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Study finds structural brain alterations in patients with irritable bowel syndrome
A large academic study has demonstrated structural changes in specific brain regions in female patients with irritable bowel syndrome (IBS), a condition that causes pain and discomfort in the abdomen, along with diarrhea, constipation or both. A collaborative effort between UCLA and Canada's McGill University, the study appears in the July issue of the journal Gastroenterology. The findings show that IBS is associated with both decreases and increases in grey matter density in key areas of the brain involved in attention, emotion regulation, pain inhibition and the processing of visceral information.
IBS affects approximately 15 percent of the U.S. population, primarily women. Currently, the condition is considered by the medical field to be a "functional" syndrome of the digestive tract not working properly rather than an "organic" disorder with structural organ changes. Efforts to identify structural or biochemical alterations in the gut have largely been unsuccessful. Even though the pathophysiology is not completely understood, it is generally agreed that IBS represents an alteration in brain-gut interactions. These study findings, however, show actual structural changes to the brain, which places IBS in the category of other pain disorders, such as lower back pain, temporomandibular joint disorder, migraines and hip pain — conditions in which some of the same anatomical brain changes have been observed, as well as other changes.
A recent, smaller study suggested structural brain changes in IBS, but a larger definitive study hadn't been completed until now. "Discovering structural changes in the brain, whether they are primary or secondary to the gastrointestinal symptoms, demonstrates an 'organic' component to IBS and supports the concept of a brain-gut disorder," said study author Dr. Emeran Mayer, professor of medicine, physiology and psychiatry at the David Geffen School of Medicine at UCLA." Also, the finding removes the idea once and for all that IBS symptoms are not real and are 'only psychological.'The findings will give us more insight into better understanding IBS."
Researchers employed imaging techniques to examine and analyze brain anatomical differences between 55 female IBS patients and 48 female control subjects. Patients had moderate IBS severity, with disease duration from one to 34 years (average 11 years). The average age of the participants was 31. Investigators found both increases and decreases of brain grey matter in specific cortical brain regions. Even after accounting for additional factors such as anxiety and depression, researchers still discovered differences between IBS patients and control subjects in areas of the brain involved in cognitive and evaluative functions, including the prefrontal and posterior parietal cortices, and in the posterior insula, which represents the primary viscerosensory cortex receiving sensory information from the gastrointestinal tract.
"The grey-matter changes in the posterior insula are particularly interesting since they may play a role in central pain amplification for IBS patients," said study author David A. Seminowicz, Ph.D., of the Alan Edwards Centre for Research on Pain at McGill University. "This particular finding may point to a specific brain difference or abnormality that plays a role in heightening pain signals that reach the brain from the gut." Decreases in grey matter in IBS patients occurred in several regions involved in attentional brain processes, which decide what the body should pay attention to. The thalamus and midbrain also showed reductions, including a region — the periaqueductal grey — that plays a major role in suppressing pain. "Reductions of grey matter in these key areas may demonstrate an inability of the brain to effectively inhibit pain responses," Seminowicz said. The observed decreases in brain grey matter were consistent across IBS patient sub-groups, such as those experiencing more diarrhea-like symptoms than constipation. "We noticed that the structural brain changes varied between patients who characterized their symptoms primarily as pain, rather than non-painful discomfort," said Mayer, director of the UCLA Center for Neurobiology of Stress. "In contrast, the length of time a patient has had IBS was not related to these structural brain changes." Mayer added that the next steps in the research will include exploring whether genes can be identified that are related to these structural brain changes. In addition, there is a need to increase the study sample size to address male-female differences and to determine if these brain changes are a cause or consequence of having IBS.
The study was funded by the National Institutes of Health. Additional authors include M. Catherine Bushnell, Ph.D., of McGill University, and Jennifer B. Labus, Joshua A. Bueller, Kirsten Tillisch and Bruce D. Naliboff, Ph.D., all of UCLA.
Author:
Rachel Champeau
http://www.semel.ucla.edu/news/10/jul/22/study-finds-structural-brain-alterations-patients-irritable-bowel-syndrome
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Anxiety In Your Head Could Come From Your Gut
Sept. 12, 2013
By SUSAN DONALDSON JAMES
Dr. James Greenblatt, a Boston-area psychiatrist, had a puzzling case: a teenager arrived in his office with severe obsessive–compulsive disorder (OCD), as well as attention deficit hyperactivity disorder (ADHD) and an array of digestive problems.
"Mary's parents had been running around for many years and she'd had a poor response to medicine," said Greenblatt, founder of Comprehensive Psychiatric Resources Inc. in Waltham, Mass. "When a patient doesn't respond, that's a red flag."
Greenblatt first did a simple urine test for the metabolite HPHPA, the chemical byproduct of the clostridia bacteria, and found that it was elevated. He put her on a course of high-powered probiotics to boost her good bacteria, followed by antibiotics, and her levels began to "dramatically" go down, he said.
After six months, Mary's symptoms began to disappear. And by a year, they were gone. Today, three years later, Mary is a senior in high school and has no sign of either mental disorder.
Read about the ins and outs of gut bacteria.
Greenblatt does not practice alternative medicine; his expertise is in psychopharmacology and he is a clinical faculty member at Tufts Medical School.
"I start with integrative medicine, but I have my prescription pad right by my side," he told ABCNews.com.
Greenblatt, like many others, are beginning to recognize the power of healthy gut bacteria. The average adult carries up to five pounds of bacteria -- trillions of microbes -- in their digestive tract alone.
A recent study in the journal Science showed that thin and fat people have different bacteria -- a discovery that could lead to weight-loss programs. Doctors have also been using fecal transplants to seniors when their gastrointestinal health is compromised in nursing home living.
And now, scientists think there may be a link between what's in your gut and what's in your head, suggesting that bacteria may play a role in disorders such as anxiety, schizophrenia and autism. In some patients, the strep bacterium has been linked to OCD in a condition known as PANDAS.
Strep throat can trigger obsessive-compulsive disorder.
A study published in Nutritional Neuroscience from The Great Plains Laboratory, has shown that HPHPA levels are much higher in the urine of autistic children. Those treated with antibiotics effective against the bacteria clostridia show a decrease in symptoms.
Babies are born with a sterile digestive tract and first acquire their bacteria while traveling through the birth canal and get more in breast milk and in the world outside the womb through contact with other people.
Greenblatt said he had treated hundreds of patients for dysbiosis, a condition of microbial imbalances on or inside the body. "It's a more common scenario than we know," he said.
Scientists are so far unable to identify every strain of bacteria, but they can test for the chemical byproducts that they produce, according to Greenblatt.
He said he checks every patient for HPHPA with a simple organic acid urine test before moving ahead with medications to treat symptoms.
"Eight out of 10 people are fine," he said. "But in the two patients where it's elevated, it can have profound effects on the nervous system."
"I don't know why this test isn't done on every psychiatric patient," he said. 'I question that every day."
HPHPA causes deactivation of an enzyme so that dopamine cannot be converted to the neurotransmitter neuroepinephrine, Greenblatt said, and that causes a build-up of dopamine.
"We know elevated levels in the dopamine gene cause agitation," he said, citing medical literature and case studies.
In one 2010 study at McMaster University in Canada, published in the journal Communicative and Integrative Biology, scientists found a link between intestinal microbiota and anxiety-like behavior.
Researchers compared the behaviors of normal 8-week-old mice and those whose guts were stripped of microbes. Those without bacteria showed higher levels of risk-taking and the stress hormone cortisol. They also had altered levels of the brain chemical BDNF, which has been linked to anxiety and depression in humans.
Researchers believe that in the immediate postnatal period, the "gut bacteria" have an impact on not just the immune system, but the development of the neuroendocrine and metabolic systems. Presence of microbiota regulates the "set point" for hypothalamic-pituitary-adrenal axis activity.
Research into the importance of gut bacteria is "well-established," and two other later studies have reaffirmed the McMaster study, according to its co-author Jane Foster, associate professor of neuroscience and behavioral science and part of the McMaster University & Brain-Body Institute.
"The gut bacteria talk to the brain in multiple ways through either the immune system or the enteric nervous system," said Foster. "It's sort of like if you imagine a mesh network and you took your intestinal tract and wrapped that like a hot dog bun outside a hot dog. There are more neurons that directly surround your GI tract than in the whole spinal cord."
However, while using probiotics may help a "subset of patients," she said, it's not a "magic bullet." Early life stresses, nutrition and building a strong immune system all play an important role in a person's mental health, she said.
Key life transitions -- adolescence and menopause, for example -- are when "big changes" are going on in the gut-brain relationship and probiotics might be helpful in building stronger resilience.
"Anyone who has a mental health disorder that coincides with a GI disorder is a good candidate for probiotics," she said.
One such candidate was Adam Johnson, who since the age of 5 has struggled with ADHD, anxiety and some mood disorders, and has been treated with a variety of medications.
"We know now he had too much stimulation and realize his brain worked differently than everyone else's," said his mother, Kay Lynn Johnson of Massachusetts.
Continue reading this article here http://abcnews.go.com/Health/anxiety-head-gut/story?id=20229136
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Think Twice: How the Gut's "Second Brain" Influences Mood and Well-Being
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.
So for those physically skilled and mentally strong enough to compete in the Olympic Games—as well as those watching at home—it may well behoove us all to pay more heed to our so-called "gut feelings" in the future.
http://www.scientificamerican.com/article/gut-second-brain/
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Patients with irritable bowel syndrome had significantly higher perceived stress compared with healthy controls, according to data presented at the AGA's 2015 James W. Freston Conference in Chicago.
The purpose of this study was threefold: to assess physiological markers of stress response in patients with IBS vs. healthy controls; to identify correlations between reported stress and physiological markers in patients with IBS; and to determine the effects of weight, sex and IBS type on these stress-related variables.
The researchers analyzed data from 37 patients with IBS and 69 healthy controls who completed the Perceived Stress Scale (PSS) and had fasting peripheral whole-blood specimens collected. PSS scores were 14.81 ± 6.57 for patients with IBS compared with 10.84 ± 6.23 for healthy controls (P = .003). Sex and weight did not affect PSS scores, whereas IBS subtype had an effect (P = .05). PSS scores and serum cortisol were negatively correlated (r = –0.23; P = .02). Correlations between PSS scores and intra-abdominal fat or body fat percentage were not significant.
The investigators concluded that patients with IBS have higher perceived stress than healthy controls, and that "peripheral indicators of the stress response system were found to be negatively correlated with baseline values of self-reported perceived stress. Such findings lend support to alterations of the stress response system in patients with IBD; subjects who reported increased levels of perceived stress displayed diminished levels of cortisol in comparison to their less stressed counterparts."
Baseline PSS scores were found to be significantly different between patients with IBS and healthy controls, and they were somewhat influenced by IBS type, but "although an effect of body weight and sex upon PSS scores was not found, trends were noted in the association of body fat percent and visceral adiposity," they added. "These findings warrant further inquiry, as to the potential mechanism of increased stress among subgroups of this patient population." – by Adam Leitenberger
Reference:
Weaver KR, et al. Physiological correlates of perceived stress in patients with IBS. Presented at: James W. Freston Conference; Aug. 29-30, 2015; Chicago.
http://www.healio.com/gastroenterology/irritable-bowel-syndrome/news/online/%7B965ddf43-b43f-410a-9251-6248b2d47f18%7D/perceived-stress-higher-among-patients-with-ibs
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Microbe-free mice have hypermyelination of the prefrontal cortex
author name
by Kristina Fiore
Staff Writer, MedPage Today
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Note that this mouse study found increased myelination in certain brain areas when gut microbiota were eradicated.
CHICAGO -- Gut bacteria may play a role in regulating myelination in the prefrontal cortex (PFC), researchers reported here.
Microbe-free mice had greater expression of myelin-related genes and hypermyelination in the PFC compared with control animals, Alan Hoban, PhD, of University College Cork in Ireland, and colleagues presented at a poster session at the Society for Neuroscience meeting here.
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"These animals have no microbiota, so it could be that a lack of signals from the gut aren't check-pointing oligodendrocytes, since we saw with the hypermyelinated fibers was they had so many more wraps of myelin," Hoban told MedPage Today. "That means the oligodendrocytes may be excessively turning, and whatever is missing from the gut signaling to the brain is not telling them to stop -- but that's a very broad interpretation," he cautioned.
The past decade has brought an influx of research on the role of microbiota in gut-brain interactions, including mounting evidence that mood can be impacted by the intestinal flora. But other work has also suggested that gut bugs could play a role in conditions such as autism spectrum disorder (ASD), Parkinson's, and even demyelinating disorders of the central nervous system, including multiple sclerosis.
"MS is an autoimmune disease, so we were interested in how the microbiota may be driving this," Hoban told MedPage Today.
He and his colleagues conducted genome-wide RNA sequencing in the PFC of control mice, microbe-free mice, and mice that were previously microbe-free but were re-colonized.
They conducted RNA sequencing to evaluate differential gene expression, and then validated that data with qRT-PCR. They also conducted transmission electron microscopy in order to quantify myelin thickness relative to axonal diameter, known as the g-ratio. And finally, they did Western blot analysis to assess the expression of proteins from myelin component genes in the PFC.
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Overall, they found that microbe-free mice had increased myelin gene expression, but only in the PFC -- not in five other brain regions including the cerebellum, hippocampus, amygdala, striatum, and frontal cortex.
"We examined a lot of different regions ... and we found that it was solely the PFC that displayed an increase in myelin gene expression," Hoban said.
Expression of myelinating genes was not heightened in any brain regions in control animals, nor in mice that had their microbiota restored, which suggests that myelin processing problems could be repaired, the researchers said.
Hoban and the paper's senior author John Cryan, PhD, also of University College Cork, noted that the hypermyelination seen in animals without gut bacteria "tells us the microbiome provides a break on myelination."
Indeed, the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis cannot be induced in microbe-free mice, Cryan said.
In addition to the gene expression patterns, the researchers conducted transmission electron microscopy and saw greater myelination of axons, as measured by a higher lamina number and greater myelin diameter.
The findings were also confirmed on Western blot, which revealed a greater expression of proteins from myelin component genes in the PFC in microbe-free animals.
Cryan said the next steps are trying to figure out the mechanisms behind the relationship between gut bacteria and myelination in the PFC.
"What could be driving these changes, and why is it specific to the PFC?" Cryan said. "We need to see what signals the microbiome is sending. We need to look at metabolites, at the vagus nerve and the other connections, and see whether we can recapitulate it with certain strategies or certain bacterial strains."
"We know that colonization of the entire microbiome has an effect, but what if we wanted to put back a single bacteria" to impact myelin regulation, he added.
Cryan noted that the concept of the microbiome having an influence on neurologic and psychiatric processes is relatively new and may still have its critics, but "we're slowly beginning to find that all of the fundamental processes of brain function are somehow being regulated by the microbiome."
"These findings encourage a multidisciplinary approach" to understanding disease processes for conditions like multiple sclerosis in order to develop better therapies, Cryan said.
Hoban disclosed no financial relationships with industry.
Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
This report is part of a 12-month Curriculum In Context series.
last updated 10.26.2015
Primary Source
Society for Neuroscience
Source Reference: Hoban AE, et al "Regulation of myelination in the prefrontal cortex by the microbiota" SFN 2015; Abstract 162.08.
http://www.medpagetoday.com/MeetingCoverage/SFN/54276?xid=nl_mpt_DHE_2015-10-26&eun=g379602d0r
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There's a 'second brain' in your gut — and it's smarter than you think
By Erin Van Der Meer
7/6/17
We tend to think of the brain as the control centre of the human body.
While that is the case, scientists are making new discoveries about a second, smaller brain in the gut that can function independently of the brain in our skulls.
The "second brain" or enteric nervous system (ENS) is a network of around half a billion nerve cells and neurons (about the same amount as the brain of an adult cat) in the gut wall, responsible for controlling the gastrointestinal system.
Scientists are confident learning more about it could solve gut health issues like IBS and constipation, and shed more light on the link between the gut and mental health.
Meet your second brain
Most of us have experienced the feeling of "butterflies" in the tummy when we're nervous, or our stomach "dropping" upon hearing bad news.
But this communication between the brain and the ENS isn't just one way.
Not only is the ENS involved with appetite control, signalling to the brain when we're full, but an emerging area of research suggests the second brain can affect many parts of the "main" or "big" brain, including how it processes thoughts and emotions.
Medical professionals have long been aware of the link between anxiety and depression and digestion issues like irritable bowel syndrome (IBS), thinking the former caused the latter.
But increasingly it seems to be the other way around, as studies show irritation in the gastrointestinal system can trigger mental changes.
"The gut and the brain have a bi-directional relationship; they are interconnected primarily via the vagus nerve which is able to transfer chemical messages between the two," explains Coach's go-to gut health expert, accredited practicing dietitian and founder of Travelling Dietitian Kara Landau.
"Poor gut health has been shown to lead to inflammation throughout the body; and inflammation has been shown to be associated with depression and anxiety.
"Considering our gut sends out chemical messages of its own separate from the brain, including producing around 90 percent of our mood calming neurotransmitter, serotonin, it is no surprise that having a healthy gut has been shown to be associated with enhanced mood regulation."
The potential to solve gut issues
A new study led by the Francis Crick Institute in London mapped the ENS in order to make sense of the complicated system, with the aim of identifying the cause of common gut and digestive issues, like IBS and constipation.
"Now that we have a better understanding of how the enteric nervous system is built and works, we can start to look at what happens when things go wrong, particularly during the critical stages of embryo development or early life," said Reena Lasrado, first author of the paper and researcher at the Crick Institute.
"Perhaps mistakes in the blueprint used to build the neural networks of the gut are the basis of common gastrointestinal problems."
Better understanding the ENS is also likely to help people who are overweight or obese due to overeating, as Landau explains.
"If this system is defective, correct signaling may be impeded.
"This could lead to poorer appetite regulatory hormone signaling between the gut and the brain, and therefore result in increased hunger or a decrease in satiety cues, and therefore overeating or gaining weight."
How to maintain a healthy gut brain
The evidence of the gut-mood connection is still in the early stages, but it's clear maintaining a healthy gut is crucial for mental wellbeing and overall health.
"Having a healthy gut ensures maximum nutrient absorption can take place, which supports proper hormone production and regulation, which benefits mood regulation," Landau explains.
"Ensuring we consume a gut supportive diet, high in probiotic and prebiotic-rich foods and beverages, and low in added sugar and artificial ingredients, is a great place to start.
So what should you eat to help your second brain function optimally?
"Fermented foods, probiotic-enhanced products — that are still live and able to successfully colonise in our gut — as well as prebiotic dietary fibre rich foods and resistant starch rich foods are all going to be beneficial for overall gut integrity.
"Some of the richest sources of prebiotics and resistant starch are chicory root, Jerusalem artichoke, onions and garlic, and green banana flour."
Topping fruit with natural yoghurt, mixing sauerkraut in a salad or ordering some kimchi at a Korean restaurant are also simple ways to make your gut brain smile.
http://coach.nine.com.au/2017/07/06/16/30/gut-brain-enteric-nervous-system?utm_source=newsletter&utm_medium=click&utm_campaign=2271
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Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!
Edited by Heather (07/17/17 04:36 PM)
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