Prebiotics, probiotics, fermented foods and cognitive outcomes: A meta-analysis of randomized controlled trials

Highlights

• Twenty-two studies investigated pre- and probiotics and fermented foods on cognition.

• No intervention had a significant effect on global or specific domains of cognition.

• Heterogeneity regarding the population, cognitive tests, and intervention identified.

Abstract

This systematic review and meta-analysis aimed to evaluate randomized controlled trials that investigated the use of probiotic, prebiotic, and fermented food interventions for cognitive performance. In total, 22 studies (n = 1551) were included that investigated probiotics (11 studies, n = 724), prebiotics (5 studies, n = 355), and fermented foods (6 studies, n = 472). Despite several individual studies (14 of 22) reporting significant improvements in specific cognitive domains, results of the pooled meta-analysis found no significant effect for any intervention for global cognition (Probiotics: g = 0.115, 95 %CI -0.041, 0.270, p = 0.148; Prebiotics: g = 0.077, 95 %CI -0.091, 0.246, p = 0.369; Fermented food: g = 0.164 95 %CI -0.017, 0.345, p = 0.076) or any individual cognitive domain. Most studies (16 of 22) had low risk of bias. These results do not support the use of probiotic, prebiotic, and fermented food interventions for cognitive outcomes. This may be due to the limited number of small and short-term studies as well clinical heterogeneity relating to the population, cognitive tests, and intervention. Therefore, further trials that investigate these interventions in clinical populations using adequately powered samples are warranted. PROSPERO: CRD42019137936

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.