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Gut Microbial Alterations Linked to Persistent Fatigue in Patients with IBD

Key findings

  • This prospective study examined 166 patients with quiescent inflammatory bowel disease (IBD) who reported substantial fatigue
  • There was no significant elevation in key proinflammatory cytokines in the serum
  • Depletion of serum methionine, tryptophan, proline and sarcosine was noted, among other metabolites
  • Several alterations in the gut microbiome were detected including depletion of butyrate-producing phyla
  • Serologic or proteomic markers may be useful to quantify burden of fatigue in IBD patients, and microbiome-directed therapy may be a promising avenue for its treatment

Fatigue is a common and frequently disabling manifestation of inflammatory bowel disease (IBD)—even during periods of clinical remission. The cause is unclear, so treatment options are limited.

Over the past decade, research in chronic fatigue syndrome (CFS) has suggested that altered gut microbial composition can perturb the neurotransmitter balance in the central nervous system, causing altered mood. CFS has firm diagnostic criteria, though, and chronic immune-mediated diseases such as IBD, where fatigue is more subjective, had not been examined.

In a prospective study, Nienke Z. Borren, MD, 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 identified alterations in serum metabolites and fecal microbes associated with fatigue in patients with quiescent IBD. Further study of these changes might identify factors that could be modified therapeutically.

Study Design

The researchers enrolled 166 adults who received care for quiescent Crohn's disease or ulcerative colitis at Mass General between March 2016 and December 2018. Quiescent disease was defined as endoscopic remission demonstrated within the past year, absence of symptoms at colonoscopy and until study enrollment, normal C-reactive protein and erythrocyte sedimentation rate, and normal fecal calprotectin in the past year.

Patients completed the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F)–Fatigue (FACIT-F) assessment and fatigue was defined as a score ≤43. Ninety-one patients (55%) met that definition and the others formed a non-fatigued control group.

Proteomics Analysis

There were 131 serum samples available to analyze 184 proteins. None of the key proinflammatory cytokines tested were significantly more elevated in fatigued patients than in controls. Thus, fatigue in quiescent IBD is unlikely to be driven solely by systemic inflammation.

Metabolomics Analysis

Among the patients identified, 156 had serum samples available for profiles of 100 targeted metabolites. Based on co-occurrence in the serum, most metabolites could be grouped into four distinct clusters. One cluster of 18 metabolites was significantly different in subjects with and without fatigue (β = −0.40; P =.03).

Many of the individual metabolites in that cluster, including methionine, tryptophan, proline and sarcosine, were significantly more depleted in patients with fatigue than those without.

Microbiome Analysis

Fecal samples were available from 50 patients. After adjusting for IBD type, age and gender, significant alterations in microbial abundance were identified in patients with fatigue:

  • At the genus level, reduced abundance of FaecalibacteriumRuminococcus and Alistipes and a higher abundance of Coprobacillus
  • At the species level, depletion of butyrate producers such as Faecalibacterium prausnitzii and Roseburia hominis

Functional pathway analysis showed that the butyrate and asparagine synthesis pathways were significantly depleted in patients with fatigue, while dihydrofolate reductase was significantly more abundant.

The researchers created a microbiome score for each patient. On scatterplot analysis, a more fatigue-like microbiome was strongly correlated with increasing FACIT-F score (r = −0.57; P < .001).

Correlation of Microbiome and Metabolomic Changes

Across increasing tertiles of the fatigue microbiome score, there was progressive, dose-dependent depletion of methionine, tryptophan, proline and sarcosine.

Implications for New Therapies

These findings lay the foundation to explore therapeutic interventions for IBD-related fatigue that would be directed at the microbiome, such as pre- and probiotics. The study also suggests the use of serologic or proteomic markers to quantify the burden of fatigue in IBD and perhaps other autoimmune diseases where fatigue is prevalent.

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