Probiotic Intake and Perimenopausal Psychological Assessments (PIPPA)

The Effects of a Probiotic on Emotional Processing, Cognition, and the Gut Microbiome in Perimenopausal Women

Recent evidence suggests multi-strain probiotics containing Lactobacillus rhamnosus and Bifidobacterium longum have been found to enhance emotional processing and reduce salience to negative cues in studies involving people with mood disorders, as well as improve cognitive functions, such as memory and concentration, in healthy participants. By administering computer-based tasks, questionnaires and checking biological measures (cortisol, immune markers, blood metabolites, gut microbiota) using blood and faecal samples, this experimental medicine study aims to investigate whether a probiotic supplement has an effect on emotional processing and cognition in perimenopausal women. We also aim to study changes in gut bacteria from stool samples before and after taking the supplement to see if any microbiome changes are associated with any effects in emotional processing, cognitive function, and biological markers.

Study Overview

• Status: Recruiting
• Conditions: Perimenopause; Perimenopause-Related Depression; Perimenopausal Women; Emotional Processing and Cognitive Function in Perimenopausal Women Experiencing Cognitive Perturbations
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: Multi-strain probiotic

Detailed Description

Perimenopause, the transition period leading up to menopause, involves fluctuating levels of oestrogen and other hormones, contributing to a variety of physical and metabolic changes. It is also a period associated with an increased risk of depression and a decline in cognitive functioning. When compared to the pre-perimenopausal period, perimenopausal women are two to five times more susceptible to experiencing depressive episodes. Cognitive decline, including memory and concentration issues, is also prevalent, with an estimated 44-62% of individuals reporting challenges with memory.

Research often highlights the role of the gut-brain axis, where the gut microbiota influences cognitive function and emotional processing via neurotransmitters, inflammatory markers, and stress response pathways. Recent evidence suggests that multi-strain probiotics containing Lactobacillus rhamnosus and Bifidobacterium longum enhance emotional processing and reduce salience to negative cues in studies involving people with mood disorders, as well as improving cognitive functions, such as memory and concentration, in healthy participants. One 8-week study also found preliminary evidence supporting the potential of probiotics as a safe and effective adjunctive treatment for major depressive disorder in individuals with incomplete responses to antidepressant medication. Given these observed benefits, the investigation into the effects of multi-strain probiotics to address emotional processing and cognitive disturbances and perturbations in a perimenopausal population is lacking. With the increasing demand for natural, non-pharmacological therapeutic interventions to manage perimenopausal symptoms, this project could provide valuable evidence supporting the use of probiotics as a beneficial adjunct therapy in perimenopausal health management.

The current proposal will assess the effects of a commercial probiotic on emotional processing and cognitive function in perimenopausal women, alongside changes in gut microbial composition that may mediate any observed metabolic changes and effects on inflammatory markers and metabolites. This is an important next step in elucidating the role probiotics may play in perimenopause and in generating data to guide future clinical applications of probiotics in managing perimenopausal symptoms.

• Study Type: Interventional
• Enrollment (Estimated): 106
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Phil Burnet, Professor; Phone Number: +44 1865 618327; Email: phil.burnet@psych.ox.ac.uk
• Study Contact Backup: Name: Susannah Murphy, Professor; Phone Number: +44 1865 618313; Email: susannah.murphy@psych.ox.ac.uk

Study Locations

• United Kingdom
  • England
    • Oxford, England, United Kingdom, OX3 7JX
      • Recruiting
      • University of Oxford, Department of Psychiatry
      • Contact: Phil Burnet, Professor; Phone Number: +44 1865 618327; Email: phil.burnet@psych.ox.ac.uk
      • Contact: Susannah Murphy, Professor; Phone Number: +44 1865 618313; Email: susannah.murphy@psych.ox.ac.uk
      • Principal Investigator: Phil Burnet, Professor
      • Sub-Investigator: Susannah Murphy, Professor
      • Sub-Investigator: Aimiomode Anetor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female at birth
• You are aged 45-60 years and in perimenopause (determined by changes in menstrual bleeding patterns (such as changes in cycle length of 7 days or longer in either direction from what is normal for you), AND vasomotor symptoms (e.g., hot flushes and sweats) AND mild to moderate mood or cognitive disturbances, or joint and muscle pain over the previous 12 months)
• You are willing and able to give informed consent for participation in the study
• You are sufficiently fluent in English to understand and complete tasks
• You are at least 12 months post-natal
• Willing to withhold from having grapefruit juice

Exclusion Criteria:

• Currently receive or seek treatment for any mental health condition
• Have a BMI >=30 OR <=18.5
• Have lost or gained more than 10% of body weight in a short period (e.g., 6 months), as this can affect mood and cognition
• Currently using hormonal contraception or have used hormonal contraception in the last 6 months
• Have had gender reassignment surgery or gender-affirming hormone therapy
• Had a head injury causing concussion or unconsciousness in the past 6 months
• Participated in other studies that may influence mood, cognition, or gut health in the last three months
• Are currently diagnosed with and/or treated for psychiatric or neurological disorders
• Are on perimenopausal hormone replacement therapy (HRT) (e.g., estrogen, progesterone, testosterone) or other hormone-modulating medications (e.g., GLP-1 agonists, thyroxine replacement), as these can impact mood and cognitive functions
• Currently use statins or have used statins in the last 6 months, as these may impact mood and cognitive functions
• Participated in any other study with the same tasks in the last year
• Currently use medications that influence cognition or mood, such as antidepressants, anxiolytics, antipsychotics, stimulants, mood-stabilizers, or cognitive-enhancing drugs
• Have chronic or severe gastrointestinal diseases (e.g., inflammatory bowel disease, Crohn's disease, celiac disease, or severe acid reflux; treatment with e.g., corticosteroids, antacids), as these conditions and treatments can affect the gut microbiota and immune responses differently from healthy individuals
• Have a compromised immune system
• Currently smoke, vape, or use any other nicotine products
• Have a current diagnosis of cognitive impairment or neurodegenerative disorders (e.g., mild cognitive impairment, dementia), as these conditions could confound cognitive assessments.
• Have severe medical conditions requiring ongoing medication that may independently affect cognition or mood (e.g., diabetes)
• Currently or recently used antibiotics (last 3 months), as antibiotics may alter gut microbiota and interfere with probiotic effects
• Currently or recently used probiotics or prebiotics or consumed fermented products (e.g., kimchi, kombucha, sauerkraut, kefir, etc.) on a regular basis (last 3 months), which might interfere with the study intervention
• Have known allergies or intolerances to probiotics or components in the probiotic supplement.
• Have substance abuse or dependence (e.g., alcohol, recreational drugs) that may affect mood and cognition.
• Have Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Long COVID)
• Have had a hysterectomy
• Are pregnant or lactating, as hormonal changes associated with these states could confound results.
• Score of 20 or above on PHQ-9 depression questionnaire, indicating severe depression
• Score of >1 on PHQ-9 suicidality item, indicating significant suicidality (as assessed by medical on-site professionals

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Patient Group; Participants randomised to the Placebo condition will be taking four microcrystalline cellulose powder placebo capsules daily for 60 days.	Dietary supplement: Placebo; A microcrystalline cellulose-based capsule.
Experimental: Interventional/Treatment; Participants randomised to the Probiotic condition will be taking four multi-strain probiotic capsules daily for 60 days.	Dietary supplement: Multi-strain probiotic; A commercially available probiotic known to support gut health and is generally well-tolerated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Facial Expression Recognition Task (FERT)	Accuracy, reaction time and misclassifications on the FERT compared between probiotic and placebo groups.	End of the 60-day intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Emotional Categorisation Task	Accuracy and reaction time performance on emotional word categorization task compared between probiotic and placebo groups.	End of the 60-day intervention
Emotional word recall/recognition task	Performance on emotional word recall (hits and false alarms) and recogntion (hits, false alarms and reaction time) compared between probiotic and placebo groups	End of the 60-day intervention
Digit Span Task	Maximum span length compared between probiotic and placebo groups	End of the 60-day intervention
Emotional Go/No-Go (EGNG)	Cognitive control and inhibitory control assessed using the EGNG task, including commission errors, omission errors, and reaction time to emotionally valenced stimuli. Performance will be compared between probiotic and placebo groups at post-intervention.	Post-intervention (end of 60-day intervention)
Probabilistic Reversal Learning (PRL) Task	Cognitive flexibility and reward-based learning assessed using the PRL task, including measures such as response accuracy, reversal errors, and sensitivity to reward and punishment. Performance will be compared between probiotic and placebo groups at post-intervention.	Post-intervention (end of 60-day intervention)
N-back Task	Working memory performance assessed using the n-back task, including accuracy and reaction time across task conditions. Performance will be compared between probiotic and placebo groups at post-intervention.	Post-intervention (end of 60-day intervention)
Auditory Verbal Learning Test (AVLT)	Verbal learning and memory assessed using the AVLT, including measures of immediate recall, delayed recall, and recognition memory. Performance will be compared between probiotic and placebo groups at post-intervention.	Post-intervention (end of 60-day intervention)
Serum cortisol	Serum cortisol concentration assessed using ELISA compared between the placebo and probiotic groups	Baseline and end of 60-day intervention
Inflammatory markers	Inflammatory marker concentrations (CRP, IL-1b, TNF-alpha, IL-6) assessed using ELISA compared between placebo and probiotic groups	Baseline and end of 60-day intervention
Serum metabolites	Serum metabolite profiles assessed using ELISA compared between placebo and probiotic groups	Baseline and end of 60-day intervention
Gut microbiome composition	Gut microbiome composition assessed using stool samples, including measures of alpha diversity, beta diversity, and relative abundance of microbial taxa, compared between placebo and probiotic groups.	Baseline and end of 60-day intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective measures of affective state	Questionnaire measures of affect (PANAS) compared between placebo and probiotic groups	Baseline, Day 14, Day 30, Day 44, Day 60
Subjective measures of mood	Questionnaire measures of mood (PANAS) compared between placebo and probiotic groups	Baseline, Day 14, Day 30, Day 44, Day 60
Subjective measures of menopausal symptom severity	Questionnaire measures of menopausal symptom severity (MRS) compared between placebo and probiotic groups	Baseline, Day 14, Day 30, Day 44, Day 60
Subjective measures of cognitive state	Questionnaire measures of subjective cognitive difficulties (PDQ) compared between placebo and probiotic groups	Baseline, Day 14, Day 30, Day 44, Day 60
Subjective measures of anxiety	Questionnaire measures of anxiety (GAD-7) compared between placebo and probiotic groups	Baseline, Day 14, Day 30, Day 44, Day 60
Subjective measures of anhedonia	Questionnaire measures of anhedonia (SHAPS) compared between placebo and probiotic groups	Baseline, Day 14, Day 30, Day 44, Day 60

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: ADM Protexin
• Investigators: Principal Investigator: Phil Burnet, Professor, University of Oxford

Publications and helpful links

General Publications

• Weber MT, Rubin LH, Maki PM. Cognition in perimenopause: the effect of transition stage. Menopause. 2013 May;20(5):511-7. doi: 10.1097/gme.0b013e31827655e5.
• Bromberger JT, Epperson CN. Depression During and After the Perimenopause: Impact of Hormones, Genetics, and Environmental Determinants of Disease. Obstet Gynecol Clin North Am. 2018 Dec;45(4):663-678. doi: 10.1016/j.ogc.2018.07.007. Epub 2018 Oct 25.
• Conde DM, Verdade RC, Valadares ALR, Mella LFB, Pedro AO, Costa-Paiva L. Menopause and cognitive impairment: A narrative review of current knowledge. World J Psychiatry. 2021 Aug 19;11(8):412-428. doi: 10.5498/wjp.v11.i8.412. eCollection 2021 Aug 19.
• Weber MT, Mapstone M, Staskiewicz J, Maki PM. Reconciling subjective memory complaints with objective memory performance in the menopausal transition. Menopause. 2012 Jul;19(7):735-41. doi: 10.1097/gme.0b013e318241fd22.
• Ruiz-Gonzalez C, Cardona D, Rueda-Ruzafa L, Rodriguez-Arrastia M, Ropero-Padilla C, Roman P. Cognitive and Emotional Effect of a Multi-species Probiotic Containing Lactobacillus rhamnosus and Bifidobacterium lactis in Healthy Older Adults: A Double-Blind Randomized Placebo-Controlled Crossover Trial. Probiotics Antimicrob Proteins. 2025 Oct;17(5):3525-3537. doi: 10.1007/s12602-024-10315-2. Epub 2024 Jun 27.
• Nikolova VL, Cleare AJ, Young AH, Stone JM. Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients With Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2023 Aug 1;80(8):842-847. doi: 10.1001/jamapsychiatry.2023.1817.
• Maki PM, Kornstein SG, Joffe H, Bromberger JT, Freeman EW, Athappilly G, Bobo WV, Rubin LH, Koleva HK, Cohen LS, Soares CN; Board of Trustees for The North American Menopause Society (NAMS) and the Women and Mood Disorders Task Force of the National Network of Depression Centers. Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations. Menopause. 2018 Oct;25(10):1069-1085. doi: 10.1097/GME.0000000000001174.
• Berent-Spillson A, Marsh C, Persad C, Randolph J, Zubieta JK, Smith Y. Metabolic and hormone influences on emotion processing during menopause. Psychoneuroendocrinology. 2017 Feb;76:218-225. doi: 10.1016/j.psyneuen.2016.08.026. Epub 2016 Sep 5.
• Baiao R, Capitao LP, Higgins C, Browning M, Harmer CJ, Burnet PWJ. Multispecies probiotic administration reduces emotional salience and improves mood in subjects with moderate depression: a randomised, double-blind, placebo-controlled study. Psychol Med. 2023 Jun;53(8):3437-3447. doi: 10.1017/S003329172100550X. Epub 2022 Feb 7.
• Appleton J. The Gut-Brain Axis: Influence of Microbiota on Mood and Mental Health. Integr Med (Encinitas). 2018 Aug;17(4):28-32.

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: March 12, 2026
• First Submitted That Met QC Criteria: May 12, 2026
• First Posted (Actual): May 15, 2026

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: menopause; probiotic; probiotics; gut microbiome; perimenopause; gut microbiome and perimenopause; cognition and perimenopause; emotional processing and perimenopause; mood and perimenopause; gut microbiome and cognition
• Other Study ID Numbers: PIPPA Study (735575)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No