Gut Microbiota & Gut-Brain Axis

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM

GUT MICROBIOTA & GUT-BRAIN AXIS A selection of content from the Gut Microbiota for Health 2016

January 2017

www.gutmicrobiotaforhealth.com SUMMARY

The digestive tract and the brain and brain development, and ques- are intimately linked - this, scientists tions that emerged at a recent have known for many years. What's event discussing developmental newer is the idea that the microbial influences of microbiota and other communities living in the gut have hot topics related to the gut-brain a major role to play in how the gut axis. and the brain communicate. Emer- ging scientific insights about the When it comes to brain-related gut-brain axis are of particular disorders, researchers are working interest in neurogastroenterology, to discover more about the role of the subspecialty of gastroentero- the gut microbiota in pathophysio- Prof. Dr. Paul Enck, Director of logy focusing on connections logy. Below we feature an article Research, Dept. of Psychosomatic between the central nervous providing clues about the influence Medicine and Psychotherapy, system and the enteric nervous of gut bacteria on depressive University Hospital Tübingen, system. As an organization dedi- behaviours; and turning to mecha- Germany. He is board cated to sharing new research in nisms, we provide a review of the member/treasurer of the this particular field, the ESNM is nascent study of gut bacterial European Society of pleased to support the GMFH metabolites as neuromediators. Neurogastroenterology and publishing team in bringing you this Motility and of the German document on gut microbiota and With new therapeutics, insights on Society of Neurogastroenterology the gut-brain axis. the gut-brain axis could really make and Motility, and has served as a difference for patients. Here we reviewer for many international We open with a summary editorial highlight a systematic review on journals and grant agencies. by Premysl Bercik - gastroenterolo- probiotics for improving human gist and Associate Professor in the mental health; an article on how Division of Gastroenterology at probiotics can influence social McMaster University (Canada) - behaviours in mice; and an article who, along with his colleagues, is speculating on how a high-fibre carrying out leading-edge gut-brain diet could positively affect the research that investigates links brain. between the brain, gut microbiota, and immune system. The editorial is Finally, in our editors' wrap-up followed by a selection of recent interview with Premysl Bercik, they articles on the microbiota-gut-brain discuss an important question: "Can axis from the Gut Microbiota for the science of the microbiota-gut- Science writer Kristina Campbell Health website. brain axis be made relevant to (M.Sc.), from British Columbia clinical practice?" We hope you (Canada), specializes in First, Emeran Mayer, author of a enjoy reading on this topic - and be communica-ting about the gut popular book called The Mind-Gut sure to check the GMFH website for microbiota, digestive health, and Connection, offers his perspective more scientific content about the nutrition. Author of the best on microbes in gut-brain communi- microbiota-gut-brain axis in the selling Well-Fed Microbiome cation. Then we feature brief cove- months ahead. Cookbook, her freelance work rage of several studies showing that has appeared in publications gut-brain communication is a two- around the world. Kristina joined Paul Enck way street, a review of a provoca- the Gut Microbiota for Health publishing team in 2014. tive hypothesis on sex hormones Kristina Campbell

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 2 TABLE OF CONTENT

EDITORIAL 4 SELECTED CONTENT FROM GUTMICROBIOTAFORHEALTH.COM

• Pinpointing the role of microbes in human gut-brain communication 8

• Do development and maturation of the gut-brain axis differ between the sexes? 10

• Gut microbiota changes may be responsible for depressive-like behaviours in mice through alterations in host metabolism 12

• Neuromediators in the Gut-Brain Axis 14

• Could probiotics be used to improve human mental health? 15

• The potential of probiotics and diets to reverse asocial behaviours in mice that are seen in autism spectrum disorders 17

• Can a high-fibre diet prevent and/or treat neurological disorders? 19 BOOKS AND RESOURCES 21 INTERNATIONAL SUMMIT & ECOSYSTEM 23

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 3 EDITORIAL

In humans, signals travel between the gut and the brain through networks of neurons in the central nervous system (CNS) and parts of the peripheral nervous system - namely, the division of the autonomic nervous system called the enteric nervous system (ENS). With approximately 100 billion neurons in the brain and 100 million in the spinal cord, the job of the CNS is to integrate sensory information and generate the behaviours needed to successfully interact with the environment. The 200-600 million neurons in the ENS - which extend, web-like, along the length of the digestive tract - react to chemical and mechanical stimuli from the gastrointestinal tract and contribute to the pool of information received by the brain. The vagus nerve (i.e. cranial nerve X) is an important channel by which information is transmitted between the digestive tract and the brain. Signals are bidirectional, but the vast majority (90%) travel upward, keeping the brain constantly informed about gut activity. This bidirectional communication between the brain’s emotional and cognitive centers and peripheral intestinal functions is known as the gut-brain axis.

Clinical evidence linking the diges- brains: defective and immature tive tract and the brain is well microglia(3), hypermyelinated axons known. Not only are brain and in the prefrontal cortex and an gastrointestinal diseases often upregulation of genes linked to comorbid, but also treatments for myelination(4), and altered forma- infection sometimes induce psy- tion of synapses (higher expression chiatric side effects, as in cases of of synaptic-related proteins in the antibiotic-induced psychosis(1). In striatum)(5). In addition, our lab has recent years, however, knowledge shown that germ-free mice or those about the connection between the with a severely disrupted micro- gut and the brain has been biota have altered expression of the enhanced by increased data on neuromodulator BDNF (brain- how the gut microbiota influence derived neurotrophic factor) in the gut-brain communication. hippocampus and amygdala(6).

The microbiota-gut-brain axis Human evidence for the influence of gut microbes on the brain Increasing data from mice and include placebo-controlled inter- humans show how gut microbiota vention studies suggesting that influence the gut-brain axis. Germ- modulation of the gut microbiota free mice have an abnormal may produce observable changes response to stress, differing in mood or behaviour. Several patterns of social interaction and studies(7)(8) have reported that exploratory behaviors, and altera- mixtures of different probiotic tions in cognition(2), in addition to species can positively affect brain observable differences in their function in healthy individuals. One

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 4 EDITORIAL

study to date(9) has used functional establishment of a robust, diverse magnetic resonance imaging to gut microbiota, nor how this affects observe the impact of a probiotic- long-term brain health.. However, it containing fermented milk on brain seems that avoiding major micro- function of healthy women; after biota perturbations in the first few the intervention, researchers found years of life might be required for changes in the activity of the brain the development of the brain to regions that control emotion and proceed uninterrupted. sensation. Studies like these are the first step; researchers are poised to Mechanisms learn much more about mechanisms that account for the apparent Microbiota can influence gut-brain effects of gut microbiota on the communication through neural, brain. immune, and hormonal routes. Different kinds of bacteria appear Early life influences to influence ENS neurons diffe- rently, with some exciting How important are gut microbiota responses(13) and some dampening in early life for shaping the adult them(14). Gut microorganisms can brain? Results from mice show that also influence ENS activity by exposing them to stress in early affecting production of molecules, pregnancy changes their vaginal like gamma-aminobutyric acid microbiome and, at birth, can (GABA)(15), which act as local induce changes in the offspring’s neurotransmitters. Immune signal- gut microbiota. Potentially these ling is another way the gut micro- changes can reprogram the biota seems to alter messages to offspring’s brain and affect later- the brain, since evidence shows the life behaviour(10). Studies using gut microbiota can affect immune mouse maternal separation as a cells located in the gut mucosa model of early-life stress have that modify activity of sensory found some of the well described neurons of the ENS(16). Further- reactions of mice to stress more, the gastrointestinal tract and (anxiety-like behavior and beha- its bacteria contribute to the vioral despair) in adulthood only body’s production of hormones occur if the mice have a gut and neurotransmitters(17), which microbiota(11). And several studies affect different processes through- have now shown that some of the out the body, including those that alterations observed in the brains affect the brain. and behaviours in germ-free mice can be prevented if the mice are In some cases, gut-brain signalling exposed to a complex gut micro- could be initiated by metabolites - biota in early life(12). biologically active small molecules that are the products of gut bacte- In humans it is not certain how rial metabolism. Many of the early-life events contribute to the known metabolites exert their

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 5 EDITORIAL

effects on multiple tissues and Promising therapeutics Researchers will need to increas- organs in the body, including the ingly look at humanized mice to brain. Short-chain fatty acids Despite the complexity of brain make mechanistic connections. To (SCFAs) have been singled out as function and mental disorders in find ways of applying gut micro- particularly important metabolites humans, and the difficulty in trans- biota research in clinical settings, with possible influences on brain lating research from rodents to innovation will also be required in function(18), but thousands of humans, research hints at the computational analyses, and meth- others exist. Some of them are potential of gut microbiota altera- odologies including culture based thought to perform neuromediator tions for influencing gut-brain axis profiling , allowing rapid integra- and/or endocrine functions(19), but in humans. What will really benefit tion of large amounts of data. Gut how they work is not well under- patients, in health and disease, are microbiota is enabling new stood. Learning more about these the new therapeutic options that perspectives on the modifiability molecules is one of the keys to emerge from this area of research. of the gut-brain axis with the progress in the field of gut-brain A number of promising methods potential to optimize brain communication. for modifying the gut microbiota health—and we are only at the to influence brain function in beginning of the journey. Links to disease certain contexts are emerging: probiotics, prebiotics, diet, antibi- Microbial alterations are observed otics, phages, and ‘ecobiotherapy’ in a growing list of disorders (supplying a complete community involving the human brain, includ- of microbes prepared synthetically ing autism spectrum disorder, or through fecal microbiota trans- anxiety, depression, obsessive- plantation). compulsive disorder, post- traumatic stress disorder, alcoho- The future lism, anorexia, and Parkinson's disease. The next step for each of Actionable advice and therapeutics these disorders is to go beyond in the field of the gut-brain axis are associations and investigate not yet a reality. We still have whether or not the microbiota play important to questions to answer a pathophysiological role. Our in the field, including: How do group, for example, recently found human genetics and gut micro- Premysl Bercik that transferring the microbiota of biota together influence brain Gastroenterologist and individuals with comorbid anxiety function? What are the limits of Associate Professor in the induced anxiety-like behavior in each factor’s influence on the Division of Gastroenterology at gnotobiotic mice. More studies of brain? Which gut bacteria or McMaster University (Canada) this kind with humanized models bacterial metabolites are the most will advance knowledge about influential in specific disease contributors to these brain-related conditions? And how can we disorders. manipulate the gut microbiota in a lasting and beneficial way in order to change brain function?

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 6 EDITORIAL

Sources

(1) Mostafa S & Miller BJ. Antibiotic- (11) De Palma G, et al. Microbiota and host associated psychosis during treatment of determinants of behavioral phenotype in urinary tract infections: a systematic maternally separated mice. Nature review. J Clin Psychopharmacol. 2014; Communications. 2015; 6. 34(4):483-90. (12) Diaz Heijtz R, et al. Normal gut (2) Luczynski P, et al. Growing up in a microbiota modulates brain development Bubble: Using Germ-Free Animals to and behavior. Proc Natl Acad Sci USA. Assess the Influence of the Gut Micro- 2011; 108(7):3047–3052. biota on Brain and Behavior. International Journal of Neuropsychopharmacology. (13) Kunze WA, et al. Lactobacillus reuteri 2016. enhances excitability of colonic AH neurons by inhibiting calcium-dependent (3) Erny D, et al. Host microbiota potassium channel opening. Journal of constantly control maturation and Cellular & Molecular Medicine. 2009; function of microglia in the CNS. Nature 13(8b):2261-2270. Neuroscience. 2015; 18:965–977. (14) Khoshdel A, et al. Bifidobacterium (4) Hoban AE, et al. Regulation of prefron- longum NCC3001 inhibits AH neuron tal cortex myelination by the microbiota. excitability. Neurogastroenterology & Translational Psychiatry. 2016; 6:e774. Motility. 2013;25(7):e478–e484.

(5) Diaz Heijtz R, et al. Normal gut micro- (15) Bravo JA, et al. Ingestion of Lactoba- biota modulates brain development and cillus strain regulates emotional behavior behavior. Proc Natl Acad Sci USA. 2011; and central GABA receptor expression in 108(7):3047e52 a mouse via the vagus nerve. PNAS USA. 2011; 108(38):16050–16055. (6) Bercik P, Denou E, Collins J, Jackson W, et al. The intestinal microbiota affect (16) Verdú EF, et al. Specific probiotic central levels of brain-derived neuro- therapy attenuates antibiotic induced tropic factor and behavior in mice. visceral hypersensitivity in mice. Gut. Gastroenterology. 2011; 141(2):599-609. 2006; 55(2):182-90.

(7) Steenbergen L, et al. A randomized (17) Yano JM, Yu K, Donaldson GP, Shastri controlled trial to test the effect of GG, et al. Indigenous bacteria from the multispecies probiotics on cognitive gut microbiota regulate host serotonin reactivity to sad mood. Brain, Behavior, biosynthesis. Cell. 2015 Apr 9; 161(2):264- and Immunity. 2015; 48:258–264. 76.

(8) Benton D, Williams C, Brown A. Impact (18) Kimura I, et al. Short-chain fatty acids of consuming a milk drink containing a and ketones directly regulate sympa- probiotic on mood and cognition. Eur J thetic nervous system via G protein- ClinNutr. 2007;61(3):355–361. coupled receptor 41 (GPR41). Proc Natl Acad Sci USA. 2011;108:8030–8035. (9) Tillisch K, et al. Consumption of fermented milk product with probiotic (19) Oleskin AV & Shenderov BA. Neuro- modulates brain activity. Gastroenterol- modulatory effects and targets of the ogy. 2013;144(7):e1391–e1394. SCFAs and gasotransmitters produced by the human symbiotic microbiota. (10) Jašarević E, Howerton CL, Howard CD, Microbial Ecology in Health and Bale TL, et al. Alterations in the Vaginal Disease.2016; 27. Microbiome by Maternal Stress Are Associated With Metabolic Reprogram- ming of the Offspring Gut and Brain. Endocrinology. 2015; 156(9):3265-76.

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 7 SELECTED CONTENT Pinpointing the role of microbes in human gut-brain communication

Published in DIGESTIVE HEALTH, GUT BRAIN AXIS, GUT MICROBIOTA Written on August 3, 2016 by Kristina Campbell

When Michael Gershon called the digestive system “the second brain” in his 1999 book, it was because scientists were beginning to realize that the gut and the brain in humans were engaged in constant conversation. Emeran Mayer, a leading researcher in the field of the gut-brain axis, affirms that this connection has been known for years. “Gut-brain communication is firmly established. There’s no question,” Mayer says in an interview with GMFH editors. “There’s extensive animal data and clinical observations: if you feel stressed you will feel the effects in your gut, if you feel anxious you notice the butterflies in your stomach, if you’re depressed, you may develop constipation.” Science writer Kristina Campbell (M.Sc.), from Mayer, a gastroenterologist who consequences of disruptions in this British Columbia encountered many patients in his communication. (Canada), specializes in career with curious constellations communica-ting about of gut-brain symptoms, became Mayer has authored a new book, the gut microbiota, preoccupied with finding out the The Mind-Gut Connection, aimed at digestive health, and how this back-and-forth messaging covering gut-brain communication nutrition. Author of the occurs. He had more questions for a lay audience. In it, he best selling Well-Fed than answers in his clinical practice, emphasizes the role of the gut Microbiome Cookbook, but a breakthrough came when microbes and the many aspects her freelance work has more data began to emerge on the that require more investigation in appeared in publications microbiome. human populations. He says that, around the world. remarkably, the gut microbiota Kristina joined the Gut “I’ve spent my entire career during certain periods in life may Microbiota for Health studying brain-gut interactions,” set the framework for subsequent publishing team in 2014. says Mayer. “Only in the last five patterns of gut-brain years I’ve included the microbiome communication. in our studies.” He notes that this new angle is starting to advance “Almost certainly the most scientists’ understanding of how important effects happen early in gut-brain communication life, starting prenatally and in the occurs—both from the bottom up first three years when the microbes, and from the top down—and the as well as the basic brain circuit[s],

“Mayer has authored a new book, The Mind-Gut Connection, aimed at covering gut-brain communication for a lay audience.”

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 8 SELECTED CONTENT Pinpointing the role of microbes in human gut-brain communication are being assembled and become In Mayer’s gastroenterology adult-like,” Mayer says. practice, he sees many who could b e n e f i t f r o m n e w Mayer says knowing that microbes microbiome-based therapeutic play a part in gut-brain approaches to both gastrointestinal communication—and indeed, in and brain disorders, yet he currently many other aspects of brain health advises caution. He says, “We’re and function—necessitates a new really just beginning to understand approach in medicine. “The book what a healthy microbiome is, and makes the case for a new ecological how it is altered in different view of health and disease,” he says. diseases. I think in five years we’ll “Such a new view is essential if we know a lot more, and may be able want to strive for optimal health to use our knowledge about the gut and not just prevention or microbiome for diagnosis, treatment of disease.” At the end of prediction of treatment outcomes his book, Mayer provides and for the development of new suggestions on how to improve therapies.” health by targeting the gut microbiome, like limiting animal fat and consuming more fermented foods and probiotics.

“Such a new view is essential if we want to strive for optimal health and not just prevention or treatment of disease.”

Source: Mayer E. The Mind-gut connection: How the hidden conversation within our bodies impacts our mood, our choices, and our overall health. New York, NY: Harper Wave; 2016.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/pinpointing-role-microbes-human -gut-brain-communication/

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 9 SELECTED CONTENT Do development and maturation of the gut-brain axis differ between the sexes?

Published in GUT BRAIN AXIS Written on March 28, 2016 by Andreu Prados

A recent review, published by postdoctoral researcher Dr. Eldin Jasarevic from the Department of Animal Biology in the University of Pennsylvania, argues that sex differences influence the development, maturation, and maintenance of the gut microbiome-brain axis throughout the lifespan.

The gut-brain axis (GBA) involves there is a rise in short chain fatty bidirectional communication acid (SCFA) - producing micro- between the central and enteric biota, which suggests a role for nervous systems, which facilitates maternal-derived microbial Andreu Prados holds a the integration of peripheral and substrates in foetal neurodevelop- Bachelor of Science central immune, metabolic, and ment. However, there is a vast Degree in Pharmacy & endocrine signals. Recent advances expansion of bacterial diversity Human Nutrition and have described the importance of during late gestation when oestro- Dietetics. Science writer gut microbiota in influencing these gens are at maximal peak and SCFA specialised in gut micro- interactions. The formation of the exposure decreases in order to biota and probiotics, gut-brain axis begins immediately meet the offspring’s increased working also as lecturer following colonization by microbial nutritional and metabolic demands. and consultant in nutri- communities that reside within the During the postnatal period, micro- tion and healthcare. birth canal. Sex-specific maturation bial colonization may influence sex of the gut, hormones, and brain differences in immunocompetent occur in parallel across the lifespan. cells’ maturation and function in the Shifts in structure and function of brain. Environmental perturbations the gastrointestinal tract and brain such as stress during critical provide windows of opportunity for windows of development influence intervention during distinct life gut-brain signalling and are linked stages. to metabolic reprogramming of the offspring gut and brain. Sex diffe- Existing evidence from studies both rences in the gut microbiome in animals and humans supports emerge during puberty and that during the prenatal period, the continue into adulthood. Puberty is metabolic demand of male and a period of increased sex-specific female foetuses on the mother risk for stress, which could affect differs, and the maternal gut micro- later-life behaviour and anxiety. biome orchestrates nutritional Likewise, the researchers suggest status during development. For that gut microbial communities instance, during the first trimester may alter host hormones and affect

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 10 SELECTED CONTENT Do development and maturation of the gut-brain axis differ between the sexes? neurotransmitters that are critical In conclusion, microbial communi- for normal communication between ties contribute to several physi- the gut and brain. In adulthood, gut ological processes throughout the microbiota are more stable and lifespan. Sexually dimorphic com- appear better adapted to environ- munication between the gut micro- mental challenges. Interestingly, sex biome and the brain occurs in paral- may determine risk for negative lel to immune, metabolic and neural symptoms related to gut health. changes, which suggests that Indeed, gender bias in autoimmun- sex-specific transitions could be ity is influenced by microbiota. For considered in health and disease instance, sex-specific changes on states. gut physiology and gut microbiota composition can explain, at least in part, the increased female risk for autoimmune disorders and aller- gies.

“Interestingly, sex may determine risk for negative symptoms related to gut health.”

Source: Jasarevic E, Morrison KE, & Bale TL. Sex differences in the gut microbiome-brain axis across the lifespan. Philos Trans R Soc Lond B Biol Sci. 2016; 371(1688):20150122. doi:10.1098/rstb.2015.0122.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/development-maturation-gut -brain-axis-differ-sexes/

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 11 SELECTED CONTENT

Gut microbiota changes may be responsible for depressive-like behaviours in mice through alterations in host metabolism

Published in ANXIETY & DEPRESSION, DYSBIOSIS Written on June 29, 2016 by Paul Enck

A recent study, led by Dr. Peng Xie from the Chongqing Medical University in China, has demonstrated that intestinal ‘dysbiosis’ may have a causal role in the development of depressive-like behaviours in mice through altering host metabolism.

It has been previously described depressive disorder (MDD) (n= 58) that the gut microbiota may be an exhibited significant alterations in environmental factor that can their gut microbiota relative to modulate brain physiology healthy controls (n = 63). through the microbiota-gut-brain Decreased microbial diversity in Prof. Dr. Paul Enck, axis. Zheng and colleagues have MDD patients were characterized Director of Research, demonstrated that the absence of by alterations in the relative abun- Dept. of Psychosomatic gut microbiota in germ-free (GF) dances of the phyla Firmicutes, Medicine and Psycho- mice led to a decreased Actinobacteria and Bacteroidetes. therapy, University depression-like behaviour as However, these results are not Hospital Tübingen, evidenced by a significantly consistent with a previous study by Germany. He is board decreased immobility time in the Jiang et al. in which increased member/treasurer of the forced swimming test—used as an faecal bacterial diversity was European Society of index of depression-like found in the active-MDD vs. the Neurogastroenterology behaviour—compared with their healthy control group but not in and Motility and of the conventionally raised specific the responded-MDD vs. the German Society of pathogen-free (SPF) counterparts. healthy control group. Bacteroides, Neurogastroenterology These results suggest a link Proteobacteria, and Actinobacte- and Motility, and has between the microbiota-gut-brain ria increased in level, whereas that served as reviewer for axis and depression-like behaviour. of Firmicutes was reduced in MDD many international groups compared with the healthy journals and grant In addition, the researchers control group. agencies. showed that patients with major

“Decreased microbial diversity in MDD patients were characterized by alterations in the relative abundances of the phyla Firmicutes, Actinobacteria and Bacteroidetes.”

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 12 SELECTED CONTENT

Gut microbiota changes may be responsible for depressive-like behaviours in mice through alterations in host metabolism

When mice were transplanted the microbiota of MDD patients (n=5) this induced depression-like behaviours in GF recipient mice, while transplantation of the microbiota of healthy controls (n=5) did not induce such behavioural changes. Characteristics of the gut microbiota responsible for distin- guishing depressed from healthy humans were also observed in recipient mice. The mice harbou- ring the gut microbiota from MDD patients exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metabolism. These results demonstrate that the role of gut microbiota in the development of depressive-like behaviours may be mediated through alterations in the host’s metabolism.

In sum, gut microbiota can contribute to depression-like behaviour in mice through altering host metabolism. These findings, if found to be applicable to humans, could provide a new approach for CREDIT: NATURE depression therapies.

Source: Zheng P, Zeng B, Zhou C, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Molecular Psychiatry. 2016; 1-11. doi: 10.1038/mp.2016.44.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/gut-microbiota-changes-may- responsible-depressive-like-behaviours-mice-alterations-host-metabolism/

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 13 SELECTED CONTENT

Neuromediators in the Gut-Brain Axis

Published in GUT BRAIN AXIS Written on March 11, 2016 by Boris Shenderov

It is increasingly clear that brain processing is influenced by the gastrointestinal microbiota; study of the gut-brain axis has shown evidence that gut bacteria interact with the enteric nervous system and the central nervous system. Good brain function depends on neuromediators — that is, substances that carry messages between neurons, or from a neuron to another type of cell.

Could an increased understanding Evidence suggests an important of neuromediators be the key to role for neuromediators in micro- unlocking how the gut and the bial communication, both within Dr. Boris Shenderov is a brain influence each other? and between species. In Table 1 of professor of this review article, authors microbiology who This review paper by Russian describe the effects (and/or asso- conducts research at researchers Oleskin, El’-Registan, ciations) of neuromediators, from the G.N. Gabrichevsky and Shenderov describes how catecholamines to nitric oxide, on Moscow Research microorganisms engage in collec- microbial populations. Table 2 Institute of tive activities (likened to “social outlines the production of neuro- Epidemiology and behavior”), how they exchange mediators by different bacterial Microbiology. He has information (or “communicate”), species. These communicative authored more than and how they form associations activities of microbes may prove to 500 scientific papers composed of many individual cells have measurable effects on brain and abstracts (“biosocial systems”). Cell coordi- function. In the future, this infor- throughout his career. nation in various microbial bioso- mation may be used in the deve- cial systems such as colonies and lopment of new probiotic prepara- biofilms depends on the microbes’ tions that have a targeted neuro- chemical contact and physical chemical effect. interaction. This review focuses on aspects of chemical communication.

Source: Oleskina AV, El’-Registanb GI, Shenderov BA. Role of Neuromediators in the Functioning of the Human Microbiota: “Business Talks” among Microorganisms and the Microbiota-Host Dialogue. Microbiology 2016; 85(1): 1-22.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/neuromediators-gut-brain-axis/

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 14 SELECTED CONTENT Could probiotics be used to improve human mental health?

Published in ANXIETY & DEPRESSION, PROBIOTICS Written on August 26, 2016 by Andreu Prados

Recent advances in research have described the importance of gut microbiota in influencing interactions between the central and the enteric nervous systems. These brain-gut interactions appear to be bidirectional by means of neural, endocrine, immune, and humoral signals. Most of the data have been acquired using rodents (mice or rats) and pigs.

Evidence of microbiota-mental health interactions comes from the association of intestinal dysbiosis with central nervous system disorders (e.g. anxiety-depressive behaviours) and functional gastrointestinal disorders (e.g. irritable bowel syndrome) with mental health comorbidities. Andreu Prados holds a Bachelor of Science Few human studies assessing the abilities (including spatial and Degree in Pharmacy & effect of probiotic supplementa- non-spatial memory) included Human Nutrition and tion on mental health through Bifidobacterium (B. longum, B. Dietetics. Science writer modulation of brain-gut pathways breve, and B. infantis) and Lacto- specialised in gut micro- have been conducted to date. bacillus (L. helveticus, L. rhamno- biota and probiotics, However, a recent systematic sus, L. plantarum, and L. casei). working also as lecturer review of 38 randomized Doses between 109 and 1010 and consultant in nutri- controlled trials in both animals colony-forming units (CFU) for tion and healthcare. and humans (25 were in animals, 15 durations of 2 weeks in animals in humans and 2 studies were and 4 weeks in humans showed conducted in humans and sufficient effects. Although transla- animals), led by Prof. Paul Enck tions of animal studies to human from the Department of Psychoso- studies suggest possibilities, matic Medicine and Psychotherapy further studies are worthwhile, at University Hospital Tübingen in especially in patients with mental Tübingen (Germany), has diseases that usually show gastro- concluded that probiotics could be intestinal comorbidities. In addi- effective in improving psychiatric tion to behavioural measurements disease-associated functions and such as psychological question- memory abilities. The paper by naires or scales, more neuroimag- Wang, et al. found probiotics that ing studies in humans are needed showed efficacy in improving in order to study what area is psychiatric disorder-related altered in the brain that causes behaviours (anxiety, depression, behavioural changes after the mood, stress response) and memory consumption of probiotics.

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 15 SELECTED CONTENT Could probiotics be used to improve human mental health?

On the other hand, a recent consumers of gamma-aminobutyric systematic review of 10 rand- acid (GABA). In this context a omized controlled trials in humans noteworthy and important step (including 6 trials that were also forward is the recent identification included in the Wang, et al. of a species of gut bacteria, called systematic review), led by Dr. Paul KLE1738, which can only grow in Ritvo from York University in the presence of gamma- “On the whole, Toronto, Ontario (Canada), aminobutyric acid (GABA). KLE1738 current research provides limited support for the is a newly discovered human gut use of probiotics in reducing bacterium that may have an supports the idea anxiety-depressive symptoms in unusual metabolism that is based that microbial humans. Although it seems that on consuming GABA, the major probiotic supplementation could inhibitory neurotransmitter of the communities in the lead to psychological benefits, central nervous system. Other gut may play an substantial methodological limita- mechanisms involving serotonin- tions were found as the main pro- producing bacteria could also have important role in blem in generalizing its findings. equal potential relevance for mental health.” The researchers emphasized that depression and other mood disor- further follow-up intervention ders. studies are needed in order to better understand the potential On the whole, current research human mental health benefits of supports the idea that microbial probiotic supplementation. communities in the gut may play an important role in mental health. One of many possible mechanisms Further human studies in this area that could explain the role of gut are needed in order to elucidate microbes in affecting brain func- which patients could benefit from tion is through modulating the probiotic supplementation for level of microbial producers and improving their mental function.

Source: Pirbaglou M, de Souza RJ, Stearns JC, Motamed M, Ritvo P. Probiotic supplementation can positively affect anxiety and depressive symptoms: a systematic review of randomized controlled trials. Nutr Res. 2016, doi:10.1016/j.nutres.2016.06.009.

Wang H, Lee IS, Braun C, Enck P. Effect of probiotics on central nervous system functions in animals and humans – a systematic review. J Neuro- gastroenterol Motil. 2016, doi: 10.5056/jnm16018.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/probiotics-used-improve-human- mental-health/

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 16 SELECTED CONTENT

The potential of probiotics and diets to reverse asocial behaviours in mice that are seen in autism spectrum disorders

Published in AUTISM, GUT BRAIN AXIS, GUT MICROBIOTA Written on September 5, 2016 by Andreu Prados

It has been previously suggested that a high-fibre diet can prevent neurodegeneration by increasing gut microbiota derived butyrate in the colon, but how changes in gut bacteria could influence brain development and function is still poorly studied.

A recent study, led by Dr. Mauro Costa-Mattioli from the Baylor College of Medicine in Houston, Texas (USA), has found that the reintroduction of a commensal bacterial strain can reverse asocial behaviours in mice that are seen in autism spectrum disorders (ASDs).

Andreu Prados holds a Bachelor of Science Previous human epidemiological weight. At 7-12 weeks of age Degree in Pharmacy & studies that have found that behavioural and electrophysiologi- Human Nutrition and maternal obesity during pregnancy cal experiments were performed in Dietetics. Science writer could increase children’s risk of order to study social behaviour in specialised in gut micro- neurodevelopmental disorders, maternal regular diet (MRD) and biota and probiotics, including ASDs. Besides this, maternal high-fat diet offspring. working also as lecturer recurrent gastrointestinal pro- Maternal high-fat diet offspring and consultant in nutri- blems are frequently reported in displayed impaired sociability and tion and healthcare. individuals with ASDs. Based on dysbiosis of the gut microbiota. these observations, the researchers sought to explore the Buffington and colleagues next connections between changes in tested whether the gut microbiota diet, the gut microbiome, and mediated MHFD-induced social social behaviours. deficits. To this end, at 3 weeks an MHFD mouse was co-housed with First of all, female mice were fed three MRD mice. As a result, either a regular diet (RD, consisting co-housing MHFD with MRD of 13.4% kcal from fat, 30% kcal offspring rescued both social from protein, and 57% kcal from dysfunction and the microbiota carbohydrates) or a high-fat diet phylogenetic profile of the socially (HFD, consisting of 60% kcal from impaired mice born to mothers on fat, 20% kcal from protein, and a high-fat diet. Taken together, 20% kcal from carbohydrates) for 8 these data indicate that gut micro- weeks. Females then were paired biota mediates MHFD-induced with males to produce offspring social deficits and suggest that that all were given RD after wean- MHFD offspring may lack one or ing. Maternal high-fat diet (MHFD) more beneficial bacterial species significantly increased maternal required for normal social behaviour.

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 17 SELECTED CONTENT

The potential of probiotics and diets to reverse asocial behaviours in mice that are seen in autism spectrum disorders

Faecal transplant experiments in The reward circuitry in the socially Filippo Muratori from the IRCCS germ-free mice suggested that impaired mice was also assessed. Stella Maris Foundation and dysbiosis of the gut microbiota in According to Dr. Costa-Mattiol, “in University of Pisa, aims to explore the mice born to mothers on a response to social interaction there supplementation with a probiotic high-fat diet could be involved in was a lack of synaptic potentiation mixture in pre-schoolers with ASD. their social deficits. in a key reward area of the brain As some ASD patients may have that could be seen in the normal some gastrointestinal problems In order to elucidate the specific control mice.” It is noteworthy that that may be associated with a bacterial species involved in social the reintroduction of L. reuteri in higher rate of irritability, aggres- deficits of the mice, the resear- the maternal-high-fat-diet offspring sive behaviours and sleep distur- chers performed metagenomic also restored the changes in bances, therefore the treatment of sequencing of faecal samples from synaptic function in the reward these symptoms with probiotics both MHFD and MRD offspring. circuitry. opens a new therapeutic approach Lactobacillus reuteri was the most in ASD. Intervention studies in drastically reduced in the gut On the whole, a maternal high-fat humans are warranted to develop microbiota of mice born to moth- diet may lead to dysbiosis of the evidence-based guidelines for the ers on the high-fat diet. gut microbiota of offspring and use of probiotics as a non- induce behavioural alterations that pharmacological option comple- In the high-fat-diet fed offspring, can be restored via selective mentary to the recommended elective reintroduction of L. reuteri reintroduction of L. reuteri. treatments for ASD, which are originally isolated from human based on an integrated approach breast milk restored the social Based on the hypothesis that including behavioural treatments, deficits in the mice-but not repeti- changes in the gut microbiota may drugs and other options. tive behaviours and anxiety- and it be relevant to the development of also restored levels of oxytocin, a behavioural symptoms associated hormone that plays a crucial role in with ASD, interventional studies social behaviours and has been are currently being developed. For associated with autism in humans. instance, a pilot study that is currently underway, led by Dr.

Source: Buffington SA, Di Prisco GV, Auchtung TA, et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell. 2016; 165(7):1762-75. doi:10.1016/j.cell.2016.06.001.

Santocchi E, Guiducci L, Fulceri F, et al. Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry. 2016; 16:183. doi:10.1186/s12888-016-0887-5.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/potential-probiotics-diets-reverse- asocial-behaviours-mice-seen-autism-spectrum-disorders/

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 18 SELECTED CONTENT Can a high-fibre diet prevent and/or treat neurological disorders?

Published in FIBERS, FOOD & INGREDIENTS Written on March 23, 2016 by Andreu Prados

In recent years, interest has grown in how diet influences brain function through the gut microbiome , yet the topic is still largely understudied. A recent review article, led by Dr Rajiv R. Ratan from the Brain and Mind Research Institute (BMRI) in New York, explores the provocative idea a high-fibre diet can prevent neurodegeneration in the brain by increasing butyrate in the colon.

Diet-derived substrates impact expression in mammalian cells bacterial community structure and through histone deacetylase inhibi- Andreu Prados holds a metabolism in the colon. Short- tion, although this effect is not Bachelor of Science chain fatty acids (SCFAs) formed specific to histone proteins alone. It Degree in Pharmacy & by microbial fermentation have an is a potential therapeutic for neuro- Human Nutrition and important effect on both colonic logical diseases, as many common Dietetics. Science writer and systemic host health. Butyrate neurological diseases show specialised in gut micro- in particular is primarily synthesized reduced histone acetyltransferase biota and probiotics, through the fermentation of (HAT) activity. Sodium butyrate working also as lecturer resistant starch (e.g. tubers) and (NaB) has demonstrated neuro- and consultant in nutri- fructo-oligosaccharides (FOS) (e.g. trophic effects in mouse models of tion and healthcare. bananas and asparagus) by bacte- Parkinson’s disease, in cisplatin- ria in the colon. Butyrate can also induced hearing loss, and in cases be produced in lower concentra- of disease-associated or toxicity- tions by mammalian cells and can induced dementia, such as be found in plant oils and animal Alzheimer’s disease. These effects fats (e.g. butter is the richest result in an improvement of behav- dietary source of butyrate). ioural outcomes, including learning and memory, which can be Butyrate is a molecule with a wide explained by the up-regulation of range of biological functions, which genes involved in promoting cell makes it attractive for therapeutic survival, plasticity and regeneration. purposes. It has been shown to exert direct effects upon gene

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 19 SELECTED CONTENT Can a high-fibre diet prevent and/or treat neurological disorders?

Furthermore, butyrate can assist as in colonocytes, T cells, and micro- lower psychological stress in an energy metabolite to produce glia. It is thought that this receptor healthy human subjects and in adenosine triphosphate (ATP). It could be a good target for thera- subjects with chronic fatigue serves as a preferred energy source peutics in Parkinson’s disease. syndrome by increasing butyrate- for colonocytes and the researchers producing bacteria. However, of this review hypothesize that if Available data shows a strong elevated SCFAs in the bloodstream sufficient butyrate levels could be connection between the gut micro- due to increased gut permeation by reached in the brain, it could be biota, butyrate and the brain. abnormal microbiota may be unfa- used as an energy substrate, as in According to a study performed in vorable for children with autism the colon. This would be an impor- mouse models, either butyrate- spectrum disorders. tant outcome, as energy dysho- producing bacteria or an oral meostasis occurs in the brain in gavage of NaB can restore blood- In conclusion, a high-fibre diet is many neurological diseases (e.g. in brain barrier permeability in germ- hypothesized to prevent and/or Alzheimer’s, the brain has reduced free mice. Also, mice fed a diet high treat brain disorders by elevating glucose utilization from the earliest in fermentable fibre recover faster butyrate in the gut. More research stages of the disease). Aside from and show attenuated neuroinflam- is needed in order to elucidate the its metabolic effects, butyrate mation after exposure to lipopoly- possible pharmacological beneficial might help to rectify the disease- saccharide. Taking these data effect of butyrate on brain disor- associated mitochondrial dysfunc- together, the authors hypothesize ders, including neurodegenerative tion in the brain secondary to that the elevated butyrate from the diseases and psychological disor- reduced brain glucose availability. dietary fibre fermentation may ders. contribute to both the beneficial Last, but not least, butyrate can act neurological and immune effects on as a G protein-coupled receptor host health. (GPCR) activator. Some GPCRs have been identified as receptor Regarding human populations, the targets for SCFAs. Strikingly, beneficial effects of a high-fibre butyrate induces anti-inflammatory diet on memory and cognition are effects through activation of GPR109a, starting to be explored. Several which is a kind of GPCR expressed studies show that probiotics could

Source: Bourassa MW, Alim I, Bultman SJ, Ratan RR. Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health? Neurosci Lett. 2016; doi:10.1016/j.neulet.2016.02.009.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/can-high-fibre-diet-prevent-andor -treat-neurological-disorders/

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 20 BOOKS & RESOURCES

Connecting the Dots between Digestion and Emotion: Book Review of Emeran Mayer’s The Mind-Gut Connection

Published in GUT BRAIN AXIS Written on August 3, 2016 by Kristina Campbell

Digestion and emotion have long been treated separately in medicine and science, like dots far apart on a map. Despite the phrase “gut feeling” that implicitly connects the belly and the brain, the reality is that gut physiology, microbes, and the mind have all been studied independently. It’s why, when you walk into a doctor’s office complaining of both constipation and a low mood, you might have two different conversations and get two different prescriptions.

In his new book, The Mind-Gut travel both upward and downward Connection, gastroenterologist (though mostly upward) between and University of California Los the digestive system and the brain. Angeles (UCLA) professor of The messages are sent in various medicine Dr. Emeran Mayer starts ways: hormones, the vagus nerve to skillfully draw lines between “information highway”, and certain these far-apart dots. Mayer uses signaling molecules of immune the book to explain the different cells. One chapter is dedicated to ways the gut and the brain com- “microbe-speak”—the gut microbiota’s municate, emphasizing the contribution to gut-brain commu- nascent science on the important nication. One major way that gut role played by the gut microbiota. microbes respond to constant incoming information about their Mayer’s genuine curiosity about his host’s emotional state and stress patients is what seemed to lead level, it seems, is by adjusting their him into a career of research production of metabolites. focused on the gut-brain axis. He took seriously the patients who Next, the book explores how inter- came into his office with bizarre- actions between the mind and gut sounding stories—sudden, unex- microbiome can inform everyday plained vomiting in the mornings; emotional experiences. Here Mayer extreme anxiety about toxic waste makes much of the influence of in the colon. The book is the prod- early-life events on the gut-brain uct of his lifelong drive to find out dialogue, an idea supported by more. fascinating research done in mice. He even speculates that research In the first part of the book, Mayer might reveal a key role for the gut Emeran Mayer explains in patient detail how messages microbiota in determining how

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 21 BOOKS & RESOURCES

Connecting the Dots between Digestion and Emotion: Book Review of Emeran Mayer’s The Mind-Gut Connection

long and how intense our emotions In The Mind-Gut Connection, become on a daily basis. Mayer has a good handle on the science in a realm where sticking The third part of the book is about to the facts is not an easy task. optimizing brain-gut health. Mayer Much easier would have been to explains how diet plays a role in draw careless lines between the shaping the gut microbiota; he dots with a Sharpie, and then (as “Dietary differences draws from research in cultural others do) try to sell the resulting may even shape groups that have dramatically picture. gutbrain different diets from a typical person in North America. Dietary In this first popular book to give a communication: for differences may even shape gut- scientifically balanced view of how example, chapter brain communication: for example, gut microbes contribute to gut- chapter nine outlines the compel- brain communication, Mayer’s nine outlines the ling evidence for the mechanisms main strength is his restraint. He compelling by which high-fat diets could harm doesn’t claim to have a miracle evidence for the the brain. The book turns then to cure for depression or panic the need to rediscover the Mediter- attacks. But he does report that mechanisms by ranean diet as well as beneficial when encountering patients who which high-fat diets fermented foods. suffer from these conditions, he takes the time to explain the could harm the Recommendations are offered in a connections between what they brain.” final chapter; some are based on feel in their minds and what they evidence and others (like eating experience in their bodies. And it organically grown foods) seem to seems to give them a pocketful of feature distinctly Californian validation, of hope. Things small, concerns. But all of the exhorta- but not trivial. tions resonate—for example, “enjoy meals together” is a good reminder to today’s fast-living families.

Source: Mayer E. The Mind-gut connection: How the hidden conversation within our bodies impacts our mood, our choices, and our overall health. New York, NY: Harper Wave; 2016.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/connecting-dots-digestion-emotion -book-review-emeran-mayers-mind-gut-connection/

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