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

Abstract

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). A similar trend was observed for the Shannon and Faith diversity indexes at the middle of CRT. However, at the end of CRT, there were no significant differences for any alpha diversity indexes between fatigued and nonfatigued participants. 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.

Changes in Gut Microbiome Associated With Co-Occurring Symptoms Development During Chemo-Radiation for Rectal Cancer: A Proof of Concept Study

“…Our LDA analyses, however, revealed that before-treatment participants with co-occurring symptoms were enriched in microbes classified to the genus Bacteroides . This finding is in line with our previous work showing higher relative abundances of Bacteroides in the stool of fatigued participants undergoing CRT (Gonzalez-Mercado et al, 2020). Bacteroides , including B. fragilis , plays an important role in systemic inflammation and neurodegeneration processes (Zhao & Lukiw, 2018).…”

“…Because of the small sample sizes, our results are exploratory in nature and should be interpreted with caution. Nonetheless, this proof-of-concept pilot study builds on prior evidence from our group that CRT-induced comorbidities/symptoms may be associated with gut-microbial dysbiosis (Gonzalez-Mercado et al, 2020; Gonzalez-Mercado et al, 2019). In the present study, we compared the severity of fatigue, sleep disturbance, and depression scores before and at the end of CRT between participants who developed co-occurring symptoms by the end of CRT ( n = 24) and those who developed no symptom ( n = 7).…”

“…Previous research suggests that gut microbial perturbation/dysbiosis, a disruption in the balance, diversity, and function of symbiotic intestinal microbial communities (Perez et al, 2020) may be an important correlate of the symptom experience among patients with pelvic cancer undergoing treatments, perhaps mediated by the gut–brain axis (Bajic et al, 2018; Gonzalez-Mercado et al, 2019, 2020; Jordan et al, 2018). We previously demonstrated that gut microbial dysbiosis in RC patients was characterized by significantly lower alpha (within-sample) diversity at the end of CRT compared to before treatment using both Shannon diversity (community diversity) and the observed operational taxonomic units (OTUs [community richness]) for the RC sample as a whole ( p < 0.05; Gonzalez-Mercado et al, 2020). In addition, Shannon diversity was associated with fatigue or sleep-disturbance scores (Gonzalez-Mercado et al, 2019, 2020).…”

“…We previously demonstrated that gut microbial dysbiosis in RC patients was characterized by significantly lower alpha (within-sample) diversity at the end of CRT compared to before treatment using both Shannon diversity (community diversity) and the observed operational taxonomic units (OTUs [community richness]) for the RC sample as a whole ( p < 0.05; Gonzalez-Mercado et al, 2020). In addition, Shannon diversity was associated with fatigue or sleep-disturbance scores (Gonzalez-Mercado et al, 2019, 2020). However, it is not yet known if there is a relationship between gut microbiome perturbation and co-occurrence of symptoms during CRT for RC.…”

Associations between the gut microbiome and fatigue in cancer patients

“…Multiple studies have shown that the intestinal microbiome of cancer patients is different from that of patients without cancer. In addition, gut microbial dysbiosis prior to radiation therapy may predict fatigue in cancer patients 9 , and chemoradiotherapy can influence colorectal cancer patients’ intestinal microbiome composition and contribute to fatigue 10 .…”