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Psychobiotics: bacterial hope for depression?

Mark Greener Increasing evidence links the gastrointestinal tract, skin, mouth, • The gastrointestinal microbiome microbiome’s composition with nose and vagina. The lower gastro- seems to be causally involved in the several psychiatric and intestinal tract is the most diverse development of the hypothalam- neurological diseases, including niche, being colonised with more ic-pituitary adrenal (HPA) axis.6 autism, schizophrenia, attention than 30 000 different strains of bac- • Bacterial products, such as endo- deficit hyperactivity disorder, teria. To put this in context, the toxins produced by gram-negative Parkinson’s disease, Alzheimer’s ‘most generous estimates’ suggest , can influence mood and disease and multiple sclerosis - that an acre of undisturbed tropical cognition by, for example, activat- Mark Greener investigates. rainforest may contain 15 000 ing the immune system and directly different .1 stimulating receptors on glial cells.5 raditionally, clinicians’ attitudes This diverse population of gas- Ttowards the 100 trillion bacteria trointestinal bacteria releases Researchers are exploring the details harboured by the human body numerous signalling molecules that of these and several other potential ‘oscillated between benign neglect may influence the brain and behav- pathways that link the gut microbiome and suspicious distrust’.1 After all, iour through immunological and brain. This article can only skim commensal bacteria can be a reser- (cytokines), endocrinological (cor- the surface of this research and the voir of antibiotic-resistant patho- tisol) and neural (the vagus nerve pathogenic and therapeutic implica- gens. But over recent years, and enteric nervous system) mech- tions – several insightful recent reviews researchers increasingly recognised anisms.2 For example: offer more detail.2,3,6 that the ‘microbiome’ influences • Certain gastrointestinal bacteria numerous aspects of human biol- produce neurotransmitters – Transplanting depression ogy including digestion, the including gamma-aminobutyric While many of the details await fur- immune system, metabolic path- acid (GABA), serotonin, catechola- ther research, there seems little ways and responses to certain drugs. mines and acetylcholine – and their doubt that the gut microbiome Now increasing evidence links the precursors, such as tryptophan.2,5 influences the brain and behaviour. microbiome’s composition with sev- Neurotransmitters released by bac- Depressed patients, for example, eral psychiatric and neurological dis- teria may, for example, induce epi- show marked changes in the com- eases, including autism, schizophrenia, thelial cells to release molecules position of their gastrointestinal attention deficit hyperactivity disor- that modulate signalling in the microbiome.2,3 Transplanting this der, Parkinson’s disease, Alzheimer’s enteric nervous system.2 abnormal microbiome may even disease and multiple sclerosis.2,3 The • Increases in pro-inflammatory ‘transplant’ depression. recognition of the microbiome’s cytokines seems to be associated For instance, researchers trans- potential importance inspired a new with depression and some other planted faecal microbiotas from 34 therapeutic strategy that uses ‘psycho- psychiatric conditions. The compo- depressed patients and 33 healthy biotic’ supplements containing live sition of the microbiome can influ- controls into rats who had their gastro- to improve mental ence the balance of pro- and intestinal bacteria depleted with a health.4 Indeed, a recent study offers anti-inflammatory cytokines.6 cocktail of antibiotics. Rats that ‘the first evidence’ that may • The vagus nerve modulates gastroin- received a transplant from depressed help reduce negative thoughts associ- testinal motility and conveys informa- patients showed a dysregulated micro- ated with sad mood’.5 tion from the gut to the brain. biota and exhibited anhedonic and Stimulating the vagus also seems to be anxiety-related behaviours compared More diverse than the anti-inflammatory. Indeed, modula- with those who received a transplant rainforest tion of the vagus may be a common from controls.3,7 Against this back- Basically, the pathway for the actions of antidepres- ground, probiotics are attracting occupies five niches: the lower sants, anxiolytics and psychobiotics.6 increasing interest as a means to www.progressnp.com Progress in Neurology and Psychiatry I Vol. 22 Iss. 1 2018 I 9 News review I Psychobiotics

restore a beneficial microbiota and treatment. B. longum 1714 seemed to the imposition of chronic stress to influence behaviour. attenuate the increases in cortisol and promote anxiety may mean the For instance, mice raised in sterile subjective anxiety induced by the cold mice react differently to healthy environments lack a microbiome. The pressor test compared with placebo. humans.3 germ-free mice showed exaggerated Consuming the also Some researchers suggest that physiological reactions to stress com- seemed to reduce daily stress reported combining species of probiotics pared to normal controls. Colonising by the volunteers.4 may increase effectiveness by, for the gut using probiotics reversed this In addition, the psychobiotic was example, colonising different exaggerated stress response.6 Indeed, associated with ‘subtle improvements’ niches. So a recent Dutch study several researchers have shown that, in in visuospatial memory that depended assessed a containing animal models at least, chronic admin- on the hippocampus and enhanced bifidum W23, Bifido- istration of probiotics can reduce anx- electroencephalographic activity in bacterium lactis W52, iety-like and depressive-like the prefrontal cortex, which, among acidophilus W37, Lactobacillus brevis behaviours. Probiotics also normalise other functions, is also involved with W63, W56, Lacto- physiological changes linked to these memory. The authors concluded that bacillus salivarius W24 and Lactococ- behaviours, such as altered immune consumption of B. longum 1714 ‘is cus lactis (W19 and W58).5 function and changes in levels of cor- associated with reduced stress and The study enrolled 40 healthy ticosterone, noradrenaline and improved memory’.4 people without mood disorders brain-derived neurotrophic factor Further research needs to who took the probiotic or placebo (BDNF),4 which is important for unravel the mechanisms through once daily for four weeks. Com- learning and memory. which B. longum 1714 might modu- pared with placebo, those who Anxiety and depression seem to late stress and cognition. For exam- received the probiotic showed sig- be associated with reduced levels of ple, the reduction in daily and nificantly reduced overall cognitive BDNF.6 For example, in preclinical acute stress may underlie the reactivity to sad mood on the the studies the improved visuospatial memory. In revised Leiden index of depression 1714 strain selectively improves addition, the psychobiotic seems, in sensitivity (LEIDS-r) scale, a trait stress-related behaviours, physiol- animal models, to increase BDNF that indicates vulnerability ogy and cognition.4 Similarly, in levels and stimulate neurogenesis. to depression.5 stress-sensitive mice, Lactobacillus Further studies could ascertain if Reductions in rumination and rhamnosus JB-1 reduced anxiety-like the same applies to humans.4 aggressive thoughts accounted behaviour in the elevated plus Probiotics’ effects on stress and for most of the probiotic’s bene- maze, despair-like behaviour in the cognition may, however, be specific to fits. Each LEIDS-r subscale has a forced swim test and stress-induced each strain. For instance, as men- maximum score of 24. Baseline corticosterone levels. L. rhamnosus tioned above, L. rhamnosus JB-1 mean aggression scores were 8.80 JB-1 also enhanced learning in a showed promising effects in mouse and 8.68 in the placebo and pro- fear conditioning model, increased models. But when researchers assessed biotic arms respectively. After GABA levels in the brain and mod- four weeks treatment with L. rhamno- four weeks, the scores were 8.45

ulated expression of GABAA and sus JB-1 in 29 healthy volunteers, the and 6.25 respectively. Baseline 8 GABAB receptors. probiotic did not alter stress-related mean rumination scores were outcomes, HPA response, inflamma- 11.75 and 11.20 in the placebo Human studies tion or cognitive performance and probiotic arms respectively. More recently, evidence emerged that compared with placebo.8 After four weeks, the scores were some probiotics induce beneficial In other words, promising 11.85 and 8.25 respectively.5 changes in humans, although further results in animal models may not The authors comment that as studies are needed. For instance, one always translate into clinical bene- the study enrolled people with min- study enrolled 22 healthy volunteers, fits.8 Several factors probably con- imal to mild scores on the Beck who received placebo and then B. tribute to the discordance. For Anxiety Inventory and the Beck longum 1714 daily both for four weeks. example, mice and humans differ Depression Inventory II, ‘it is not The volunteers underwent the socially in their . So mice surprising … that the beneficial evaluated cold pressor test, which and humans might also react dif- effect of probiotics intervention was combines psychological and physio- ferently to probiotics. Moreover, selective for cognitive reactivity to logical stress, at baseline and after the inherently anxious strain or depression and not for self-report

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symptoms of depression or anxiety’. small, with a short follow up and References Nevertheless, the authors concluded typically enrolled healthy volun- 1. Dorit R. The Superorganism Revolution. American Scientist 2014;102:330–3. that: ‘These results provide the first teers. So while the results are prom- 2. Cenit M, Sanz Y, Codoñer-Franch P. Influence evidence that the intake of probiotics ising, whether psychobiotics could of gut microbiota on neuropsychiatric may help reduce negative thoughts become an adjunctive treatment for disorders. World J Gastroenterol 2017;23: 5 5486–98. associated with sad mood’. anxiety or depression remains 3. Sherwin E, Dinan T, Cryan J. Recent Another approach uses prebiot- moot. Initially, clinical studies could developments in understanding the role of ics – in other words, nutrients that target disorders associated with the gut microbiota in brain health and disease. Ann NY Acad Sci 2017 doi:10.1111/nyas.13416 stimulate the growth or activity of stress-related changes in the brain- (Epub head of print). specific bacteria. For instance, in gut axis that have a cognitive com- 4. Allen AP, Hutch W, Borre YE, et al. mice a combination of the prebiot- ponent, such as irritable bowel Bifidobacterium longum 1714 as a translational psychobiotic: modulation of ics fructo-oligosaccharide and syndrome (IBS). Indeed, people stress, electrophysiology and neurocognition galacto-oligosaccharide improved with IBS seem to show impaired in healthy volunteers. Transl Psychiatry depression-like and anxiety-related visuospatial memory on the Paired 2016;6:e939. 5. Steenbergen L, Sellaro R, van Hemert S, et behaviours that were induced by Associate Learning (PAL) test. B. al. A randomized controlled trial to test the chronic psychosocial stress. In longum 1714 was associated with effect of multispecies probiotics on cognitive addition, the combina- subtly improved PAL performance reactivity to sad mood. Brain Behav Immun 4 2015;48:258–64. tion reduced HPA activation and in healthy volunteers. Neverthe- 6. Sarkar A, Lehto SM, Harty S, et al. dysregulation of the microbiota less, while further studies are Psychobiotics and the manipulation of associated with chronic stress. needed, modulation of the gut bacteria-gut-brain signals. Trends Neurosci 2016;39:763–81. Galacto-oligosaccharide supple- microbiome seems to offer an excit- 7. Kelly JR, Borre Y, O’ Brien C, et al. Transferring ments also appear to attenuate the ing potential new approach to the the blues: Depression-associated gut increase in cortisol on waking from management of several microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 2016;82:109–18. sleep in healthy volunteers and common neurological and 8. Kelly JR, Allen AP, Temko A, et al. Lost shift attention from negative psychiatric conditions. in translation? The potential psychobiotic towards positive stimuli.3 (JB-1) fails to modulate stress or cognitive performance in Current studies of psychobiotics Mark Greener is a freelance medical healthy male subjects. Brain Behav Immun and prebiotics are, however, relatively writer. 2017;61:50–9.

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