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Objectives   The objectives of this proof of concept study were to (a) examine the temporal changes in fatigue and diversity of the gut microbiome over the course of chemoradiotherapy (CRT) in adults with rectal cancers; (b) investigate whether there are differences in diversity of the gut microbiome between fatigued and nonfatigued participants at the middle and at the end of CRT; and (c) investigate whether there are differences in the relative abundance of fecal microbiota at the phylum and genus levels between fatigued and nonfatigued participants at the middle and at the end of CRT.Methods   Stool samples and symptom ratings were collected prior to the inception of CRT, at the middle (after 12–16 treatments) and at the end (after 24–28 treatments) of the CRT. Descriptive statistics and Mann–Whitney  U  test were computed for fatigue. Gut microbiome data were analyzed using the QIIME2 software.Results   Participants ( N  = 29) ranged in age from 37 to 80 years. The median fatigue score significantly changed at the end of CRT (median = 23.0) compared with the median score before the initiation of CRT for the total sample (median = 17.0;  p  ≤ 0.05). At the middle of CRT, the alpha diversity (abundance of Operational Taxonomic Units) was lower for fatigued participants (149.30 ± 53.1) than for nonfatigued participants (189.15 ± 44.18,  t (23) = 2.08,  p  ≤ 0.05). At the middle of CRT, the alpha diversity (abundance of Operational Taxonomic Units) was lower for fatigued participants (149.30 ± 53.1) than for nonfatigued participants (189.15 ± 44.18,  Proteobacteria ,  Firmicutes , and  Bacteroidetes  were the dominant phyla for fatigued participants, and  Escherichia ,  Bacteroides ,  Faecalibacterium , and  Oscillospira  were the most abundant genera for fatigued participants.Conclusion   CRT-associated perturbation of the gut microbiome composition may contribute to fatigue.

The Role of Gut Microbiome Perturbation in Fatigue Induced by Repeated Stress from Chemoradiotherapy: A Proof of Concept Study