Review articlePrebiotics, probiotics, fermented foods and cognitive outcomes: A meta-analysis of randomized controlled trials
Introduction
The microbiota-gut-brain axis – characterized as the interplay between the gut microbiota and the brain – has emerged as a potentially relevant pathway for human health. This includes mental illness, behaviours that drive mental health, and cognitive performance (Cryan and Dinan, 2012; Long-Smith et al., 2019; Gareau, 2016). Studies in germ-free and antibiotic-exposed rodent models provide compelling support for the role of the gut microbiota in cognitive performance. For example, antibiotic-induced dysbiosis resulted in impaired novel object recognition (using the open field test) and stress-induced memory dysfunction (using acute water avoidance stress) in C57BL/6 N mice (Gareau et al., 2011; Fröhlich et al., 2016). Preclinical studies suggest that this impairment may be mediated via several identified mechanisms of action including: modulation of brain-derived neurotrophic factor where animal studies suggest that hippocampal levels can be modulated following the manipulation of the microbiota (Cryan et al., 2019); increased short chain fatty acid production, which possess immunomodulatory functions; and modulation of oxidative stress and the tryptophan-kynurenine pathway (Komanduri et al., 2019; Marx et al., 2017; O’Mahony et al., 2015).
The term “psychobiotics” refers to probiotic and prebiotic interventions that beneficially affect mental and cognitive outcomes due to their interaction with the gut microbiota (Sarkar et al., 2016). The exact mechanisms by which various psychobiotic interventions may influence cognition is yet to be fully elucidated; however, different forms of psychobiotics (e.g. prebiotic and probiotic interventions) have differential effects on the microbiota composition and thus likely exert differing effects on the pathways of communication between the gut and the brain. Although the exact mechanisms are not fully resolved they likely involve differential effects on the immune system, the synthesis and metabolism of metabolites and neurotransmitters and activation of the vagus nerve, among others.
Probiotic interventions deliver specific strains of bacteria that may influence gut microbiota composition and activity. The provision of Bifidobacterium breve strain A1 reversed behavioural measures (alternation behaviour in a Y maze test and latency time in a passive avoidance test) of cognitive dysfunction in an animal model of Alzheimer’s disease (ddY mice injected with Aβ protein 25–35) (Kobayashi et al., 2017). Furthermore, fMRI studies have reported that probiotic interventions can modulate the activity in regions of the brain involved in cognitive performance such as the frontal cortex compared to placebo (Bagga et al., 2018, 2019; Tillisch et al., 2013). For example, in a study in 45 healthy adults, a 4-week administration of a multi-strain probiotic intervention (7.5 × 106 CFU/g) modulated functional activity in brain regions associated with higher-order cognitive processes such as problem-solving, reasoning, attention, decision-making, learning, and creativity. These results provide preliminary data to suggest that probiotic interventions may influence cognitive performance.
Prebiotics, as defined by the International Scientific Association for Probiotics and Prebiotics, are “a substrate that is selectively utilized by host microorganisms conferring a health benefit” (Gibson et al., 2017). Compounds with prebiotic properties provide substrates for the metabolism of commensal bacterial, in contrast to probiotics, which deliver external strains of probiotic bacteria. Examples of supplemented prebiotic formulations include carbohydrate-based compounds such as fructooligosaccharides and inulin as well as polyphenols and polyunsaturated fatty acids (Sanders et al., 2019). Provision of prebiotic fiber resulted in improved cognitive flexibility in animal models and can influence biochemical pathways involved in cognitive performance including brain-derived neurotropic factor (Williams et al., 2016). Furthermore, lacto-fermented foods such as yogurt, kefir, and sauerkraut are an additional intervention that may contain probiotic and prebiotic factors as well as bioactive metabolites that are produced during the fermentation processes (Aslam et al., 2020; Ano et al., 2015). For example, certain probiotic bacteria that are present in fermented foods can initiate production of the neurotransmitter, gamma-aminobutyric acid (GABA) (Aslam et al., 2020).
Due to the mechanistic plausibility of interventions that target the gut microbiota, there have been several recent clinical trials that have investigated the efficacy of prebiotic, probiotic and fermented food interventions for cognitive performance. A recent systematic review of 14 prebiotic intervention studies that measured cognitive performance (n = 7 studies) and mood (n = 12 studies) outcomes reported mixed results with some, but not all, studies finding improvements in verbal episodic memory, working memory and executive function. The greatest efficacy was demonstrated by acute prebiotic interventions that measured cognitive outcomes within 10 min to 4 h of prebiotic administration (Desmedt et al., 2019). However, the prior review by Desmedt et al. included studies of lower quality study designs (e.g. pre/post study designs) and prebiotic interventions that were combined with other bioactive compounds (e.g. glucosamine), which may have influenced outcomes. Furthermore, as this review was restricted to prebiotic interventions only, there is a need to investigate the efficacy of probiotic and fermented food interventions. Due to the lack of large clinical trials that have investigated prebiotic, probiotic and fermented food interventions for cognition, a meta-analysis, whereby the results of smaller studies are pooled, improves the level of precision in determining intervention effect. However, no meta-analysis has established the overall efficacy of such interventions. Hence, the aim of this systematic review and meta-analysis was to determine the efficacy of prebiotic, probiotic and fermented food interventions in improving measures of cognitive performance in adults compared to control conditions. We hypothesised that prebiotic, probiotic and fermented food interventions would improve measures of global cognitive function, working memory and executive function.
Section snippets
Methods
This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines as a methodological template (Moher et al., 2009), and was prospectively registered in an international registry of systematic reviews (PROSPERO registration no. CRD42019137936).
Study selection
The search strategy resulted in 1043 de-duplicated studies that were screened to identify 22 eligible studies for inclusion (see Table 1, Fig. 1).
Study characteristics
A total of 1551 participants were enrolled in the included studies, with an average of 50 participants in each study. Trials ran from two days to 24 weeks with 12 weeks being the most common trial length (9/22). Most studies investigated probiotic, prebiotic, or fermented foods interventions as a stand-alone intervention (n = 18 studies). Four studies
Discussion
This is the first meta-analysis and systematic review to quantitatively investigate the effect of probiotic, prebiotic, and fermented food interventions on cognitive outcomes. A total of 22 independent studies were included, with over 1500 individuals randomized to either prebiotic, probiotic or fermented food interventions vs. control conditions. Fourteen of the included studies reported that a probiotic, prebiotic or fermented food intervention resulted in significant improvements in at least
Conclusion
Based on the currently available emerging evidence, results of this meta-analysis do not support the use of probiotic, prebiotic, and fermented food interventions for cognitive function. The lack of treatment effect may be attributed to the limited number of studies in the existing literature, the lack of statistically powered studies and potentially low statistical power of some included meta-analyses, and the significant clinical heterogeneity relating to the population, cognitive test
Funding
WM is supported by Deakin University postdoctoral fellowship. MH is supported by an Australian Rotary Health and Deakin University postgraduate scholarship. NMD is supported by a Dementia Australia Research Foundation PhD scholarship. AS has received research funding from: Abbott Nutrition, Australian Research Council, Arla Foods, Australian Wine Research Institute, Bayer, Biotechnology and Biological Sciences Research Council, Cognis, Cyvex, DuPont, European Commission Framework 5 Research and
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2022, Journal of Functional FoodsCitation Excerpt :On the other hand, different microorganisms might need to grow and reproduce in clusters and symbiotically, its activity could not be guaranteed when a single microorganism was isolated by modern science and technology, which was the main reason (Castellanos et al., 2020; Geva-Zatorsky et al., 2017). Probiotics have shown significant effects in promoting the digestion and absorption of nutrients, maintaining the homeostasis of gut microbiota, antivirus, inhibiting inflammation, and improving the body's antioxidant and immune capabilities, especially in people with low immunity, constipation, and people who were prone to inflammation (Manzoor et al., 2022; Marx et al., 2020; Su et al., 2020; Zepeda-Hernández et al., 2021). At the same time, the application of probiotics in fishery and breeding industry was also widely used to improve the reproductive ability and immunity of animals (Golder et al., 2022; Rohani et al., 2022).
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