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A double blind, placebo controlled, randomised pilot trial examining the effects of probiotic administration on mood and cognitive function

Authors:
Lauren Owen at Nestlé Institute of Health Sciences S.A.
Lauren Owen
Margot T. M. Reinders at University Medical Center Utrecht
Margot T. M. Reinders
R Narramore
R Narramore
R Narramore
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A. M. R Marsh
A. M. R Marsh
A. M. R Marsh
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Proceedings of the Nutrition Society
Winter Meeting, 11–12 December 2013, Diet, gut microbiology and human health
A double blind, placebo controlled, randomised pilot trial examining the
effects of probiotic administration on mood and cognitive function
L. Owen
1
, M. Reinders
2
, R. Narramore
3
, A. M. R Marsh
3
, F. Gar Lui
3
, R. Baron
3
,
Sue Plummer
4
and B. M. Corfe
3
1
School of Psychology, Keele University, UK,
2
Utrecht University, Netherlands,
3
Molecular Gastroenterology Research
Group, Academic Unit of Surgical Oncology, Department of Oncology, University of Sheffield, Royal Hallamshire
Hospital, Sheffield, UK and
4
Cultech Limited, Christchurch Rd Port Talbot, Neath Port Talbot
There is a growing body of evidence indicating that the gut microbiota communicates with the CNS influencing mood and
behaviour
(1–7)
and a role for the microbiota in the development of brain plasticity and the subsequent physiological response has
been suggested
(2)
. Furthermore treatment with probiotics has been shown to alter functional task-related brain activity and changes
in midbrain connectivity
9
. To date no study has demonstrated cognitive modification in response to probiotic treatment. The aims of
the study were i) To examine the mood effects of probiotic supplementation at rest and in response to psychological stressors ii) To
examine the effects of probiotic administration on cognitive functioning.
In this pilot study, healthy participants (n= 50) were recruited to take part in a double blind, randomised, controlled trial.
Participants were randomized to receive either a probiotic preparation comprising two strains of Lactobacillus acidophilus CUL60
(NCIMB 30157) and CUL21 (NCIMB 30156), Bifidobacterium lactis CUL34 (NCIMB 30172) and Bifidobacterium bifidum
CUL20 (NCIMB 30153) at a total of 2.5 ×10
10
cfu/capsule or a placebo for 6 weeks. The sample population comprised 18 males
and 32 females, mean age 23.22 years (range 19–38, SD 3.846), with a BMI <30. Participants underwent morphometric measurements
(height, weight, % total body fat, hip and waist measurement) and completed mood, stress and depression questionnaires (Bond Lader
Mood Scales, Stait Trait Anxiety Inventory and NASA Task Load Index). Participants also were required to perform a battery of
computerised cognitive test (COMPASS) measuring attention, executive function, working memory and episodic memory.
In terms of mood measures, a significant interaction showed that ‘trait’anxiety levels decreased in the active probiotic condition
whilst increasing in the placebo condition over the course of the 6 week intervention (p=0.042). A significant interaction was also
observed for tasks of attention; ‘continuity of attention increased in response to the probiotic treatment and decreased with the pla-
cebo group (p= 0.035). No morphometric changes between the two treatment conditions were recorded during the intervention per-
iod. The findings of this pilot trial provide a justification for further studies to characterise the potential cognitive and mood enhancing
benefits of probiotics in healthy populations.
This work was supported by Bioceticals, NSW Australia and Cultech Limited, S. Wales, UK.
1. Cryan JF & Dinan TG (2012) Nat. Rev. Neurosci.13, 701–712.
2. Sudo N et al. (2004) The Journal of physiology 558, 263–275.
3. O’Mahony L et al. (2005) Gastroenterology.128, 541–551.
4. Gaykema R et al. (2004) Brain. Behav. Immun.18, 238–245.
5. Goehler LE et al. (2005) Brain. Behav. Immun.19, 334–344.
6. Goehler LE et al. (2008) Brain. Behav. Immun.22, 354–366.
7. Lyte M et al. (2006) Physiol. Behav.89, 350–357.
Proceedings of the Nutrition Society (2014), 73 (OCE1), E29 doi:10.1017/S0029665114000433
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Introduction: Posttraumatic stress disorder (PTSD) is a psychiatric disorder, resulting from exposure to traumatic events. Current recommended first-line interventions for the treatment of PTSD include evidence-based psychotherapies, such as Cognitive Processing Therapy (CPT). Psychotherapies are effective for reducing PTSD symptoms, but approximately two-thirds of veterans continue to meet diagnostic criteria for PTSD after treatment suggesting there is an incomplete understanding of what factors sustain PTSD. The intestine can influence the brain and this study evaluated intestinal readouts in subjects with PTSD. Methods: Serum samples from controls without PTSD (n=40) from the Duke In-Trust Program were compared to veterans with PTSD (n=40) recruited from the Road Home Program at Rush University Medical Center. Assessments included microbial metabolites, intestinal barrier, and intestinal epithelial cell function. Additionally, intestinal readouts were assessed in PTSD subjects before and after a 3-week CPT-based intensive treatment program (ITP) to understand if treatment impacts the intestine. Results: Compared to controls, veterans with PTSD had a pro-inflammatory intestinal environment including lower levels of microbiota-derived metabolites acetic, lactic, and succinic acid, intestinal barrier dysfunction (lipopolysaccharide (LPS) and LPS binding protein), an increase in HMGB1, and a concurrent increase in the number of intestinal epithelial cell-derived extracellular vesicles. The ITP improved PTSD symptoms but no changes in intestinal outcomes were noted. Conclusion: This study confirms the intestine is abnormal in subjects with PTSD and suggests that effective treatment of PTSD does not alter intestinal readouts. Targeting beneficial changes in the intestine may be an approach to enhance existing PTSD treatments.
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... There have been a number of human intervention studies involving beneficial microbes and mood-related outcomes. [129][130][131][132][133][134][135][136][137] To the best of our knowledge, there has yet to be an intervention study involving microbes and patients with MDD or anxiety disorders. However, the benefits observed in the available clinical studies suggest that a movement toward trials involving patients with depression, anxiety, or subsyndromal disorders is warranted. ...
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... However, there are a growing number of studies providing data on effects of probiotic bacteria on the human immune system and on microflora of the GIT (Holzapfel and Schillinger, 2002;Foligne et al., 2007;Verdú et al., 2009;Wen et al., 2012). Increasingly, reports of the human/animal microbiome playing a central role in other key aspects of health functionality are emerging, including beneficial impacts on the treatment of metabolic disorders, such as obesity and type 2 diabetes, improvement of bowel function in patients with colorectal cancer, potential cognitive, and mood-enhancing benefits, antidepressant, and anxiolytic (antianxiety) activity (Desbonnet et al., 2008;Bravo et al., 2011;DiBaise et al., 2012;Lee et al., 2014a;Owen et al., 2014). The latter anxiolytic effect has even led to the emergence of the new term, psychobiotic, coined by Dinan et al. (2013) as a "live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness." ...
Probiotic-based strategies for therapeutic and prophylactic use against multiple gastrointestinal diseases
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  • Jul 2015
Probiotic bacteria offer a number of potential health benefits when administered in sufficient amounts that in part include reducing the number of harmful organisms in the intestine, producing antimicrobial substances and stimulating the body’s immune response. However, precisely elucidating the probiotic effect of a specific bacterium has been challenging due to the complexity of the gut’s microbial ecosystem and a lack of definitive means for its characterization. This review provides an overview of widely used and recently described probiotics, their impact on the human’s gut microflora as a preventative treatment of disease, human/animal models being used to help show efficacy, and discusses the potential use of probiotics in gastrointestinal diseases associated with antibiotic administration.
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... The impact of exometabolites upon cephalic phase of appetite has not been well explored; however, it is reasonable to hypothesise that it does contribute to the wider mechanisms of appetite control as precedents have been shown in microbiome-mood interactions. For example, perturbations of the gut flora have been associated with schizophrenia and depression (68,69) ; probiotic interventions in mouse models have demonstrated anxiolytic potential of microbial intervention (70) ; probiotic interventions have also shown impact upon brain activity (71) and on cognitive outcome (72) . Recent reviews have suggested potential mechanisms of action, including modulation of afferent signalling by SCFA, cytokine-mediated responses triggered through Toll-like receptors in the mucosa responding to the microbiome, and modulation of γ-aminobutyric acid mediated signalling (15) . ...
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The Therapeutic Role of Exercise and Probiotics in Stressful Brain Conditions
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  • PHARMACOL THERAPEUT
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Cryan, J.F. & Dinan, T.G. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat. Rev. Neurosci. 13, 701-712
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Infections with bacterial pathogens can induce increased anxiety-like behaviors in rodents without otherwise noticeable behavioral or physiological symptoms of sickness, as shown with the food-borne pathogen Campylobacter jejuni. This observation implicates the ability of the brain to sense, and respond to, such an infection. We tested our hypothesis that intestinal infection with the gram-negative bacterium C. jejuni leads to activation of certain brain regions that process gastro-intestinal sensory information. The induction of c-Fos protein as a marker for neuronal activation was assessed in the brains of mice inoculated orally with live C. jejuni, as compared to saline-treated controls. Upon colonization of the intestines, C. jejuni activated visceral sensory nuclei in the brainstem (the nucleus of the solitary tract and the lateral parabrachial nucleus) both one and two days after the oral challenge. In addition, increased c-Fos expression occurred in the hypothalamic paraventricular nucleus on the second day. This neural response occurred in the absence of measurable systemic immune activation, as serum levels of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 were undetectable and/or unchanged. These findings support the notion that information about infection with C. jejuni in the gut is indeed relayed to the visceral sensory structures in the brain. The brain responses observed could contribute to changes in behavior observed after infection.
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Activation in vagal afferents and central autonomic pathways: Early responses to intestinal infection with Campylobacter jejuni
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  • Aug 2005
Abundant evidence now supports the idea that multiple pathways or mechanisms underlie communication from the immune system to the brain. The presence of a variety of mechanisms suggests that they may each contribute something different to immunosensory signaling. For instance, brain mediated immune signal transduction is dependent upon the presence of circulating mediators whereas peripheral sensory nerves are more likely to be important early on in an infection, prior to elevation of circulating cytokines, or in local infections within the terminal fields of these nerves. To test the hypothesis that local infection in the gut activates vagal sensory neurons, we assessed expression of the neuronal activation marker c-Fos in neurons in the vagal sensory ganglia and in the primary sensory relay nucleus for the vagus, the nucleus of the solitary tract (nTS) in mice treated orally either with saline or live Campylobacter jejuni (C. jejuni). Male CF1 mice were inoculated orally with either C. jejuni or saline, and c-Fos expression in the vagal sensory neurons and brain 4-12 h later was assessed via immunohistochemistry. Oral inoculation with C. jejuni led to a significant increase in c-Fos expression in neurons bilaterally in the vagal ganglia, in the absence of elevated levels of circulating pro-inflammatory cytokines. C. jejuni treatment activated neurons in the nTS, as well as in brain regions associated with primary viscerosensory pathways and the central autonomic network. These findings provide evidence that peripheral sensory neurons contribute an early signal to the brain regarding potential pathogens.
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Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium
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  • Nov 2006
  • PHYSIOL BEHAV
Symptoms of anxiety frequently occur concomitant to the development and persistence of inflammatory bowel disease (IBD) in patients. In the present study, we utilized an animal model of IBD, infection with Citrobacter rodentium, to determine whether the infection per se can drive anxiety-like behavior. Nine-week-old CF-1 male mice were challenged orally with either saline or C. rodentium. Early in the infective process (7-8 h later), mice were tested on a hole-board open field apparatus for anxiety-like behavior measurement. Immediately following behavioral testing, plasma samples were obtained for immune cytokine analysis and colons were excised for histological analysis. In additional animals, vagal ganglia were removed and processed for c-Fos protein detection. Challenge with C. rodentium significantly increased anxiety-like behavior as evidenced by avoidance of the center area and increased risk assessment behavior. Plasma levels of the cytokines IFN-gamma, TNF-alpha and IL-12 were not different. However vagal sensory ganglia from C. rodentium-treated animals evinced significantly more c-Fos protein-positive neurons, consistent with vagal afferent transmission of C. rodentium-related signals from gut to brain. Histological examination of the colon indicated a lack of overt inflammation at the 8 h post-challenge time point, indicating that the differences in behavior were unlikely to follow from inflammation-related stress. The results of the present study demonstrate that infection with C. rodentium can induce anxiety-like symptoms that are likely mediated via vagal sensory neurons.
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Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: Possible anatomical substrates for viscerosensory modulation of exploratory behavior
Article
  • Apr 2008
  • BRAIN BEHAV IMMUN
The presence of certain bacteria in the gastrointestinal tract influences behavior and brain function. For example, challenge with live Campylobacter jejuni (C. jejuni), a common food-born pathogen, reduces exploration of open arms of the plus maze, consistent with anxiety-like behavior, and activates brain regions associated with autonomic function, likely via a vagal pathway. As yet, however, little is known regarding the interface of immune sensory signals with brain substrates that mediate changes in behavioral states. To address this issue, we challenged mice with either C. jejuni or saline, and 7-8h later assessed anxiety-like behavior using the open holeboard, and used immunohistochemical detection of the protein c-Fos as an activation marker in the brain. C. jejuni treatment was associated with increased avoidance of the center regions of the holeboard, compared to saline-treated controls. Exposure to the holeboard induced activation in multiple brain regions previously implicated in anxiety-like behavior, including the lateral septum (LS), paraventricular (PVN) and dorsomedial hypothalamic nuclei (DMH), basolateral and central nuclei of the amygdala (BLA, CEA), bed nucleus of the stria terminalis (BST) and periaquiductal grey (PAG), compared to homecage controls. In C. jejuni-treated animals c-Fos induction also occurred in autonomic regions, as previously reported. The PVN, BLA, parts of the BST, medial prefrontal (mPFC) and anterior cingulate responded to both C. jejuni treatment and the holeboard, suggesting a role for these regions in the enhanced anxiety-like behavior observed. In saline-treated animals, anxiety-like behavior was predicted by activation in the CEA and BLA, whereas in C. jejuni-treated animals, c-Fos expression in the BST predicted the degree of anxiety-like behavior. These findings implicate the PVN, amygdala and BST as interfaces between gastrointestinal pathogenic challenge and brain regions that mediate behavioral responses to stress, and reinforce these nuclei as anatomical substrates by which viscerosensory stimuli can influence behavior.
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The Journal of physiology 558
  • Jan 2004
  • 263-275
  • N Sudo
Sudo N et al. (2004) The Journal of physiology 558, 263–275.
  • Jan 2004
  • BRAIN BEHAV IMMUN
  • 238-245
  • R Gaykema
Gaykema R et al. (2004) Brain. Behav. Immun. 18, 238-245.
  • Jan 2005
  • GASTROENTEROLOGY
  • 541-551
  • L O'mahony
O'Mahony L et al. (2005) Gastroenterology. 128, 541-551.