Advertisement

Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome

      Background & Aims

      Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities. We performed a prospective study to evaluate the effects of Bifidobacterium longum NCC3001 (BL) on anxiety and depression in patients with IBS.

      Methods

      We performed a randomized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood samples were collected. Patients were then randomly assigned to groups and given daily BL (n = 22) or placebo (n = 22) for 6 weeks. At weeks 0, 6, and 10, we determined patients’ levels of anxiety and depression, IBS symptoms, quality of life, and somatization using validated questionnaires. At weeks 0 and 6, stool, urine and blood samples were collected, and functional magnetic resonance imaging (fMRI) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters, and neurotrophin levels.

      Results

      At week 6, 14 of 22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7 of 22 patients in the placebo group (P = .04). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto-limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo.

      Conclusion

      In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity. ClinicalTrials.gov no. NCT01276626.

      Keywords

      Abbreviations used in this paper:

      ANCOVA (analysis of covariance), BDNF (brain-derived neurotrophic factor), BL (Bifidobacterium longum NCC3001), BOLD (Blood Oxygen Level Dependent), CGRP (calcitonin gene-related peptide), CI (confidence interval), CRP (C-reactive protein), FDR (false discovery rate), fMRI (functional magnetic resonance imaging), GLM (general linear model), HAD (Hospital Anxiety and Depression), HAD-D (HAD-depression), HPA (hypothalamic-pituitary-adrenal), 5-HT (5-hydroxytryptamine), IBS (irritable bowel syndrome), IL (interleukin), ITT (intention-to-treat), NMR (nuclear magnetic resonance), OPLS (orthogonal projection to latent structures), OPLS-DA (OPLS discriminant analysis), PP (per-protocol evaluation), QoL (quality of life), ROI (region of interest), RR (relative risk), rRNA (ribosomal RNA), SF-36 (Short Form Health Survey), STAI (State-Trait Anxiety Inventory)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lacy B.E.
        • Mearin F.
        • Chang L.
        • et al.
        Bowel disorders.
        Gastroenterology. 2016; 150: 1393-1407
        • Canavan C.
        • West J.
        • Card T.
        Review article: the economic impact of the irritable bowel syndrome.
        Aliment Pharmacol Ther. 2014; 40: 1023-1034
        • Drossman D.A.
        • Hasler W.L.
        Rome IV—Functional GI disorders: disorders of gut-brain interaction.
        Gastroenterology. 2016; 150: 1257-1261
        • Palsson O.S.
        • Drossman D.A.
        Psychiatric and psychological dysfunction in irritable bowel syndrome and the role of psychological treatments.
        Gastroenterol Clin North Am. 2005; 34: 281-303
        • Simrén M.
        • Barbara G.
        • Flint H.J.
        • et al.
        Intestinal microbiota in functional bowel disorders: a Rome foundation report.
        Gut. 2013; 62: 159-176
        • Barbara G.
        • Feinle-Bisset C.
        • Ghoshal E.C.
        • et al.
        The intestinal microenvironment and functional gastrointestinal disorders.
        Gastroenterology. 2016; 150: 1305-1318
        • Ford A.C.
        • Quigley E.M.M.
        • Lacy B.E.
        • et al.
        Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis.
        Am J Gastroenterol. 2014; 109: 1547-1561
        • Bercik P.
        • Verdu E.F.
        • Foster J.A.
        • et al.
        Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.
        Gastroenterology. 2010; 139: 2102-2112
        • Bercik P.
        • Park A.J.
        • Sinclair D.
        • et al.
        The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication.
        Neurogastroenterol Motil. 2011; 23: 1132-1139
        • Hughes P.A.
        • Harrington A.M.
        • Castro J.
        • et al.
        Sensory neuro-immune interactions differ between irritable bowel syndrome subtypes.
        Gut. 2013; 62: 1456-1465
        • McKean J.
        • Naug H.
        • Nikbakht E.
        • et al.
        Probiotics and subclinical psychological symptoms in healthy participants: a systematic review and meta-analysis.
        J Altern Complement Med. 2017; 23: 249-258
        • Tillisch K.
        • Labus J.
        • Kilpatrick
        • et al.
        Consumption of fermented milk product with probiotic modulates brain activity.
        Gastroenterology. 2013; 144: 1394-1401
        • Longstreth G.F.
        • Thompson W.G.
        • Chey W.D.
        • et al.
        Functional bowel disorders.
        Gastroenterology. 2006; 130: 1480-1491
      1. Snaith RP, Zigmond AS. The hospital anxiety and depression scale with the irritability depression–anxiety scale and the Leeds situational anxiety scale manual. Published by GL Assessment Ltd., 1994.

        • Puhan M.
        • Frey M.
        • Büchi S.
        • et al.
        The minimal important difference of the hospital anxiety and depression scale in patients with chronic obstructive pulmonary disease.
        Health Qual Life Outcomes. 2008; 6: 46
        • Gaudry E.
        • Spielberger C.D.
        • Vagg P.
        Validation of state-trait distinction in anxiety distinction.
        Multivariate Behav Res. 1975; 10: 331-341
        • Roalfe A.K.
        • Roberts L.M.
        • Wilson S.
        Evaluation of the Birmingham IBS symptom questionnaire.
        BMC Gastroenterol. 2008; 8: 30
        • O'Donnell L.J.
        • Virjee J.
        • Heaton K.W.
        Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate.
        BMJ. 1990; 300: 439-440
        • Passos M.C.
        • Lembo A.J.
        • Conboy L.A.
        • et al.
        Adequate relief in a treatment trial with IBS patients: a prospective assessment.
        Am J Gastroenterol. 2009; 104: 912-919
        • McHorney C.A.
        • Ware Jr., J.E.
        • Raczek A.E.
        The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs.
        Med Care. 1993; 31: 247-263
        • Kroenke K.
        • Spitzer R.L.
        • Williams J.B.
        The PHQ-15: validity of a new measure for evaluating the severity of somatic symptoms.
        Psychosom Med. 2002; 64: 258-266
        • Hall G.B.
        • Doyle K.A.
        • Goldberg J.
        • et al.
        Amygdala engagement in response to subthreshold presentations of anxious face stimuli in adults with Autism Spectrum Disorders: preliminary insights.
        PloS One. 2010; 5: e10804
        • He X.
        • Yablonskiy D.A.
        Quantitative BOLD: mapping of human cerebral deoxygenated blood volume and oxygen extraction fraction: default state.
        Magn Reson Med. 2007; 57: 115-126
        • De Palma G.
        • Blennerhassett P.
        • Lu J.
        • et al.
        Microbiota and host determinants of behavioral phenotype in maternally separated mice.
        Nat Commun. 2015; 6: 7735
        • Rougé C.
        • Goldenberg O.
        • Ferraris L.
        • et al.
        Investigation of the intestinal microbiota in preterm infants using different methods.
        Anaerobe. 2010; 16: 362-370
        • Genovese C.R.
        • Lazar N.A.
        • Nichols T.
        Thresholding of statistical maps in functional neuroimaging using the false discovery rate.
        Neuroimage. 2002; 15: 870-878
        • Maldjian J.A.
        • Laurienti P.J.
        • Kraft R.A.
        • et al.
        An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fmri data sets.
        NeuroImage. 2003; 19: 1233-1239
        • Harmer C.J.
        • Mackay C.E.
        • Reid C.B.
        • et al.
        Antidepressant drug treatment modifies the neural processing of nonconscious threat cues.
        Biol Psychiatry. 2006; 59: 816-820
        • Fu C.H.
        • Williams S.C.
        • Cleare A.J.
        • et al.
        Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study.
        Arch Gen Psychiatry. 2004; 61: 877-889
        • Hooper L.V.
        • Littman D.R.
        • Macpherson A.J.
        Interactions between the microbiota and the immune system.
        Science. 2012; 336: 1268-1273
        • Collins S.M.
        • Surette M.
        • Bercik P.
        The interplay between the intestinal microbiota and the brain.
        Nat Rev Microbiol. 2012; 10: 735-742
        • Bercik P.
        • Denou E.
        • Collins J.
        • et al.
        The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
        Gastroenterology. 2011; 141 (599–560)
        • Bravo J.A.
        • Forsythe P.
        • Chew M.V.
        • et al.
        Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
        Proc Natl Acad Sci U S A. 2011; 108: 16050-16055
        • Messaoudi M.
        • Violle N.
        • Bisson J.F.
        • et al.
        Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers.
        Gut Microbes. 2011; 2: 256-261
        • Benton D.
        • Williams C.
        • Brown A.
        Impact of consuming a milk drink containing a probiotic on mood and cognition.
        Eur J Clin Nutr. 2007; 61: 355-361
        • Akkasheh G.
        • Kashani-Poor Z.
        • Tajabadi-Ebrahimi M.
        • et al.
        Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial.
        Nutrition. 2016; 32: 315-320
        • Whalen P.J.
        • Rauch S.L.
        • Etcoff N.L.
        • et al.
        Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge.
        J Neurosci. 1998; 18: 411-418
        • Davis M.
        The role of the amygdala in fear and anxiety.
        Annu Rev Neurosci. 1992; 15: 353-375
        • Myers B.
        • Greenwood-Van Meerveld B.
        Corticosteroid receptor-mediated mechanisms in the amygdala regulate anxiety and colonic sensitivity.
        Am J Physiol Gastrointest Liver Physiol. 2007; 292: G1622-G1629
        • Bashashati M.
        • Rezaei N.
        • Shafieyoun A.
        • et al.
        Cytokine imbalance in irritable bowel syndrome: a systematic review and meta-analysis.
        Neurogastroenterol Motil. 2014; 26: 1036-1048
        • Haroon E.
        • Raison C.L.
        • Miller A.H.
        Psychoneuroimmunology meets neuropsycho-pharmacology: translational implications of the impact of inflammation on behavior.
        Neuropsychopharmacology. 2012; 37: 137-162
        • Murray P.S.
        • Holmes P.V.
        An overview of brain-derived neurotrophic factor and implications for excitotoxic vulnerability in the hippocampus.
        Int J Pept. 2011; 2011: 654085
        • Duclot F.
        • Kabbaj M.
        Epigenetic mechanisms underlying the role of brain-derived neurotrophic factor in depression and response to antidepressants.
        J Exp Biol. 2015; 218: 21-31
        • Boulange C.L.
        • Neves A.L.
        • Chilloux J.
        • et al.
        Impact of the gut microbiota on inflammation, obesity, and metabolic disease.
        Genome Med. 2016; 8: 42
        • Selmer T.
        • Andrei P.I.
        p-Hydroxyphenylacetate decarboxylase from Clostridium difficile. A novel glycyl radical enzyme catalysing the formation of p-cresol.
        Eur J Biochem. 2001; 268: 1363-1372
        • Goodhart P.J.
        • DeWolf Jr., W.E.
        • Kruse L.I.
        Mechanism-based inactivation of dopamine beta-hydroxylase by p-cresol and related alkylphenols.
        Biochemistry. 1987; 26: 2576-2583
        • Togsverd M.
        • Werge T.M.
        • Tanko L.B.
        • et al.
        Association of a dopamine beta-hydroxylase gene variant with depression in elderly women possibly reflecting noradrenergic dysfunction.
        J Affect Disord. 2008; 106: 169-172
        • Kapoor A.
        • Shandilya M.
        • Kundu S.
        Structural insight of dopamine beta-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms.
        PLoS One. 2011; 6: e26509
        • Johnston M.
        • Pollard B.
        • Hennessey P.
        Construct validation of the hospital anxiety and depression scale with clinical populations.
        J Psychosom Res. 2000; 48: 579-584

      Supplementary References

        • Bartram A.K.
        • Lynch M.D.
        • Stearns J.C.
        • et al.
        Generation of multimillion-sequence 16S rRNA gene libraries from complex microbial communities by assembling paired-end Illumina reads.
        Appl Environ Microbiol. 2011; 77: 3846-3852
        • Martin M.
        Cutadapt removes adapter sequences from high-throughput sequencing reads.
        EMB netjournal. 2011; 17: 10-12
        • Masella A.P.
        • Bartram A.K.
        • Truszkowski J.M.
        • et al.
        PANDAseq: paired-end assembler for illumina sequences.
        BMC Bioinformatics. 2012; 13: 31
      1. Ye Y. Fast and accurate identification and quantification of abundant species from pyrosequences of 16S rRNA by consensus alignment. IEEE Int Conf Bioinformatics Biomed 2010:153–157.

        • Schloss P.D.
        • Westcott S.L.
        • Ryabin T.
        • et al.
        Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities.
        Appl Environ Microbiol. 2009; 75: 7537-7541
        • Caporaso J.G.
        • Kuczynski J.
        • Stombaugh J.
        • et al.
        QIIME allows analysis of high-throughput community sequencing data.
        Nat Methods. 2010; 7: 335-336
        • Wang Q.
        • Garrity G.M.
        • Tiedje J.M.
        • et al.
        Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy.
        Appl Environ Microbiol. 2007; 73: 5261-5267
        • DeSantis T.Z.
        • Hugenholtz P.
        • Larsen N.
        • et al.
        Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB.
        Appl Environ Microbiol. 2006; 72: 5069-5072
        • McMurdie P.J.
        • Holmes S.
        phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data.
        PloS One. 2013; 8: e61217
        • Moco S.
        • Collino S.
        • Rezzi S.
        • et al.
        Metabolomics perspectives in pediatric research.
        Pediatr Res. 2013; 73: 570-576
        • Collino S.
        • Martin F.P.
        • Rezzi S.
        Clinical metabolomics paves the way towards future healthcare strategies.
        Br J Clin Pharmacol. 2013; 75: 619-629
        • Trygg J.
        • Wold S.
        O2-PLS, a two-block (X-Y) latent variable regression (LVR) method with an integrated OSC filter.
        J Chemom. 2003; 17: 53-64
        • Cloarec O.
        • Dumas M.E.
        • Craig A.
        • et al.
        Statistical total correlation spectroscopy: an exploratory approach for latent biomarker identification from metabolic 1 H NMR data sets.
        Anal Chem. 2005; 77: 1282-1289

      Linked Article