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Fatigue in Patients with IBD Linked to Changes in Gut Microbiome

Key findings

  • In this prospective study, proteomic, metabolomic and microbiome analysis was conducted of serum/fecal samples from 166 adults with quiescent inflammatory bowel disease (IBD), of whom 55% reported significant fatigue symptoms
  • Blood samples from patients with fatigue showed no significant elevation in several key pro-inflammatory cytokines compared with non-fatigued controls, suggesting fatigue in IBD is not likely to be driven solely by systemic inflammation
  • Alterations in amino acid metabolism and depletion of serum tryptophan were associated with fatigue, and this metabolomic alteration was underpinned by several alterations in the gut microbiome, including depletion of butyrate-producing phyla
  • Serologic or proteomic markers might someday be used to quantify the burden of fatigue in IBD and perhaps other autoimmune diseases, and microbiome-directed therapy (e.g., pre- and probiotics) may be a promising approach to treatment

One of the most common extraintestinal manifestations of inflammatory bowel disease (IBD) is fatigue, which is reported by nearly 80% of patients overall and more than 40% of those in clinical remission.

An increasing body of research suggests alterations in the composition of the gut microbiome perturb the neurotransmitter balance of the central nervous system. A link between the gut–brain axis and fatigue has been observed in chronic fatigue syndrome, where small cohorts demonstrated gut microbial alterations.

Now, Nienke Z. Borren, MSc, former research fellow in the Division of Gastroenterology at Massachusetts General Hospital, Ashwin N. Ananthakrishnan, MBBS, MPH, director of the Mass General Crohn's and Colitis Center, and colleagues have provided the first evidence that alterations in serum metabolites and fecal microbes are associated with fatigue in patients with IBD. Given the prevalence of fatigue in patients with various autoimmune diseases, their findings may have broad relevance, as they explain in Clinical Gastroenterology and Hepatology.

Study Methods

The researchers prospectively studied 166 adults with IBD in clinical and endoscopic remission (106 with Crohn's disease, 60 with ulcerative colitis) who received care between March 2016 and December 2018. Patients completed the 13-item Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F) scale, which has been validated for use in IBD. 55% met a prespecified definition of fatigue (score ≤43) and the others formed the non-fatigued control group.

Proteomics and Inflammatory Cytokine Analysis

A total of 131 serum samples (72 from patients with fatigue) were analyzed for 184 proteins. Levels of cytokines associated with inflammation, such as interleukin (IL)-6, were undetectable or low in patients with fatigue compared with control subjects.

IL-12B, IL-7, NBL1 and IL-12 were significantly associated with fatigue on multivariable analysis but not multiple hypothesis testing. Thus, persistent fatigue in quiescent disease is not likely to be due primarily to systemic inflammation.

Metabolomics Analysis

Metabolomic profiles for 100 metabolites were generated for 156 patients (84 with fatigue). A cluster of 18 metabolites was significantly different in patients with and without fatigue. In addition, many of the metabolites were individually depleted in patients with fatigue, including methionine, tryptophan, proline and sarcosine.

Microbiome Analysis

The researchers used fecal samples from 50 patients (26 with fatigue) to examine whether alterations in the gut microbiome underpin metabolomic alterations.

  • At the genus level, fatigued patients showed significantly reduced abundance of Faecalibacterium, Ruminococcus and Alistipes and a significantly higher abundance of Coprobacillus
  • At the species level, butyrate producers such as Faecalibacterium prausnitzii and Roseburia hominis were significantly less abundant in fatigued patients than controls
  • Pathway analysis showed significant depletion of the butyrate synthesis pathway and asparagine synthase in patients with fatigue and significantly more abundant dihydrofolate reductase

An increasing fatigue microbiome score was strongly and significantly correlated with worsening FACIT-F score.

Correlation of Microbiome and Metabolomic Alterations

As the fatigue microbiome score increased (by tertiles), there were "dose dependent" significant decreases in serum levels of methionine, tryptophan, proline and sarcosine.

Laying the Groundwork

This study is a key step toward defining biomarkers and novel therapeutic options for fatigue in IBD and other autoimmune diseases. Assuming the results are validated, serologic or proteomic markers could be useful to quantify the burden of fatigue, and microbiome-directed therapy (e.g., pre- and probiotics) may be a promising approach to treatment.

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