edge research is currently investigating how the second brain mediates the body's immune response; after all, at least 70 percent of our immune system is aimed at the gut to expel and kill foreign invaders.

U.C.L.A.'s Mayer is doing work on how the trillions of bacteria in the gut 'communicate' with enteric nervous system cells (which they greatly outnumber). His work with the gut's nervous system has led him to think that in coming years psychiatry will need to expand to treat the second brain in addition to the one atop the shoulders."

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According to John's Hopkins,

"If you’ve ever "gone with your gut' to make a decision or felt 'butterflies in your stomach' when nervous, you’re likely getting signals from an unexpected source: your second brain. Hidden in the walls of the digestive system, this 'brain in your gut' is revolutionizing medicine’s understanding of the links between digestion, mood, health and even the way you think.

Scientists call this little brain the enteric nervous system (ENS). And it’s not so little. The ENS is two thin layers of more than 100 million nerve cells lining your gastrointestinal tract from esophagus to rectum.

What Does Your Gut’s Brain Control?

Unlike the big brain in your skull, the ENS can’t balance your checkbook or compose a love note. 'Its main role is controlling digestion, from swallowing to the release of enzymes that break down food to the control of blood flow that helps with nutrient absorption to elimination,' explains Jay Pasricha, M.D., director of the Johns Hopkins Center for Neurogastroenterology, whose research on the enteric nervous system has garnered international attention. 'The enteric nervous system doesn’t seem capable of thought as we know it, but it communicates back and forth with our big brain—with profound results.'

The ENS may trigger big emotional shifts experienced by people coping with irritable bowel syndrome (IBS) and functional bowel problems such as constipation, diarrhea, bloating, pain and stomach upset. 'For decades, researchers and doctors thought that anxiety and depression contributed to these problems. But our studies and others show that it may also be the other way around,' Pasricha says. Researchers are finding evidence that irritation in the gastrointestinal system may send signals to the central nervous system (CNS) that trigger mood changes.

'These new findings may explain why a higher-than-normal percentage of people with IBS and functional bowel problems develop depression and anxiety,' Pasricha says. 'That’s important, because up to 30 to 40 percent of the population has functional bowel problems at some point.'

New Gut Understanding Equals New Treatment Opportunities

This new understanding of the ENS-CNS connection helps explain the effectiveness of IBS and bowel-disorder treatments such as antidepressants and mind-body therapies like cognitive behavioral therapy (CBT) and medical hypnotherapy. 'Our two brains ‘talk’ to each other, so therapies that help one may help the other,' Pasricha says. 'In a way, gastroenterologists (doctors who specialize in digestive conditions) are like counselors looking for ways to soothe the second brain.'

Gastroenterologists may prescribe certain antidepressants for IBS, for example—not because they think the problem is all in a patient’s head, but because these medications calm symptoms in some cases by acting on nerve cells in the gut, Pasricha explains. 'Psychological interventions like CBT may also help to 'improve communications' between the big brain and the brain in our gut,' he says.

Still More to Learn About Mind-Gut Link

Pasricha says research suggests that digestive-system activity may affect cognition (thinking skills and memory), too. 'This is an area that needs more research, something we hope to do here at Johns Hopkins,' he says.

Another area of interest: Discovering how signals from the digestive system affect metabolism, raising or reducing risk for health conditions like type 2 diabetes. 'This involves interactions between nerve signals, gut hormones and microbiota—the bacteria that live in the digestive system,'Pasricha says."

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According to Neurology Advisor,

"Recently, evidence has accumulated to support a complex neurobiologic basis for migraine, with origins beyond the brain. The prevailing theory involves the gut-brain axis, which postulates a complex interplay between the brain and the gastrointestinal tract. However, the precise mechanism that links the brain and the gut and triggers a migraine event remains unclear."

Read more about it here:

Image Source: The Smithsonian.

According to The Smithsonian,

"The human microbiome—a collection of bacteria, archaea, fungi and viruses commingling in the gut and intestines—has been linked to a wide range of human health conditions, including digestive health and the prevention of autoimmune diseases. Some research has even identified a possible link between gut health and brain function. Building on this work, a study published yesterday in Nature Microbiology reveals that clinical depression could be affected by the amounts of certain bacteria in the gut.

The research team, led by microbiologist Jeroen Raes of the Catholic University of Leuven in Belgium, found that almost all gut bacteria are able to produce neurotransmitters, which are chemicals like dopamine and serotonin that enable communication between neurons. If these 'chemical messengers' are sent to receptors in the brain, they can influence mood and behavior. The researchers also identified two strains of bacteria that are lacking in the guts of people who have been diagnosed with depression.

The study adds to mounting evidence that an association between gut health and the brain exists. However, it does not establish whether poor mental health causes depletion of the bacteria, or if the missing bacteria intensifies symptoms associated with mood disorders. More research is needed to conclusively say that gut bacteria influences mental health, says Mark Lyte, a professor of microbiology at Iowa State University who wasn’t involved in the study.

'The studies are just really starting,' Lyte says. 'We do not fully understand what all the genes in all the bacteria do, so don't make the conclusion that we understand everything about the microbiota in terms of their genetic capacity to make [neurotransmitters]. We only understand a fraction of that.' Scientists recently identified more than 100 new species of bacteria in the human gut, underscoring how much we still have to learn about the functions of the microbiome.

Raes and his team studied the gut bacteria of over 2,000 European participants to examine a possible link between the microbiome and mental health. In their study, the team tested the genomes of 532 strains of bacteria to determine if the bacteria could create neurotransmitters. Over 90 percent of the bacteria in the study demonstrated the ability to produce one or more of these chemical messengers.

The body’s longest nerve, the vagus nerve, runs from the brainstem to the lowest part of the intestines. The nerve is thought to be a two-way highway, sending signals from the brain to the gut to regulate digestion and bringing signals from the gut to the brain. The latter function provides a possible pathway for neurotransmitters produced by gut bacteria to influence mental health, Raes says. The team found that both Coprococcus and Dialister bacteria were depleted among individuals with depression, even when controlling for the effects of antidepressants. Coprococcus was also found to have a biological pathway associated with dopamine, a neurotransmitter known to influence mental health.

The next step, Lyte says, is to develop a more complete understanding of how these two strains of bacteria function in the gut. Scientists have studied the genetic traits of some bacteria extensively, like E. Coli, but the genomes and traits of bacteria like Coprococcus and Dialister have yet to be carefully examined. Lyte says that scientists will need to use 'old-school' microbiology, growing these bugs in petri dishes to see how they function. A bacterium that behaves one way on paper could function very differently when exposed to a diverse environment of microbes similar to the human gut.

'You have to grow these bugs up and see what they do [in different environments] to understand what they’re going to do when they’re in the host,' Lyte says.

Additionally, Raes says his team has only identified bacteria that could influence mental health at the genus level, and that it’s crucial to identify the specific species of bacteria that are absent in people with depression to test a possible relationship between the gut and the brain. While lower levels of Dialister were associated with depression, a recent paper linked higher levels of Dialister with arthritis. It could be that prevalence of one species of Dialister increases risk of arthritis while prevalence of another reduces risk of depression, Raes says, but determining such specifics will require additional studies.

The ability to produce neurotransmitters also might be unique to bacteria that evolved in the gut, as the capability hasn’t been found in wild bacteria outside the microbiome. 'It feels like an evolutionary adaptation to the symbiosis of bacteria and [humans],' Raes says. 'If you start thinking about that, then your head explodes. Bacteria live within us and have found all these ways to communicate with us and potentially influence our behavior.'

Emma Allen-Vercoe, a professor of microbiology at the University of Guelph in Ontario, says she is excited about the future potential of microbiome research. While many more studies would be required before scientists could perform a treatment trial, Allen-Vercoe believes that Coprococcus and Dialister could be great candidates to use as psychobiotics, or probiotics that target mental health. Finding a way to grow these microbes so they could be administered to patients would be 'far from trivial,' but she hopes scientists can eventually introduce the bacteria into human guts of and examine the results.

'When I read this paper I was super excited, because I really think this is a new frontier in medicine,' Allen-Vercoe says. 'Thinking outside the box in terms of using microbes in the gut to treat diseases that traditionally haven’t been associated with the gut is quite exciting, because we’re thinking about things in a whole different way. They’ve really started something here.'"

Thank you, to one of our group members, Sarah L., for bringing the article above to my attention! I really appreciate it!

So, the brain in your gut can affect your memory. It makes me think that if you have little or no motility, it could contribute to memory loss, in addition to other things like sleep deprivation, malnutrition, and medication. It seems like a lot of issues can cause memory loss in those who suffer from Gastroparesis/DTP. Personally, I have to carry around a journal to write things in because I forget a lot of things. More research is going into this, so hopefully, we will have answers soon.


Unknown said...

This was very helpful, thank you for posting this! I've had Gastroparesis for about 7 years but in the past year my memory has gotten a lot worse and I haven't been able to figure out why, but this definitely makes sense!

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