Gut-Brain sources cited by Dr. John Cryan

April 20th 2017

@ the University of Illinois Chicago

Lecture given to the department & student body

A gut feeling about the brain:

Microbiota as a key regulator of neuro-development and behavior

Dr. John F. Cryan has been speaking, teaching, and directing laboratory research about the gut-microbiota-brain axis for more than a decade. He is currently a professor at University College Cork Ireland. He is on the advising board for many scientific journals, and is Chief Editor of Neuro-pharmacology.

Recalling Pinocchio and Geppetto his woodcarving pupeteer, at times it seems the human body is controlled by the trillions of microbes that surround us and are within us. The genetic code for that microbial environment, some argue, is more influential than our own genetic code, with about an equal number of "cells" that are human and microbial.

“All diseases begin in the gut,” the ancient physician Hippocrates said.

How began the gut-brain axis?

Alexis St. Martin – was a patient with an intestinal injury.

William Beaumont – the surgeon began experimenting through a “window” into the digestive system. He found anger hindered digestion, and the brain’s emotional states were affecting the gut by timing the digestive juices churn through meat.

Pavlov, and all the greats of modern physiology pickup on this… bidirectional relationship between the gut and the brain.

Here from, begins an amazing conversation into the research interests of Dr. Cryan.

This short one hour lecture was more of a bibliography, citing about sixty article titles and - in a couple sentences - elaborating upon how each of these microbiota-neuroscience research articles (at least a couple dozen by Dr. Cryan himself) contributes to the profound overarching claim: that the microscopic envelope within and around us plays a regulating - not influential - role upon our neuro-development and behavior.

Browse through the titles. I have missed a completing the cites for many articles here and some others towards the end… of his lecture. Depending upon your particular interests within this topic, please use this listing (blog-post) as an outline to the lecture delivered, a door to other scientists’ work, but most importantly, as a chronology that establishes microbial “regulatory” roles in humans.

What does stress have to do with the gut-brain axis?

“It’s not stress that kills us, its our reaction to it,” Hans Selye 1. Early life stress alters behavior immunity and microbiota in rats; implications for irritable bowel syndrome and psychiatric illnesses ~ Stobhain M. O Mahony

2. Prenatal stress PNS, physiology & the gut Microbiota; Maternal prenatal stress is associated with the infant intestinal microbiota ~Maartje A.A. Zjilmans

Revisiting the humans as host to bacteria, we find them to easily outnumber our cells. Most of the microbiota in a newborn child coat the baby during birth through the vagina. C-section births have a lesser diversity of microbiota. These children are more susceptible to allergies, diabetes, and asthma. 3. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats ~ Dominguez-Bello et al.

4. Mother’s littlest helpers Katie Hinde and Zachery T. Lewis Programming infant gut microbiota, they measured how the influence of dietary and environmental factors changed the microbiomial flora. Breast milk contain antibodies that help babies. Also, the carbohydrate oligosaccarides cannot be digested by humans. The bacteria use these sugars to generate key metabolites we need. You are what your microbes eat! 5. Targeting the microbiota-gut-Brain Axis: prebiotics have anxiolytic and antidepressant- like effects and reverse the impact of chronic stress in Mice Aurelijus Burokas These series of articles show how adolescent brain development is influenced by the microbiome, how alcohol changes the microbiome (in rats), and changes with age in humans. 6. Adolescent brain vulnerability and psychopathology through the generations: role of diet and dopamine Richard M. O Connor 7. What is bugging your teen? The microbiota and adolescent mental health Karen-Anne McVey Neufeld 8. Sex-Dependent effects of a Targeted Microbiota depletion in adolescence Desbonnet et al 2015 9. Drink bugs Chronic vapor alcohol exposure induces marked changes in the gut microbiome in mice Veronica L. Peterson Nicholas J Jury 10. Adding fuel to the fire: the impact of stress on the aging brain Jack A Prenderville 11. Gut microbiota and extreme longevity Gut micro biota and aging Paul W. O’Toole Eli Metchnikoff was perhaps the earliest researcher to make the gut-microbiome-brain connection. Although he won the Nobel Prize in 1908, his probiotic research efforts were largely left until the late 20th century. Microbes are natures chemists; they manufacture so much for us, many neurotransmitters also made by them… Microbial metabolites become the intermediant biochemical ‘lubricants’ in myriad processes. 12. Revisiting metchnikoff: age-related alterations in microbiota-g-b axis in the mouse: Karen A scott 13. Signaling along the b-g-m axis Cryan and Dinan 14. Cross talk between diet-derived macro & micronutrients: the microbiota and its metabolites, and the brain 15. Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior 16. Postnatal microbial colonization programs the hypo-thalamic -pituitary – adrenal system for stress response in mice Nobuuki Sudo , Yoichi Chida 17. Normal gut microbiota modulates brain development and behavior Rochells Diaz Heijtz 18. Reduced anxiety like behavior and central neurochemical change Experiments use ‘germ free’ mice to inform how ‘specific pathogen free’ or modeled, derived microbiota might behave in specific strains of mice in, carefully monitored environments. 19. Abnormal brain development in male mice lacking microbiota Clarke et al. 20. Bacterial infection causes stress-induced memory dysfunction in mice Melanie G Gareau 21. The intestinal microbiota affect central levels… ? 22. Microbiota determines amygdala volume & dendritic morphology 23. Microbiome regulates amygdala dependent fear recall Haban et al., Mol psychiat (2017) 24. Regulation of prefrontal cortex myelination by the microbiota AE Hoban , RM Stilling 25. The gut microbiota influences blood-brain barrier permeability in mice; Viorica Braniste 26. Host microbiota constantly control maturation Daniel Erny Brain development, dendritic morphology, PFC myelination, stress, stress-induced memory dysfunction: all very broad and bold claims attributing ‘regulatory influence’ if not mechanisation by microbiota. Understanding the experimental link here to make these statements within each paper is fundamental. 27. Microbiota and neuroimmune signalling – target microglia activation in John F. Cryan 28. Gut microbiota regulate motor deficits and neuroinflammation in a model of parkinson’s disease Timothy R. Sampson et. al. Autism spectrum disorders Association of maternal report infant and toddler gastrointestinal symptoms with autism evidence from a prospective birth 29. Social deficits in mice lacking microbes; sociability ; Desbonnet et al . 30. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disoders Microbial reconstitution reverses maternal diet induced social and synaptic deficits in offspring Toward effective probiotics for autism and other neurodevelopmental Core symptoms of Autism are manifest (in mice models) when core microbes of the gut are not present. This extends the argument of a ‘social deficiency’ that is a hallmark of Autism spectrum disorder. #32 is bold and #33 builds upon the idea to harness probiotics for neurodevelopment. We have not ‘co-evolved with our microbial ancestors. They were here first! Nothing in biology makes sense except in the light of evolution. Cryan will point out how he back tracked in his own work because of this critique from a collegue below: 31. Review: friends with social benefits Stilling et al 32. Front Cell infect microbial… 2014 Theodosius Dobzhansky 33. Microbiota, neurodevelopmental & mental illnesses A psychology of the human -b-g-m axis: Andrew P Allen 34. Probiotics & prebiotics reduce anxiety and behavioral despair Bravi et al PNAS 35. Lactobacillus rhamnosus treatment alters zebrafish shialing ? behavior Borrelli et al. 36. How do bacteria signal to the brain? Role of the vagus nerve; Bravo et al. from PNAS a publication 37. Vagotomy and subsequent risk of parkinsons disease Elisabeth Svensson All signals from the gut-microbiota-brain, the g-m-b axis may not necessarily be good. The vagus nerve is an important super-highway that connects the peripheral nervous system with the CNS. Below, we have fecal microbiota transplants that contain microbes used novely – and cautiously – to treat a number of symptoms. This work is in its early stages… and changing what medicine means through … Repoop-ulates Crack-sules 38. Microbiota transplantation modifies host behavior Collins et al 39. Transferring the blues Kelly et al. The Psychobiotic revoltion: Does correlation move us towards causation? 40. Psychobiotics: a novel class of psychotropic Timothy G Dinan Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress electrophysiology and neurocognition in healthy volunteers Lost in translation: the potential psychobiitic 41. Diet and the extinction of microbiome Sonnenburg et al Nature Why do not the Amish people get allergies? 42. Missing microbiomes Martin J. Blaster 43. Feeding the brain and nurturing the mind; Linking nutrition and the gut microbiota to brain development Manu S Goyal ; dietry based strategies to alleviate poverty in Africa What emerges from the narrative of this research is that humans are certainly not in as much control of our development, behavior, disease, social interactions, and psychology as we once thought. The brain’s Geppetto are the microbiota, pupeteers of neural function and behavior.

“OVER-SELLING the microbiome award” This is a quirky award given by Jonathan Eisen out of University California – Davis to researchers that place too much weight on the microbiome, or perhaps stretch the mechanisation / causation argument beyond the evidence their research presents us. One thing is certain, our state of the gut will markedly affect our state of mind. Questions at the end of the lecture suggested: A look at the reserve direction: most studies initiate with the microbiota of the gut and move up to the brain; what about the other way around? Scientists should look at how the brain influences the micro-flora of our bodies. How does reducing stress affect our microbiome? The literature reviews negative symptoms within psychiatrics because they give us a better understanding- what about the positives? Within that line of thought, exercise and the microbiome is currently being researched at the University of IL Chicago, through the swim team here.