Review ArticleProbiotic supplementation can positively affect anxiety and depressive symptoms: a systematic review of randomized controlled trials
Introduction
Microbial organisms in the human gastrointestinal tract, known as the gastrointestinal (GI) microbiota, play an important role in human health and well-being [1], [2], [3]. Composed largely of communities of bacteria, the GI microbiota exert a dynamic regulatory influence on the development and maintenance of digestive, metabolic, and immune functioning within hosts [1], [2], [3], [4], [5]. Moreover, early life deficits in certain bacterial communities or their later alterations (ie, dysbiosis) appear to influence human pathophysiology and development, particularly in inflammatory bowel disorders and colorectal cancer [4], [6]. The apparently extensive nature of microbial influences on host physiology has motivated some to view the GI microbiota as virtually an additional organ, with functions that merit more intensive examination [1]. The Human Microbiome Project is now making a consolidated effort to better characterize the diversity and relevance of these internally residing microorganisms [7].
Preclinical animal models, largely involving rodents and swine, have played an important role in shaping current understanding of the local and systemic immune-metabolic effects of the GI microbiota. Among these, are several recent rodent-based investigations that suggest roles for the GI microbiota in regulating key aspects of central nervous system (CNS) physiology, mood, and behavior [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. Specifically, these include demonstrations of altered neurochemical-behavioral profiles in germ-free (GF) mice. These GF studies point to: (a) regional differences in central gene expression, neurochemical concentrations, and turnover rates [8], [9], [10], [11], [12], [13], (b) exaggerated hypothalamic-pituitary-adrenal axis stress responses [8], [10], [11], [13], (c) reductions in anxious behaviors linked to changes in the GI microbiota, [9], [10], [11], and (d) greater social cognitive deficits [14], additionally related to the GI microbiota. These and other related investigations have shown that bacterial colonization early in life in GF mice can result in neurochemical modifications that influence stress and anxiety [8], [9], [11], [12]. Similar beneficial neurochemical and behavioral effects have also been reported in mice with normal GI microbiota after supplementation with probiotic bacteria, primarily the Bifidobacteria (eg, Bifidobacterium longum 1714, Bifidobacterium breve 1205) [15], [16] and Lactobacillus strains (eg, Lactobacillus rhamnosus JB-1) [17]. In parallel, swine-based models also highlight the critical role of the GI microbiota and bacterial supplementation in enhancing immune development and functioning [18], [19], [20], [21], [22], [23], [24], [25], [26]. These data include evidence of altered immune development and function in differentially raised (conventional vs isolator-raised) newborn [18], [19] and GF piglets [20], [21]. Moreover, probiotic supplementation in swine has been shown to positively impact GI microbiota, leading to: (a) increased production of short (eg, Butyrate) and branched chain fatty acids [22], (b) reduced concentrations of Clostridium and increased concentrations of Lactobacillus[22], [23], (c) improved immune functioning [22], [24], (d) greater antioxidant activity [25], and (e) reduced expression of proteins linked to the stress response [26] following supplementations with Lactobacillus fermentum I5007[22], [25], [26], Lactobacillus delbrueckii subsp. bulgaricus 2038[23], and Lactobacillus acidophilus[24].
Taken together, these observations highlight the importance of interrelationships between GI microbiota, CNS, and immune functioning in rodents and swine [8], [9], [11], [12], [26]. However, questions remain about the effectiveness of probiotic supplementation in improving human mental health, specifically in relation to anxiety and depressive symptomatology. Given that probiotic supplementation in humans has previously been linked to improved gastrointestinal, immune, and cardiovascular health [27], [28], [29], the primary objective of this review is to systematically evaluate findings from published randomized controlled trials (RCTs), evaluating the effects of probiotic supplementation on depressive and anxiety symptoms in healthy and clinically diagnosed patients. Specifically, we evaluated the hypothesis that probiotic supplementation in humans would result in reduced depressive and anxiety symptoms, an important question with translational implications for psychiatric research.
Section snippets
Approach: search strategy and inclusion criteria
A systematic literature search was carried out using MEDLINE, PsycINFO, PubMed, Scopus, and Web of Science databases for the period of January 1990 to January 2016. Search terms included probiotic* OR bacteria OR bifidobacterium OR lactobacillus AND depression* OR anxiety* OR mental health (see Appendix A for the exemplar MEDLINE search strategy). These searches were further supplemented by reviewing bibliographies of the trials selected for inclusion to identify additional studies. Studies
Study and participant characteristics
Search results, as shown in Fig. 1, led to a total of 158 citations across MEDLINE (n = 45), PsycINFO (n = 7), PubMed (n = 37), Scopus (n = 34), and Web of Science (n = 35) databases, with 5 additional citations identified by manual search (see Supplementary data for MEDLINE search strategy) [33], [34], [35], [36], [37]. After removal of duplicate citations (n = 47), of the remaining 111 citations, 91 were excluded based on the review of titles and abstracts, leaving 20 citations for further
Discussion
The health benefits of some fermented foods and symbiotic human-bacterial interactions have long been acknowledged [43], [44]. But only recently has there been a focus on better understanding their underlying mechanisms and the broader physical and mental health implications. Although swine-based models have been extensively employed to better understand the contributions of GI microbiota to immune development and function [18], [19], [20], [21], [22], [23], [24], [25], [26], rodent-based
Conclusions and future directions
In summary, despite limitations and/or inconsistencies in current findings, it appears that probiotic supplementation had a positive impact on reducing anxiety and depressive symptoms in several studies. These current findings must be regarded as tentative until future trials address the intricacies of GI microbiota-GBA-CNS interactions, particularly in relation to specific (probiotic) strains, mediating biochemical pathways, and activated neuroanatomy (Fig. 2). To this end, (a) an extension of
Acknowledgments
Authors would like to thank Vina Mohabir for her expertise in the design of Fig. 2. Authors report no conflicts of interests. Meysam Pirbaglou, Paul Ritvo, and Joel Katz conceived of the idea. Meysam Pirbaglou and Mehras Motamed performed database searches, evidence summaries, and drafting of the manuscript. Paul Ritvo, Joel Katz, Russell de Souza, and Jennifer Stearns provided critical commentary and revision of the manuscript.
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