Probiotics improve depression in IBS sufferers

Relation

Pinto-Sanchez MI, Hall GB, Ghajar K, et al. ProbioticBifidobacterium longumNCC3001 reduces depression levels and alters brain activity: a pilot study in patients with irritable bowel syndrome [published online ahead of print May 5, 2017].Gastroenterology.

Draft

Randomized, placebo-controlled, double-blind pilot study

Participant

Forty-four adults (ages 26 to 58; 54% female) with irritable bowel syndrome (IBS)-D (diarrhea subtype) or IBS-M (mixed subtype), diagnosed according to the Rome III criteria, with concurrent mild to moderate depression and/or anxiety.

Study parameters assessed

anxiety and depression levels; IBS symptoms; brain activation patterns; serum inflammatory markers; neurotransmitters and neurotrophins; urine metabolome profiles; and stool microbiota profiles.

intervention

Bifidobacterium longumNCC3001 powder, 1 g (10 billion CFU) in 100 to 200 ml of lactose-free milk, soy milk or rice milk once daily for 6 weeks. The study began with a 1-month run-in period, followed by 6 weeks of intervention/placebo and 4 additional weeks of follow-up.

Primary outcome measure

A drop of 2 or more points on the Hospital Anxiety and Depression Scale (HAD).

Secondary outcome measures

• Verbesserung bei Angst und Depression (HAD-Scores)
• Verbesserung der Angst (State-Trait Anxiety Inventory)
• IBS global angemessene Entlastung
• IBS-Symptome
• Somatisierung
• Lebensqualität
• Veränderungen in den Aktivierungsmustern des Gehirns (funktionelle Magnetresonanztomographie). [fMRI])
• Entzündungsmarker im Serum
• Neurotransmitter und aus dem Gehirn stammender neurotropher Faktor
• Metabolomisches Profil des Urins
• Profil der Stuhlmikrobiota

Key insights

Researchers found no statistically significant difference in HAD anxiety scores (relative risk [RR]: 1.31; 95% confidence interval [CI]: 0.72-2.42;P= 0.54), but they did so with ratings of depression (RR: 1.98; 95% CI: 1.16-3.38;P=0.04); 64% of the probiotic group met the primary outcome threshold (decrease of at least 2 points on the depression measure) compared to 32% in the placebo group.

There were non-statistically significant improvements in anxiety and depression scores (as a continuous outcome, vs>2 threshold). The probiotic group was 60% more likely to report “adequate relief” from 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 after treatment.

Interestingly, the researchers showed that participants who took probiotics showed a reduced fMRI fear response 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]-γInterleukin [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 found no statistically significant differences between the two groups in any of these outcomes.

However, there were reductions in urinary methylamines and aromatic amino acid metabolites, including 4-cresol sulfate, in those taking probiotics, and participants' depression scores correlated with 4-cresol sulfate levels.

Practice implications

This was a fascinating 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 that appears not to be related to significant microbiome changes or inflammation, but rather to changes in key host/bacterial metabolites.

While the microbiome profiles did not differ with the probiotic intervention, this was the case with metabolomics. The connection between the reduction in 4-cresol sulfate levels and the depression score in the probiotic group is particularly interesting. We know that 4-cresol sulfate inhibits dopamine β-hydroxylase and reduced dopamine β-hydroxylase activity is associated with depression.^1-3Therefore, reduced 4-cresol sulfate levels may reduce dopamine β-hydroxylase inhibition, suggesting a mechanism of action for this probiotic strain as it is related to depression.

For the most part, this was a well-conducted study. Previous studies had shown that a reduction in anxiety or depression in the range of 1 to 2 on the HAD scale was the minimal improvement that patients would consider important.⁴This study was designed to detect a difference above this level (>2 points difference). However, the study is limited by its size. It is not surprising that some of the secondary results did not reach statistical significance - perhaps there was not enough power to detect them.

The biggest concern is the potential for funding distortions. This study was funded by Nestle and 4 of the authors are employees of Nestle or Nestec (a subsidiary of Nestle). Nestec holds a patent for the strain used in the study (US 8916145 B2).⁵However, the study design was sound, and although we know that industry-sponsored studies are a risk factor for biased effect estimates, downgrading the quality of a particular study based solely on its funding source is somewhat controversial.^6.7

A total of 10 billion CFU per dayB longNCC3001 for 6 weeks appears to improve depression but not anxiety in IBS-D/M patients, with twice as many patients in the intervention group achieving threshold improvement (64% vs. 32%). The effect is clinically significant and lasts up to 4 weeks after treatment. Interestingly, the mechanism appears to be independent of changes in microbiota diversity but may be related to the host bacterial metabolome. Of course, larger follow-up studies are warranted, and the results of this study may only be specific to IBS-D/M patients.