February 2017 Issue
Brain Health: Exploring the Microbiome-Gut-Brain Axis
By Carrie Dennett, MPH, RDN, CD
Vol. 19, No. 2, P. 14
Do the origins of cognitive and mental health disease lie in the intestine?
Traditionally, Western science has treated mind and body as separate entities, but the explosion of research on the gut microbiota and our understanding of the role it plays in human health and functioning is having an impact on more than just the world of medicine. It's also ushering in what may be a paradigm shift in the world of neuroscience.1
Scientists have known for years about the gut-brain axis, the two-way communication between the central nervous system (CNS) and the enteric nervous system (ENS). The ENS covers the entire gastrointestinal (GI) tract, so the gut-brain axis links the emotional and cognitive centers of the brain with intestinal functions.2 This connection is clear when we become aware of GI pain or distress, and also when stress or anger causes our stomach to "be tied up in knots," or when we have "a gut feeling."3
An emerging twist in our knowledge of the gut-brain axis is the concept of a microbiome-gut-brain axis.2 Evidence from preclinical animal research and a limited number of human clinical studies suggests that the microbiota interacts locally with intestinal cells and the ENS, but also has direct interaction with the CNS via neural, endocrine, immune, and metabolic pathways.2-5 The microbiota has even been called the "peacekeeper" between the gut and brain.6
Some of the first evidence of the microbiome-gut-brain connection came from successes using antibiotics to treat hepatic encephalopathy, a decline in brain function caused by severe liver disease.7,8 This led researchers to speculate about potential adverse effects of gut microbes in other brain disorders.9 It's also noteworthy that an altered gut microbiome likely plays a central role in the onset of celiac disease,10 which has neurological manifestations including loss of coordination, headache, and cognitive dysfunction.9
Animal studies have revealed that temporary changes in the gut microbiota influence brain chemistry and behavior in mice, affecting memory, learning, and anxiety levels.11 There's strong evidence from animal studies that gut microbes can activate the vagus nerve, which constantly "listens in" on the gut, alerting the brain to the presence of inflammatory cytokines (cell-signaling molecules).12 Chronic activation of the vagus nerve contributes to anxiety, panic disorders, and depression.3,13 In addition, animal studies have demonstrated that the gut microbiota can modulate the hypothalamic-pituitary-adrenal axis, which controls the body's stress response and plays a role in cognition and mood disorders.4,5,13-15
Because most of the body's immune cells dwell in the intestinal lining, the health, diversity, and abundance of the microbiota affects inflammation levels in the body. The gut microbiota also influences the CNS via the immune system by producing or inhibiting inflammatory and anti-inflammatory cytokines.13,15 Systemic, low-level inflammation plays a role in mental health disorders and cognitive decline13,14,16 as well as the progression of Parkinson's disease, Alzheimer's disease, and multiple sclerosis (MS).17
The microbiota also can induce production of several neurotransmitters, including serotonin, 95% of which is produced in the gut.2,3,13,18 Bacteria in the large intestine ferments dietary fiber to produce short-chain fatty acids,2,4 which in animal models have improved cognitive function in various neurological diseases.12
Early Brain Development and Disease
Normal development of the gut microbiota is necessary to support normal brain development shortly after birth,19 and may have long-lasting effects on behavior and cognitive function.11,12,18,20,21 A sparse microbiota early in life is associated with increased risk of anxiety, autism, and irritable bowel syndrome while a sparse microbiota later in life is associated with Alzheimer's and Parkinson's disease.22 There's also growing evidence that the origins of schizophrenia and other psychiatric illnesses may lie in early brain development.19
Anxiety and Depression
Both human and animal studies have demonstrated that administering probiotics (beneficial microbes) can reduce inflammation, anxiety, and signs of distress.14 A 2013 study randomized 36 healthy women to one of the following three groups: probiotic yogurt, nonfermented milk product with no probiotics, or no yogurt or milk products. After four weeks of twice-daily consumption, brain scans indicated that the women who ate the probiotic-rich yogurt had less of a negative emotional response when shown photos of people who were angry, sad, or fearful.23
Prebiotic fiber, which feeds gut bacteria, is another factor. Carbohydrate malabsorption has been linked to depression in females,11 and a study published in 2015 in The American Journal of Clinical Nutrition found that a diet high in refined carbohydrates increases the risk of depression in postmenopausal women. That study found that a diet high in fiber from whole grains, vegetables, and whole fruit was associated with a lower risk of depression.24 In addition, many people with celiac disease or irritable bowel syndrome also suffer from mood disorders.1,21
So which comes first, gut disturbances or mood disorders? "I often tell my patients, 'Everything starts in the gut,'" says Michelle Babb, MS, RD, CD, author of Anti-Inflammatory Eating for a Happy, Healthy Brain: 75 Recipes for Alleviating Depression, Anxiety, and Memory Loss. "With that being said, many of my patients who suffer from depression and/or anxiety have difficulty nourishing themselves well, and that undoubtedly leads to more GI distress."
Many children with an autism spectrum disorder (ASD) also have GI symptoms.4 Several small studies have demonstrated altered gut microbiota in children with ASD compared with children without the disorder,4,18 but interpreting these data is complicated by the fact that children with ASD are more likely to have a history of antibiotic use and often have different diets than children without ASD, two factors that can affect the gut microbiota.4
Cognitive Aging and Dementia
Age-related changes in the gut microbiota, which may be caused by a combination of diet changes, increased use of medications that affect the GI tract, and slowing of gut function are associated with chronic, low-grade inflammation, or "inflammaging."12,25,26
Researchers think that inflammation promotes cognitive decline both in the context of normal aging and in the development of Alzheimer's and clinical dementia.16,21,25
Parkinson's Disease and MS
GI dysfunction often precedes the onset of motor symptoms in Parkinson's disease and is found in MS patients and their families.27,28 Evidence that the gut microbiota is altered in both Parkinson's disease and MS has raised questions about whether changes to the microbiota could be a biomarker for these diseases, allowing for prevention or for earlier, more effective treatment.27,29 Further studies are needed to test the hypothesis that Parkinson's disease and MS begin in the gut.29,30
Schizophrenia and Bipolar Disorder
A 2013 study from researchers at John's Hopkins University found evidence of increased gut bacterial translocation and damage to the GI barrier in schizophrenic patients that wasn't related to effects of drug therapy.31 An imbalance of inflammatory and anti-inflammatory cytokines also has been noted in both schizophrenia and bipolar disorder,13 and a few case studies have shown successful treatment of bipolar disorder with nutritional changes designed to target the gut-brain axis.13
Research to date supports the role of gut bacteria in brain development and function, but little of this is clinical human research, says Hannah Holscher, PhD, RD, an assistant professor and director of the Nutrition and Human Microbiome Laboratory at the University of Illinois at Urbana-Champaign, who spoke on this topic at the Academy of Nutrition and Dietetics' annual meeting in Boston.32 "A lot of it has been conducted in preclinical animal models, which are quite important for setting the stage and improving our understanding of these relationships."
Information from human studies is limited for several reasons, including the increased complexity of studying the human microbiome, broader variations in the human diet, environmental influences, genetic variation, and the difficulty of measuring subtle changes in human emotional and cognitive function.33 More research must be done to understand the mechanisms involved in the microbiota-gut-brain axis so scientists can develop therapeutic strategies.3
Despite the interest in probiotics, there are limitations to the current research, and different probiotic strains have different effects.32,34 "Where research is lacking is how specific strains of bacteria or combinations of strains might be used therapeutically to target certain conditions or neurological issues," Babb says. "I think there's the potential for the whole field of neurogastroenterology to take center stage to advance our approaches to personalized nutrition and functional medicine."
For now, a diet rich in whole plant foods, with the addition of probiotic-rich fermented foods, is a surer bet for supporting physical and mental health. "The bottom line is that diet modulates the GI microbiome, and eating a diet rich in different types and sources of fiber will help support a diverse microbiome," Holscher says.32
— Carrie Dennett, MPH, RDN, CD, is the nutrition columnist for The Seattle Times and speaks frequently on nutrition-related topics. She also provides nutrition counseling via the Menu for Change program in Seattle.
1. Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014;34(46):15490-15496.
2. Carabotti M, Scirocco A, Maselli MA, Severia C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203-209.
3. Forsythe P, Kunze WA. Voices from within: gut microbes and the CNS. Cell Mol Life Sci. 2013;70(1):55-69.
4. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701-712.
5. Wang Y, Kasper LH. The role of microbiome in central nervous system disorders. Brain Behav Immun. 2014;38:1-12.
6. Mu C, Yang Y, Zhu W. Gut microbiota: the brain peacekeeper. Front Microbiol. 2016;7:345.
7. Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997;337(7):473-479.
8. Rothenberg ME, Keeffe EB. Antibiotics in the management of hepatic encephalopathy: an evidence-based review. Rev Gastroenterol Disord. 2005;5(Suppl 3):26-35.
9. Galland L. The gut microbiome and the brain. J Med Food. 2014;17(12):1261-1272.
10. Cenit MC, Olivares M, Codoñer-Franch P, Sanz Y. Intestinal microbiota and celiac disease: cause, consequence or co-evolution? Nutrients. 2015;7(8):6900-6923.
11. Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol. 2012;10(11):735-742.
12. Leung K, Thuret S. Gut microbiota: a modulator of brain plasticity and cognitive function in ageing. Healthcare (Basel). 2015;3(4):898-916.
13. Chrobak AA, Nowakowski J, Dudek D. Interactions between the gut microbiome and the central nervous system and their role in schizophrenia, bipolar disorder and depression. Arch Psychiatry Psychother. 2016;2:5-11.
14. Deans E. Microbiome and mental health in the modern environment. J Physiol Anthropol. 2016;36(1):1.
15. Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF, Burnet PW. Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends Neurosci. 2016;39(11):763-781.
16. Ozawa M, Shipley M, Kivimaki M, Singh-Manoux A, Brunner EJ. Dietary pattern, inflammation and cognitive decline: the Whitehall II prospective cohort study [published online January 29, 2016]. Clin Nutr. doi: 10.1016/j.clnu.2016.01.013.2016;pii: S0261-5614(16)00035-2.
17. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918-934.
18. Yarandi SS, Peterson DA, Treisman GJ, Moran TH, Pasricha PJ. Modulatory effects of gut microbiota on the central nervous system: how gut could play a role in neuropsychiatric health and diseases. J Neurogastroenterol Motil. 2016;22(2):201-212.
19. Goyal MS, Venkatesh S, Milbrandt J, Gordon JI, Raichle ME. Feeding the brain and nurturing the mind: linking nutrition and the gut microbiota to brain development. Proc Natl Acad Sci U S A. 2015;112(46):14105-14112.
20. Foster JA, Lyte M, Meyer E, Cryan JF. Gut microbiota and brain function: an evolving field in neuroscience. Int J Neuropsychopharmacol. 2016;19(5).
21. Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry. 2016;21(6):738-748.
22. 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: HarperCollins Publishers; 2016.
23. Tillisch K, Labus J, Kilpatrick L, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144(7):1394-1401.
24. Gangwisch JE, Hale L, Garcia L, et al. High glycemic index diet as a risk factor for depression: analyses from the Women's Health Initiative. Am J Clin Nutr. 2015;102(2):454-463.
25. Caracciolo B, Xu W, Collins S, Fratiglioni L. Cognitive decline, dietary factors and gut-brain interactions. Mech Ageing Dev. 2014;136-137:59-69.
26. Saffrey MJ. Aging of the mammalian gastrointestinal tract: a complex organ system. Age (Dordr). 2014;36(3):9603.
27. Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. 2015;30(3):350-358.
28. Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016;6:28484.
29. Jangi, S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.
30. Mulak A, Bonaz B. Brain-gut-microbiota axis in Parkinson's disease. World J Gastroenterol. 2015;21(37):10609-10620.
31. Severance EG, Gressitt KL, Stallings CR, et al. Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res. 2013;148(1-3):130-137.
32. Holsher H. The gut-brain highway: can traffic be regulated by diet? Paper presented at: Academy of Nutrition Dietetics' Food and Nutrition Conference and Expo; October 16, 2016; Boston, MA.
33. Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest. 2015;125(3):926-938.
34. Umbrello G, Esposito S. Microbiota and neurologic diseases: potential effects of probiotics. J Transl Med. 2016;14(1):298.