Pinto-Sanchez MI, Hall GB, Ghajar K, et al. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome [published online ahead of print May 5, 2017]. Gastroenterology.
Randomized, placebo-controlled, double-blind pilot trial
Forty-four adults (ages 26 to 58; 54% female) with irritable bowel syndrome (IBS)-D (diarrhea subtype) or IBS-M (mixed subtype) diagnosed by Rome III criteria, with concomitant mild to moderate depression and/or anxiety.
Study Parameters Assessed
Anxiety and depression scores; IBS symptoms; brain activation patterns; serum inflammatory markers; neurotransmitters and neurotrophins; urine metabolome profiles; and stool microbiota profiles.
Bifidobacterium longum NCC3001 powder, 1 g (10 billion CFU) in 100 to 200 mL lactose-free milk, soy milk, or rice milk once a day for 6 weeks. The study began with a 1-month run-in, followed by 6 weeks of intervention/placebo then 4 additional weeks of follow-up.
Primary Outcome Measure
A drop of 2 points or more on the Hospital Anxiety and Depression (HAD) scale.
Secondary Outcome Measures
- Improvement in anxiety and depression (HAD scores)
- Improvement in anxiety (State-Trait Anxiety Inventory)
- IBS global adequate relief
- IBS symptoms
- Quality of life
- Changes in brain activation patterns (functional magnetic resonance imaging [fMRI])
- Serum inflammatory markers
- Neurotransmitters and brain-derived neurotrophic factor
- Urine metabolomic profile
- Stool microbiota profile
The researchers did not find a statistically significant difference in HAD scores of anxiety (relative risk [RR]: 1.31; 95% confidence interval [CI]: 0.72-2.42; P=0.54), but they did with scores of depression (RR: 1.98; 95% CI:1.16-3.38; P=0.04); 64% of the probiotic group reached the primary outcome threshold (drop of at least 2 points on depression measure) compared to 32% in the placebo group.
There were nonstatistically significant improvements in anxiety and depression scores (as a continuous outcome, vs the >2 threshold). The probiotics group were 60% more likely to report “adequate relief” of their IBS symptoms (RR: 1.6; 95% CI: 0.86-2.91), but this improvement was not statistically significant in the intention-to-treat analysis (although it was in the per protocol analysis).
The effect is clinically significant and lasts up to 4 weeks post-treatment.
Interestingly the researchers were able to show that participants taking probiotics had a reduced fear response on fMRI in areas of the brain associated with emotional processing such as the amygdala.
The researchers also included many potential mechanisms of action based on secondary outcomes such as serum inflammatory markers (C-reactive protein [CRP], tumor necrosis factor [TNF]-α, interferon [IFN]-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, IL12 and IL-10/12 ratio), neurotransmitters (serotonin, substance P, and calcitonin gene-related peptide [CGRP]), brain-derived neurotrophic factor, and microbiome profiles. Surprisingly, they did not notice any statistically significant differences between the 2 groups for any of these outcomes.
However, there was a reduction of urinary methylamines and aromatic amino acid metabolites, including 4-cresol sulfate in those taking probiotics, and participants’ depression levels correlated with 4-cresol sulfate levels.
This was an intriguing study for numerous reasons. Of particular interest is the combination of patient symptoms and objective biomarkers as outcome measures. The use of biomarkers was able to suggest a mechanism of action apparently not related to significant microbiome changes or inflammation, but rather related to alterations of key host/bacterial metabolites.
While the microbiome profiles did not differ with the probiotic intervention, the metabolomics did. The correlation between reduction of 4-cresol sulfate levels and depression scores in the probiotics group is particularly interesting. We know that 4-cresol sulfate inhibits dopamine β-hydroxylase, and decreased activity of dopamine β-hydroxylase is associated with depression.1-3 So reduced 4-cresol sulfate levels may reduce inhibition on dopamine β-hydroxylase, suggesting a mechanism of action for this strain of probiotic as it relates to depression.
For the most part, this was a well-conducted study. Previous studies had shown that drops in anxiety or depression in the 1-2 range on the HAD scale was the minimal improvement that patients would consider important.4 This study was powered to detect a difference above this level (>2-point difference). However, the study is limited by its size. It is not surprising that some of the secondary outcomes did not reach statistical significance—it may not have been adequately powered to detect them.
The biggest concern is the potential for funding bias. This study was funded by Nestle, and 4 of the authors are Nestle or Nestec (a subsidiary of Nestle) employees. Nestec holds a patent for the strain used in the study (US 8916145 B2).5 The study design was solid though, and while we know industry-sponsored trials are a risk factor for biased effect estimates, downgrading the quality of a specific study due only to its funding source is somewhat controversial.6,7
In summary, 10 billion CFU per day of B longum NCC3001 for 6 weeks does seem to improve depression but not anxiety in IBS-D/M patients, with twice as many patients in the intervention group reaching a threshold improvement (64% vs 32%). The effect is clinically significant and lasts up to 4 weeks post-treatment. Interestingly, the mechanism seems to be independent of microbiota diversity changes but may be related to host-bacterial metabolome. Of course, larger follow-up studies are warranted, and the findings of this study may be specific to IBS-D/M patients only.
- Goodhart PJ, DeWolf WE Jr, Kruse LI. Mechanism-based inactivation of dopamine beta- hydroxylase by p-cresol and related alkylphenols. Biochemistry. 1987;26(9):2576-2583.
- Togsverd M, Werge TM, Tanko LB, et al. Association of a dopamine beta-hydroxylase gene variant with depression in elderly women possibly reflecting noradrenergic dysfunction. J Affect Disord. 2008;106(1-2):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.
- 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.
- Mercenier A, Blum-Sperosem S, Rochat F. Use of Bifidobacterium longum for the prevention and treatment of inflammation. Google Patents. https://www.google.com/patents/US8916145. Published December 23, 2014. Accessed July 26, 2017.
- Bero LA . Why the Cochrane risk of bias tool should include funding source as a standard item. Cochrane Database Syst Rev. 2013;12:ED000075.
- Sterne JA. Why the Cochrane risk of bias tool should not include funding source as a standard item. Cochrane Database Syst Rev. 2013;12:ED000076.