Exploring psychotherapeutic issues and agents in clinical practice
The microorganisms that live inside and on humans (known as the microbiota) are estimated to outnumber human somatic and germ cells by a factor of 10, and the majority inhabit the gastrointestinal tract (Turnbaugh et al., 2007). The collective genome of the microbiota (referred to as the microbiome) contains more than 100 times the number of genes as the human genome. Although the precise role of much of the microbiota is largely unknown, developing evidence suggests that microorganisms can exist in a symbiotic relationship within our bodies, performing many essential metabolic tasks for human physiology and perhaps being especially important for the development and activity of the immune system (Turnbaugh et al., 2007). In this month’s column, I will review the concept of the gut–brain axis and the potential therapeutic effect of intestinal microbiota on the brain.
What Is The Gut-Brain Axis?
The gut–brain axis is a communication system integrating neural, hormonal, and immunological signaling between the gut and brain (Collins, Surette, & Bercik, 2012). This system is bidirectional: intestinal microbiota can influence brain function and the brain can influence gastrointestinal function.
Experimental evidence from animal studies has demonstrated that intestinal microbes can directly and indirectly affect cognitive, behavioral, social, and other neurological functions (Sampson & Mazmanian, 2015). Signals from the intestinal microbiota potentially affect the brain via three distinct, but overlapping mechanisms: (a) direct activation of the vagus nerve, which courses from the gut to the central nervous system; (b) production or induction of various neurotransmitters, hormones, and metabolites that pass from the gut into the circulatory system and then cross the blood–brain barrier; and (c) modulation of immune system cells and their release of cytokines, which can subsequently cross the blood–brain barrier. Each of these mechanisms has known relevance to understanding psychiatric disorders and their treatment.
Not surprisingly, most studies examining the gut–brain axis have been conducted in rodents, with only a limited amount of research in humans. A goal of the federally funded Human Microbiome Project has been to identify and characterize the microbiome and ultimately enable further investigation of how changes in the microbiome might be related to health or disease (Turnbaugh et al., 2007).
What Are Probiotics?
Probiotics are defined as live organisms that are believed to exert a health benefit when ingested in adequate amounts (Hill et al., 2014). The U.S. Food and Drug Administration (FDA) has no formal definition of probiotics and regulates them based on whether they fall into an existing regulated drug, biologic, or food product category (Hoffmann et al., 2013). Live probiotic cultures are available in fermented dairy products, but tablets, capsules, or powders containing freeze-dried bacteria are commercially available. None of these products are approved by the FDA and do not require a prescription. In Europe, the European Food Safety Authority (EFSA) evaluates the health claims of probiotic products (Binnendijk & Rijkers, 2013).
Probiotic organisms are typically characterized by their genus, species, and strain, as different strains from the same genus and species may have different effects. Probiotics have been used in animal studies as a way to experimentally manipulate the intestinal microbiota and evaluate their effect on the nervous system (Bravo et al., 2012). They have also been studied in human individuals for the treatment of irritable bowel syndrome and obesity (Bravo et al., 2012; Park & Bae, 2015). The behavioral effect of probiotics in animals, as well as their putative mechanisms of action on the brain, provide a justification for investigating probiotics for their psychological effects in human individuals (Dinan, Stanton, & Cryan, 2013).
Clinical Studies of Probiotics on Mood and Anxiety Symptoms
Benton, Williams, and Brown (2007) investigated the impact on mood and memory of consuming a probiotic-containing milk drink in a randomized, double-blind, placebo-controlled trial in 132 physically healthy individuals recruited from the community. Assessments included the Profile of Mood States and the Wechsler Memory Scale. For a 3-week period, participants consumed either a probiotic-containing milk drink or a placebo daily, and 124 completed the trial. Mood and cognition were measured at baseline, and after 10 and 20 days of consumption. The probiotic did not generally change the mood of participants overall. However, participants in the bottom third of the depressed/elated dimension at baseline selectively responded by reporting themselves as happy rather than depressed after taking the probiotic. An interesting and unexpected finding was that the consumption of probiotics resulted in a slightly poorer performance on two measures of memory, although this finding may have occurred by chance.
In a pilot study of chronic fatigue syndrome, Rao et al. (2009) randomized 39 individuals to receive either Lactobacillus casei strain Shirota or a placebo daily for 2 months. Participants completed the Beck Depression and Beck Anxiety Inventories before and after the intervention. A statistically significant decrease in anxiety symptoms occurred among those taking the probiotic compared to placebo.
Messaoudi et al. (2011) investigated the effects on anxiety, depression, stress, and coping strategies of a probiotic formulation (consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) among 55 healthy individuals in a double-blind, placebo-controlled, randomized 30-day study. Assessments included the Hopkins Symptom Checklist, Hospital Anxiety and Depression Scale, Perceived Stress Scale, Coping Checklist, and a 24-hour urinary free cortisol. Compared to placebo, the probiotic significantly decreased scores of psychological distress on these measures and resulted in significantly decreased urinary excretion of cortisol.
Steenbergen et al. (2015) investigated the effect of a probiotic on cognitive reactivity to normal, transient changes in sad mood, which is an established marker of vulnerability to depression. The probiotic formulation contained Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis (W19 and W58). In this study, 40 healthy non-depressed individuals were enrolled in a triple-blind, placebo-controlled, randomized trial for 4 weeks. Before and after treatment, cognitive reactivity to sad mood was assessed using the revised Leiden Index of Depression Sensitivity Scale. Compared to placebo, the probiotic resulted in a significantly reduced overall cognitive reactivity to sad mood, which was largely accounted for by reduced rumination and aggressive thoughts.
Clinical Study of Probiotic Use in Schizophrenia
Dickerson et al. (2014) conducted a randomized, double-blind, placebo-controlled trial to investigate whether probiotic supplementation can reduce symptom severity in patients with schizophrenia receiving antipsychotic treatment and whether probiotics are associated with changes in bowel functioning. Following a 2-week placebo run-in period, 65 individuals with schizophrenia were randomly assigned to 14 weeks of double-blind treatment with probiotic or placebo. All study participants continued to take antipsychotic medication. The probiotic formulation was a combination of Lactobacillus rhamnosus (strain GG) and Bifidobacterium animalis (subsp. lactis strain Bb12). Psychiatric symptoms were assessed with the Positive and Negative Syndrome Scale. Participants were queried weekly about their gastrointestinal functioning. No significant differences were observed between the probiotic and placebo groups on psychiatric symptoms, but the probiotic-treated individuals were significantly less likely to develop severe bowel difficulty.
Clinical Investigation of Probiotic Use on Brain Function
Tillisch et al. (2013) investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks altered brain intrinsic connectivity or responses to emotional attention tasks. Thirty-six healthy female individuals without gastrointestinal or psychiatric symptoms were randomly assigned to one of three groups: (a) FMPP (n = 12); (b) a nonfermented milk product (n = 11, controls); or (c) no intervention (n = 13). The FMPP contained Bifidobacterium animalis (subsp. Lactis), Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis (subsp. Lactis). Study participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. FMPP intake was associated with reduced task-related response of a distributed functional network containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain function indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. These findings demonstrate that intake of a probiotic affected the activity of brain regions that control central processing of emotion and sensation (Tillisch et al., 2013).
There is strong evidence from animal studies that the intestinal microbiome has an important role in the control of brain development, function, and behavior. A small number of clinical studies (mainly in healthy individuals) using probiotic formulations as an experimental probe suggest that gut bugs may indeed act like drugs and affect the brain, but much more work is needed. Nurses should be familiar with the concept of the gut–brain axis, which encompasses an exciting area of research that may have practical relevance for psychiatric therapeutics. Because probiotics are commonly available and relatively popular, nurses should also be able to knowledgeably discuss their use with patients, but the claimed health effects of probiotic products should be viewed critically. In an analysis of health claims for probiotic products in Europe, the EFSA determined that 78% were possibly beneficial to human health, in particular the gut health effects (Binnendijk & Rijkers, 2013). However, most of the health claim applications were turned down by the EFSA because the scientific substantiation of a particular health claim was insufficient.
- Benton, D., Williams, C. & Brown, A. (2007). Impact of consuming a milk drink containing a probiotic on mood and cognition. European Journal of Clinical Nutrition, 61, 355–361. doi:10.1038/sj.ejcn.1602546 [CrossRef]
- Binnendijk, K.H. & Rijkers, G.T. (2013). What is a health benefit? An evaluation of EFSA opinions on health benefits with reference to probiotics. Beneficial Microbes, 4, 223–230. doi:10.3920/BM2013.0019 [CrossRef]
- Bravo, J.A., Julio-Pieper, M., Forsythe, P., Kunze, W., Dinan, T.G., Bienenstock, J. & Cryan, J.F. (2012). Communication between gastrointestinal bacteria and the nervous system. Current Opinion in Pharmacology, 12, 667–672. doi:10.1016/j.coph.2012.09.010 [CrossRef]
- Collins, S.M., Surette, M. & Bercik, P. (2012). The interplay between the intestinal microbiota and the brain. Nature Reviews in Microbiology, 10, 735–742. doi:10.1038/nrmicro2876 [CrossRef]
- Dickerson, F.B., Stallings, C., Origoni, A., Katsafanas, E., Savage, C.L., Schweinfurth, L.A. & Yolken, R.H. (2014). Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: A randomized placebo-controlled trial. Primary Care Companion for CNS Disorders, 16. doi:10.4088/PCC.13m01579 [CrossRef]
- Dinan, T.G., Stanton, C. & Cryan, J.F. (2013). Psychobiotics: A novel class of psychotropic. Biological Psychiatry, 74, 720–726. doi:10.1016/j.biopsych.2013.05.001 [CrossRef]
- Hill, C., Guarner, F., Reid, G., Gibson, G.R., Merenstein, D.J., Pot, B. & Sanders, M.E. (2014). The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews, Gastroenterology & Hepatology, 11, 506–514. doi:10.1038/nrgastro.2014.66 [CrossRef]
- Hoffmann, D.E., Fraser, C.M., Palumbo, F.B., Ravel, J., Rothenberg, K., Rowthorn, V. & Schwartz, J. (2013). Probiotics: Finding the right regulatory balance. Science, 342, 314–315. doi:10.1126/science.1244656 [CrossRef]
- Messaoudi, M., Lalonde, R., Violle, N., Javelot, H., Desor, D., Nejdi, A. & Cazaubiel, J.M. (2011). Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. British Journal of Nutrition, 105, 755–764. doi:10.1017/S0007114510004319 [CrossRef]
- Park, S. & Bae, J.H. (2015). Probiotics for weight loss: A systematic review and meta-analysis. Nutrition Research, 35, 566–575. doi:10.1016/j.nutres.2015.05.008 [CrossRef]
- Rao, A.V., Bested, A.C., Beaulne, T.M., Katzman, M.A., Iorio, C., Berardi, J.M. & Logan, A.C. (2009). A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathogens, 1, 6. doi:10.1186/1757-4749-1-6 [CrossRef]
- Sampson, T.R. & Mazmanian, S.K. (2015). Control of brain development, function, and behavior by the microbiome. Cell Host & Microbe, 17, 565–576. doi:10.1016/j.chom.2015.04.011 [CrossRef]
- Steenbergen, L., Sellaro, R., van Hemert, S., van Hemert, S., Bosch, J.A. & Colzato, L.S. (2015). A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain, Behavior, and Immunity, 48, 258–264. doi:10.1016/j.bbi.2015.04.003 [CrossRef]
- Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B. & Mayer, E.A. (2013). Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology, 144, 1394–1401. doi:10.1053/j.gastro.2013.02.043 [CrossRef]
- Turnbaugh, P.J., Ley, R.E., Hamady, M., Fraser-Liggett, C.M., Knight, R. & Gordon, J.I. (2007). The human microbiome project. Nature, 449, 804–810. doi:10.1038/nature06244 [CrossRef]