Clinical Characteristic and Fecal Microbiota Responses to Probiotic or Antidepressant in Patients with Diarrhea-Predominant Irritable Bowel Syndrome with Depression Comorbidity: A Pilot Study
Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits. Despite its high prevalence, the pathophysiological mechanisms underlying IBS remain poorly understood. Several hypotheses have been proposed, including visceral hypersensitivity, gastrointestinal dysmotility, low-grade inflammation of the intestinal mucosa, and dysfunction of the brain-gut interaction. The brain-gut axis is particularly relevant in IBS, as a significant proportion of patients with IBS also suffer from psychological comorbidities such as depression or anxiety. Furthermore, mental and psychological problems are known to increase the risk of developing IBS and exacerbate its symptom severity. Recent studies have also suggested that changes in the gut microbiota may contribute to both IBS and depression. Previous research has demonstrated significant alterations in gut microbiota profiles in patients with diarrhea-predominant IBS (IBS-D) and depression.
Therapies aimed at modulating the gut microbiota have shown promise in alleviating IBS symptoms. Probiotics, which are live microorganisms that confer health benefits when consumed, are among the most commonly used agents for this purpose. Probiotics can shift the composition of the gut microbiota and alleviate IBS symptoms. These shifts in gut microbiota composition and the levels of short-chain fatty acids (SCFAs), which are the main metabolic products of gut bacteria, can regulate host immune function, a key factor in the pathogenesis of IBS. Antidepressants are often prescribed for IBS patients with psychological comorbidities and have been shown to effectively alleviate both psychological and IBS symptoms. However, it remains unclear whether probiotics or antidepressants can relieve the severity of psychological comorbidities in IBS or how antidepressants affect the gut microbiota.
To explore the interaction between the gut microbiota and the brain-gut axis, this pilot study investigated the effects of probiotics and the antidepressant duloxetine on gut microbiota profiles, fecal SCFA levels, systemic inflammatory responses, and clinical outcomes in patients with IBS-D and depression. The study was approved by the Peking University Third Hospital Medical Ethics Committee and conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent, and the study was registered on the Chinese Clinical Trial Registry.
Patients with IBS-D, diagnosed according to the Rome III criteria, and depression, diagnosed using the Mini-International Neuropsychiatric Interview (MINI) DSM-IV version 5.0.0, were recruited from the Department of Gastroenterology at Peking University Third Hospital and the Outpatient Department of the Institute of Mental Health at Peking University. Eligible participants, aged between 18 and 65 years, were randomized to receive either probiotics (Bifco, containing Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis) or duloxetine (Cymbalta) for eight weeks. Data on the severity of IBS symptoms and depression, as well as fecal and blood samples, were collected before and after treatment.
The severity of IBS symptoms was assessed using the IBS-Severity Scoring System (IBS-SSS), while depression severity was evaluated using the Zung Self-Rating Depression Scale (SDS). Plasma cytokines, fecal SCFAs, and gut microbiota composition were analyzed before and after treatment. Fecal samples were collected and stored at -80°C until DNA isolation was performed. The V1-V3 regions of the bacterial 16S ribosomal RNA gene were amplified and sequenced using the Roche 454 GS FLX+ Titanium platform. Plasma cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin-6 (IL-6), interferon-gamma (IFN-γ), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), monocyte chemotactic protein-3 (MCP-3), interleukin-23 (IL-23), interleukin-1 beta (IL-1β), and macrophage inflammatory protein-1 alpha (MIP-1α), were measured using a Human Magnetic Luminex Screening Assay. Fecal SCFAs, including formate, acetate, propionate, butyrate, isobutyrate, valerate, and isovalerate, were quantified using ultra-performance liquid chromatography-tandem mass spectrometry.
A total of 162 participants were screened, and 15 patients with IBS-D and depression were recruited for the study. Nine patients received Bifco, and six received duloxetine. One patient in the Bifco group was excluded due to antibiotic use for acute prostatitis, leaving 14 patients who completed the study. In the Bifco group, significant reductions were observed in the total IBS-SSS score and its component scores, including abdominal pain, bloating, satisfaction with bowel habits, and interference with quality of life. The SDS score also showed a decreasing trend. In the duloxetine group, significant reductions were noted in the SDS score, total IBS-SSS score, and component scores, including abdominal pain, onset frequency of pain, satisfaction with bowel habits, and interference with quality of life.
Analysis of gut microbiota revealed that the overall structure of the gut microbiota was altered in both the Bifco and duloxetine groups. The relative abundance of certain bacterial genera, such as Dialister, Clostridium XVIII, and Bifidobacterium, changed significantly after Bifco treatment, while the relative abundance of Fecalibacterium, Lachnospiraceae incertae sedis, Escherichia/Shigella, and Sutterella tended to increase in the duloxetine group. Plasma levels of MCP-1 decreased significantly in both groups, and IL-1β levels decreased significantly in the Bifco group. No significant changes were observed in fecal SCFA levels, although fecal formate levels tended to increase in the Bifco group.
Correlation analysis revealed significant relationships between gut bacteria, fecal SCFAs, plasma cytokines, and IBS symptoms. For example, plasma MCP-1 levels were positively correlated with abdominal pain severity, and fecal acetate levels were negatively correlated with abdominal bloating and total IBS-SSS score. Network analysis further highlighted the complex interactions between gut microbiota, SCFAs, cytokines, and symptoms.
The findings of this study suggest that both probiotics and duloxetine can alleviate abdominal symptoms and depression in patients with IBS-D. These effects may be mediated through the modulation of gut microbiota and fecal SCFA levels, which in turn regulate peripheral inflammation and the brain-gut axis. The study provides preliminary evidence supporting the role of the microbiota-gut-brain axis in the pathophysiology of IBS-D with depression comorbidity. However, further large-scale studies are needed to confirm these findings and explore the underlying mechanisms in greater detail.
doi.org/10.1097/CM9.0000000000000071
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