Many of us have experienced the feeling of our ‘stomachs turning’ when we are nervous, scared or anxious, and there is good reason as to why this happens. The gut, often referred to as our second brain, plays an important role, not just in digestion, but also regulating the activity of our nervous system. You may have noticed this during stressful periods; perhaps your bowel habits might change, and maybe you lose your appetite, or even get stomach cramps. You can thank your ‘Microbiome-Gut-Brain Axis’ for this. This is a key process of communication between our gut, gut bacteria (microbiome) and our nervous system, stimulated by the vagus nerve, otherwise known as the ‘wandering nerve’. This nerve connects the brain to all the organs that it passes on its way down to the colon, where most of the microbiome can be found. It works by constantly sending messages, informing the gut bacteria what is going on in the environment, allowing for them to react accordingly.[i],[ii]
The billions of gut bacteria that reside in our body, mainly in the digestive tract, have a symbiotic relationship with us. We are now discovering just how important these bacteria are to our health, and that includes mental health! Our gut bacteria can produce numerous neurotransmitters,[iii],[iv] which affect our nervous system and subsequently our behaviour.[v]The importance of gastrointestinal health to nervous function has been highlighted by a study which found that out of more than a thousand people with gastrointestinal disorders, 84% suffered with anxiety, and 27% with depression.[vi]
HOW DOES THE GUT AFFECT STRESS?
Given the prevalence of ‘stress’ and related conditions in today’s society, there is a need for us to consider how our gut microbiota may modulate our stress levels. The impact of gut bacteria on the hypothalamic-pituitary-adrenal (HPA) axis - the core stress axis – has been indicated by clinical trials showing that probiotics improve anxiety[vii]and reduce cortisol[viii] (a hormone which is usually high during a stress response).
Gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter (chemical messenger) which promotes a feeling of calm.[ix] Dysfunctions in the GABAergic pathway are associated with anxiety.[x] Animal research has shown how certain probiotic strains of Lactobacillus and Bifidobacterium (including Lactobacillus rhamnosus),[xi],[xii] and the LAB4 combination[xiii] (two strains of Lactobacillus acidophilus, Bifidobacterium lactis and Bifidobacterium bifidum) can produce GABA. This research highlights the therapeutic potential of communication between our gut microbiota and our body, termed ‘inter-kingdom signalling’.[xiv]
CAN ANXIETY BE CAUSED BY REDUCED GUT BACTERIA DIVERSITY?
Serotonin is a neurotransmitter that is sometimes called the ‘happy hormone’ as low levels are linked to low mood, depression[xv] and anxiety.[xvi] More than 90% of serotonin is produced in the gut! Animal studies have shown a potential regulatory effect of the gut bacteria on its production, as serotonin levels are significantly reduced in germ-free animals (animals that have a sterile gut). An explanation may be the short chain fatty acids (SCFAs) and secondary bile acids that are produced by our gut bacteria, may enhance serotonin synthesis.[xvii] Preliminary animal research indicates that B. infantis may increase plasma tryptophan levels; a precursor to serotonin, and thus potentially increasing serotonin levels.[xviii] So, targeting the gut microbiota may be useful in potential serotonin-related disorders, such as depression.[xix]
Individuals with depression have been found to have a different microbiota composition in comparison to healthy subjects, indicating disruption to the microbiome.[xx] Research using various probiotic combinations of different Lactobacillus and Bifidobacterium strains shows a positive effect on mood in both normal and depressed adults.[xxi] The LAB4 combination can also reduce anxiety levels.[xxii] This effect appears to be primarily modulated via the serotonergic and GABAergic pathways.
HOW DOES THE GUT AFFECT COGNITION?
A depletion in gut bacteria (due to antibiotics) is associated with signs of cognitive decline and altered production of Brain-Derived Neurotrophic Factor (BDNF) and tryptophan (a pre-cursor to serotonin).[xxiii] BDNF is important for the survival of existing nerve cells and plays a vital role in learning and memory. Changes to gut bacteria have also been noted in children with autism, particularly increased levels of Clostridium species[xxiv] and Bacteroidetes, and lower levels ofBifidobacterium.[xxv]If gut dysfunction is a key factor in autistic spectrum disorder, then probiotics may offer some hope. Certain probiotics like L. acidophilus and L.rhamnosus help to support healthy gut microflora[xxvi] and reduce overgrowth of C. difficile,[xxvii] while LAB4 significantly improved short-term memory in animals.[xxviii]
THE EFFECT OF GUT PERMEABILITY
Other mechanisms by which gut bacteria may affect the central nervous system (CNS) include increased gut permeability (or leaky gut syndrome) leading to bacteria and toxins moving into areas in the body where they are not normally found and potentially moving across the blood-brain-barrier. In fact, the microbiome may be partly responsible for permeability in the CNS.[xxix]
Bacterial metabolism can produce molecules such as lipopolysaccharides (LPS), d-lactate, ammonia and other toxins, which coupled with increased intestinal permeability can increase systemic inflammation. Elevated LPS levels have been found in individuals with depression.[xxx] D-lactate can increase brain inflammation[xxxi] and has been connected to panic attacks[xxxii] and schizophrenia.[xxxiii] One study found higher levels of d-lactate-producing Enterococcus and Streptococcus species in chronic fatigue syndrome (CFS).[xxxiv] One recent study showed a correlation between increased size of brain regions and changes in the gut microbiota (higher Firmicutes, especially Clostridium and lower Bacteroides) in people with IBS, speculating that bacterial metabolites could induce specific changes in the brain.[xxxv]
Further research is needed to determine exactly how probiotics can affect mental health in humans, but for now, it is an empowering prospect. By altering the gut bacteria for the better, it may be possible to improve your brain health. It encourages us to think laterally about possible stressors on the microbiome, such as caesarean birth, antibiotics and processed food. Supporting neurotransmitter balance and reducing intestinal permeability with probiotics may help us to combat today’s rising number of mood and anxiety disorders.
[i] Alcock J et al. Is eating behaviour manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Bioessays. 2014; 36 (10): 940-9.
[ii] Bravo JA et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. PNAS. 2011; 108 (38): 16050-16055.
[iii] Lyer LM et al. Evolution of cell-cell signalling in animals: did late horizontal gene transfer from bacteria have a role? Trends Genet. 2004;20:292-299.
[iv] Valles-Colomer, M et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nature Microbiology (2019).
[v] Sharon G, et al. Specialized metabolites from the microbiome in health and disease. Cell metabolism. 2014;20(5):719-730.
[vi] Addolorato G et al. State and trait anxiety and depression in patients affected by gastrointestinal diseases: psychometric evaluation of 1641 patients referred to an internal medicine outpatient setting. Int J Clin Pract. 2008 Jul;62(7):1063-9.
[vii] Rao A.V et al. A randomized double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog. 2009; 1 (1): 6.
[viii] Messaoudi M et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011; 105 (5): 755-764.
[ix] Lydiard RB. The role of GABA in anxiety disorders. J Clin Psychiatry. 2003; 64 Suppl 3:21-7
[x] Nuss P. Anxiety disorders and GABA neurotransmission: a disturbance of modulation. Neuropsychiatr Dis Treat. 2015; 11: 165-175.
[xi] Barrett E et al. γ-Aminobutyric acid production by culturable bacteria from the human intestine.J Appl Microbiol. 2012; 113 (2): 411-417.
[xii] Shan Y et al. Evaluation of improved γ-aminobutyric acid production in yoghurt using Lactobacillus plantarum NDC75017. J Dairy Sci. 2015; 98 (4): 2138-2149.
[xiii] O'Hagan C et al. Long-term multi-species Lactobacillus and Bifidobacterium dietary supplement enhances
memory and changes regional brain metabolites in middle-aged rats. Neurobiol Learn Mem. 2017 Oct;144:36-47.
[xiv] Hughes et al. Inter-kingdom signalling: communication between bacteria and their hosts. Nat Rev Microbiol. 2008; 6(2): 111–120.
[xv] Yohn CN et al. The role of 5-HT receptors in depression. Mol Brain. 2107; 10(1): 28
[xvi] Zangrossi and Graeff. Serotonin in anxiety and panic: contributions of the elevated T-maze. Neurosci Biobehav Rev. 2014; 46 Pt 3:397-406
[xvii] Yano JM et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2): 264-76.
[xix] O'Mahony SM et al. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2014 Jul 29 [ePub ahead of print]
[xx] Jiang H et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun. 2015 Aug;48:186-94.
[xxi] Huang R. Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2016; 8 (8).
[xxii] Owen L et al. A double blind, placebo controlled, randomised pilot trial examining the effects of probiotic administration on mood and cognitive function.
[xxiii] Desbonnet L et al. Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. Brain Behav Immun. 2015 Aug; 48:165-73.
[xxiv] Parracho HM et al. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol. 2005;54(Pt 10):987–99
[xxv] Finegold SM et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16(4):444–453
[xxvi] Armuzzi A et al. Effect of Lactobacillus GG supplementation on antibiotic-associated gastrointestinal side effects during Helicobacter pylori eradication therapy: a pilot study. Digestion 2001; 63 (1):1-7.
[xxvii] Johnson et al. Is primary prevention of Clostridium difficile infection possible with specific probiotics? Int J Infect Dis. 2012 Nov;16(11):e786-92.
[xxviii] O'Hagan C et al. Long-term multi-species Lactobacillus and Bifidobacterium dietary supplement enhances
memory and changes regional brain metabolites in middle-aged rats. Neurobiol Learn Mem. 2017 Oct;144:36-47.
[xxix] Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005 Jun;57(2):173-85.
[xxx] Maes M et al. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord. 2012 Dec 1;141(1):55-62.
[xxxi] Scully TB et al. D-lactate-associated encephalopathy after massive small-bowel resection. J Clin Gastroenterol. 1989;11(4):448-51.
[xxxii] Maddock RJ et al. Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study. Mol Psych. 2009; 14: 537-545
[xxxiii] Fukushima T et al. Quantitative Analyses of Schizophrenia-Associated Metabolites in Serum: Serum D-Lactate Levels Are Negatively Correlated with Gamma-Glutamylcysteine in Medicated Schizophrenia Patients. PLoS ONE. 2004;9(7): e101652.
[xxxiv] Sheedy JR et al. Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo. 2009;23(4):621-8.
[xxxv] Labus et al. Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome Microbiome (2017) 5:49.
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