Multi-strain probiotic mixture affects brain morphology and resting state brain function in healthy subjects: an RCT
Open accessAbstract
Probiotics can alter brain function via the gut–brain axis. We investigated the effect of a probiotic mixture containing Bifidobacterium longum, Lactobacillus helveticus and Lactiplantibacillus plantarum. In a randomized, placebo-controlled, double-blinded crossover design, 22 healthy subjects (6 m/16 f; 24.2 ± 3.4 years) underwent four-week intervention periods with probiotics and placebo, separated by a four-week washout period. Voxel-based morphometry indicated that the probiotic intervention affected the gray matter volume of a cluster covering the left supramarginal gyrus and superior parietal lobule (p < 0.0001), two regions that were also among those with an altered resting state functional connectivity. Probiotic intervention resulted in significant (FDR < 0.05) functional connectivity changes between regions within the default mode, salience, frontoparietal as well as the language network and several regions located outside these networks. Psychological symptoms trended towards improvement after probiotic intervention, i.e., the total score of the Hospital Anxiety and Depression Scale (p = 0.056) and its depression sub-score (p = 0.093), as well as sleep patterns (p = 0.058). The probiotic intervention evoked distinct changes in brain morphology and resting state brain function alongside slight improvements of psycho(bio)logical markers of the gut–brain axis. The combination of those parameters may provide new insights into the modes of action by which gut microbiota can affect gut–brain communication and hence brain function.
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Studies have identified compositional and functional changes in the intestine and brain, along with distinct changes in brain morphology, resting-state brain function, brain activity, and functional connectivity in regions known to regulate stress.
“These studies have identified compositional and functional changes in the intestine and brain, along with distinct changes in brain morphology, resting-state brain function, brain activity and functional connectivity in regions known to regulate stress (472, 473).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [472]
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Mörkl, S., Narrath, M., Schlotmann, D., Sallmutter, M.-T., Putz, J., Lang, J., Brandstätter, A., Pilz, R., Lackner, H. K., Goswami, N., et al. (2025) · Gut Microbes · doi:10.1080/19490976.2025.2492377 · Cited by 40 · see citing works
“36,47,48 Also, predominant effects of the probiotic in the morning could be due to medication effects.”
Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review
Mincic, A. M., Antal, M., Filip, L. A., & Miere, D. (2024) · Clinical Nutrition · doi:10.1016/j.clnu.2024.05.036 · Cited by 35 · see citing works
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Gil-Hernández, E., Ruiz‐González, C., Rodríguez-Arrastia, M. J., Ropero‐Padilla, C., Rueda‐Ruzafa, L., Sánchez‐Labraca, N., & Román, P. (2023) · Nutrition Reviews · doi:10.1093/nutrit/nuad027 · Cited by 25 · see citing works
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“However, Absolute and relative sleep time, absolute and relative wake time after sleep onset, sleep onset latency and sleep efficiency based on actigraphy recordings were not affected by the probiotic intervention [202].”
Mi, Y., Chen, K., Lin, S., Tong, L., Zhou, J., & Wan, M. (2024) · The EPMA Journal · doi:10.1007/s13167-024-00387-z · Cited by 12 · see citing works
“A randomized controlled trial also found that probiotic intervention tended to improve patients’ mental health [82].”
Gupta, N., Agarwal, A. K., Al-Dossari, M., & El-Gawaad, N. S. A. (2023) · Brain Behavior and Immunity Integrative · doi:10.1016/j.bbii.2023.100038 · Cited by 11 · see citing works
Gut microbiota and ovarian diseases: a new therapeutic perspective
Ju, S., Kang, Z., Yang, L., Xia, Y., Guo, Y. M., Li, S., Yan, H., Mao, Q., Wang, H. P., & Zhong, L. (2025) · Journal of Ovarian Research · doi:10.1186/s13048-025-01684-5 · Cited by 11 · see citing works
Efficacy of bifidobacterium-related preparations on depression: the first meta-analysis
Huang, R., & Liu, Y. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1463848 · Cited by 10 · see citing works
Li, C., Chen, P., Deng, Y., Xia, L., Wang, X., Wei, M., Wang, X., Dong, L., & Zhang, J. (2024) · International Journal of Clinical and Health Psychology · doi:10.1016/j.ijchp.2024.100528 · Cited by 9 · see citing works
Microbiota and probiotics: chances and challenges – a symposium report
Ruxton, C. H. S., Kajita, C., Rocca, P., & Pot, B. (2023) · Gut Microbiome · doi:10.1017/gmb.2023.4 · Cited by 9 · see citing works
“One example is functional brain imaging which, in a 4-week RCT of probiotics (Rode et al., 2022), demonstrated significant changes in brainmorphology and resting-state brain function linked to stress management of the brain.”
BackgroundGut-brain axis and neuroplasticity in health and disease: a systematic review
Napoli, A. D., Pasquini, L., Visconti, E., Vaccaro, M., Rossi‐Espagnet, M. C., & Napolitano, A. (2024) · La radiologia medica · doi:10.1007/s11547-024-01938-0 · Cited by 9 · see citing works
Hunjan, G., Shah, S. S., Kosey, S., & Aran, K. R. (2025) · Journal of Neural Transmission · doi:10.1007/s00702-025-02938-8 · Cited by 7 · see citing works
“Some limitations include the absence of statistical significance, a smaller sample size, seasonal effects, and participation of healthy subjects (Rode et al. 2022).”
Huang, L., Li, X., Guo, M., Lu, W., Zhao, J., Xiao, Y., & Chen, W. (2025) · Food & Function · doi:10.1039/d5fo02921j · Cited by 7 · see citing works
König, J., Rubio, M., Forsgård, R. A., Rode, J., Axelsson, J., Grompone, G., & Brummer, R. J. (2024) · PLoS ONE · doi:10.1371/journal.pone.0312464 · Cited by 7 · see citing works
Llopis, I., Miguel, N. S., & Serrano, M. Á. (2025) · Applied Sciences · doi:10.3390/app15084564 · Cited by 8 · see citing works
Liu, X., Ning, L., Fan, W., Jia, C., & Ge, L. (2025) · Nutrition Reviews · doi:10.1093/nutrit/nuaf156 · Cited by 5 · see citing works
Hutchinson, A. N., Antonsson, A., Forsgård, R. A., König, J., Mall, J. G., & Rode, J. (2026) · npj Biofilms and Microbiomes · doi:10.1038/s41522-025-00872-x · Cited by 6 · see citing works
“In a similar healthy population, Rode et al. reported altered (increased and decreased) resting state functional connectivity after probiotics compared to placebo intervention between regions of the default mode network and regions involvedmainlyinattentionandmotorfunctions,amongstothers 43 .”
InfluentialMarx, W., Suo, C., Dissanayaka, T. D., Maleki, S., Nguyen, L., Travica, N., Mohebbi, M., Lotfaliany, M., Yücel, M., McGuinness, A. J., et al. (2025) · Gut · doi:10.1136/gutjnl-2025-335398 · Cited by 4 · see citing works
When Gut Hormones Influence Brain Function in Depression
Siba, I. P., Martynhak, B. J., & Pereira, M. (2023) · Applied Biosciences · doi:10.3390/applbiosci2010005 · Cited by 4 · see citing works
“Additionally, an increasing numbers of clinical studies show correlational findings [6,15].”
BackgroundInfluence and Selection of Probiotics on Depressive Disorders in Occupational Health: Scoping Review
Picó-Monllor, J. A., Sala-Segura, E., Tobares, R. A., Moreno-Ochando, A., Hernández-Teruel, A., & Navarro‐López, V. (2023) · Nutrients · doi:10.3390/nu15163551 · Cited by 4 · see citing works
“The use of different probiotic formulations, with no specific strain [52] or two [50] or three [49] probiotic strains alone or high doses of prebiotics [42] may account for the different results observed in these studies concerning improvements in depressive disorders.”
BackgroundResultInfluentialAssociation of gut microbiota with cerebral cortical thickness: A Mendelian randomization study
Shi, L., Liu, X., Zhang, S., & Zhou, A. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.02.063 · Cited by 4 · see citing works
From plate to brain: benefits, deficiencies, and research needs of plant-based diets
Peña‐Jorquera, H., & Cid-Jofré, V. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.09.005 · Cited by 3 · see citing works
Dubois, N., Vincent, C., & Giroux, I. (2025) · Healthcare · doi:10.3390/healthcare13222851 · Cited by 4 · see citing works
“Interestingly, a 4-week RCT conducted by Rode et al. (2022) on healthy adults found that a multi-strain probiotic intervention resulted in gray matter volume changes in the brain compared to placebo [78].”
How gut microbiota contribute to neuropsychiatric disorders: evidence from neuroimaging studies
Jia, C., Zhu, W., Yu, Y., & Xie, Q. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2026.1760096 · Cited by 3 · see citing works
“…cortex, and precuneus, while enhancing orbital frontal cortex activity, and altering resting-state connectivity in the salience and default mode networks, suggesting potential improvements in emotion regulation and cognitive control (Bagga et al., 2018; Rode et al., 2022; Tillisch et al., 2013).”
Fernández-Rodríguez, D., Bravo, M. C., Pizarro, M., Vergara-Barra, P., Hormazábal, M. J., & Leonario-Rodriguez, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26168099 · Cited by 2 · see citing works
Wijdeveld, M., Schrantee, A., Azor, J. T., van Baarzel, F., van Duinkerken, E., Nieuwdorp, M., & IJzerman, R. G. (2025) · Neuroimage Reports · doi:10.1016/j.ynirp.2025.100285 · Cited by 1 · see citing works
“…default mode network, but increased connectivity within the salience network (Bagga et al., 2019) and increased connectivity between the midbrain and the rest of the brain (Tillisch et al., 2013); however, another study using seed-to-voxel analysis showed conflicting results (Rode et al., 2022).”
Laar, H.-D., Carlman, H. M. T. E., Brummer, R. J., & Rode, J. (2025) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2025.10.014 · Cited by 1 · see citing works
Yang, R., Lin, S., Huang, L., Weng, J., Liu, Q., Chen, H., Ruan, N., & Zeng, K. (2026) · Food Science & Nutrition · doi:10.1002/fsn3.71447 · Cited by 1 · see citing works
“Recent clinical studies have demonstrated the efficacy and safety of multi-strain probiotic mixtures for improving sleep, especially the most studied Lactobacillus and Bifidobacteria (Lee et al. 2021; Rode et al. 2022).”
Role of Probiotic Supplements in Decreasing Anxiety: A Systematic Review
Hakimi, S. M. J., & Movahedi, A. (2025) · Nutrition And Food In Health And Disease · doi:10.61186/nfsr.12.2.7 · Cited by 1 · see citing works
“Based on the questionnaires from 16 studies [8,10,11,13,14,16,17,20–25, 27, 28, 30 ], the intervention generally improved anxiety”
The Benefits of Probiotics on Depression: A Systematic Mini-Review
Caruso, R., Rospigliosi, J. L. C., Checo, M., Investigaciones Biomedicas de Profamilia, S. D., de Oliveira, L. M. L., Farina, G. S., Fernandes, K. B. P., Jaldin-Pinto, A. V., Woite, N. L., Dominguez, A. M., et al. (2023) · Principles and Practice of Clinical Research Journal · doi:10.21801/ppcrj.2023.91.6
Manipulating Beneficial Gut Bacteria in Obesity-Related Emotional and Cognitive Dysfunction
Jefry Winner, G. (2025) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780190931544.013.16
Imaging BBB for treating brain disorders
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A gut feeling: Exploring the effects of probiotics on risk-taking behavior using TMS
Dantas, A. M., Schuhmann, T., Brüggen, E. C., & Jiao, P. (2026) · iScience · doi:10.1016/j.isci.2026.114696
“16,18,31 This area has also been hypothesized as a hub, integrating somatic information in human decision-making.”
Neurobiological effects of microbial treatments within psychiatry: a systematic review
Sgarbossa, C., Forth, E., Squires, S. D., Groth, A., Farid, M., Gallant, K., Desai, D., Redfearn, W., & Milev, R. V. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1745964
“Alterations in the default mode and salience networks have also been observed in many other mood and anxiety-related disorders (57, 58), suggesting the fi ndings by Rode (2022) to have clear relevance in the context of psychiatric illnesses and disorders (48).”
da Silva, M. T., Dutra, L. B., MAUS, D. W., Filho, P. S., Romão, P. R. T., Skupien, J. A., & Boeck, C. R. (2026) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2026.174228
Bottaro, F., Enrico, P., Cabasino, C., Caprioli, F., Brambilla, P., & Delvecchio, G. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2026.122287
Hutchinson, A. N., Brummer, R. J., & Rode, J. (2026) · Communications Medicine · doi:10.1038/s43856-026-01800-6
“Otherprobioticinterventionstudiesalsoobservedalteredrestingstate functionalconnectivityinvolvingthesuperiorparietallobule,intracalcarine andsupracalcarinecortex,andoccipitalpoleandcortex,butnotthecuneal cortex 14,15,17 .”
Dai, Q., Fang, C., Du, Y., Sun, H., & Duan, Z. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1856471
Food for thought: Functional foods and microbial metabolites in diet-microbiome-brain communication
Tutu, C. O., Asiedu, B. K., Akonor, P. T., Acheampong, R., Obeng, R., Owusu-Bempah, J., Mahama, S., Wiafe‐Kwagyan, M., Nartey, J., Antwi, B., et al. (2026) · Journal of Functional Foods · doi:10.1016/j.jff.2026.107529
- Authors
- Rode, J., Edebol Carlman, H. M. T., König, J., Hutchinson, A. N., Thunberg, P., Persson, J., & Brummer, R. J.
- Affiliations
- Örebro University (SE)
- Nutrition-Gut-Brain Interactions Research Centre, Faculty of Medicine and Health, School of Medical Sciences, Örebro University, 70182 Örebro, Sweden
- Corresponding author
- Rode, Julia
- Venue
- Cells
- Publisher
- MDPI AG
- Published
- 2022-09-19
- Volume
- 11
- Issue
- 18
- Pages
- 2922
- ISSN
- 2073-4409 (ISSN-L)
- PMC
- PMC9496704
- OpenAlex
- W4296524790
- Cited by
- 50
- References
- 65
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 12 · 2023: 10
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cells (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Global Medical Innovation (20150081)
- Pfizer Consumer Healthcare (20150081)
- Swedish Knowledge Foundation (20150081)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- probiotics, gut-brain axis, gray matter volume, resting-state functional connectivity, Bifidobacterium longum, Lactobacillus helveticus, Lactobacillus plantarum, supramarginal gyrus, superior parietal lobule, anxiety and depression, sleep patterns, gut microbiota, brain structure
- MeSH terms
- Bifidobacterium longum, Brain, Humans, Probiotics, Lactobacillus helveticus, Healthy Volunteers
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