Cancer is a major public health problem across the world, and it is the second leading cause of death in the United States (1, 2). In 2020, a total of 1,806,590 new cancer cases and 606,520 cancer deaths were estimated to occur in the United States (2). Pelvic cancers, such as gynecological cancer, prostate cancer, and colorectal cancer, are among the most frequently diagnosed cancers (1, 2). Pelvic radiation therapy (RT) is a core modality primarily used to treat pelvic cancers (3, 4), with the purpose of reducing tumor size to allow surgical resection of tumors or killing tumor cells that cannot be removed via surgeries (5). With the advancement of cancer treatment modalities, including pelvic RT, the cancer mortality rate has continuously decreased, with an estimated 16.9 million cancer survivors currently alive in the United States (2, 6, 7). However, the wide use of RT has resulted in a high incidence of radiation‐induced symptoms and toxicities (8, 9). Specifically, 90% of cancer patients with pelvic RT develop a permanent change in their bowel habits (4, 10), and they may develop pelvic radiation toxicities such as radiation enteritis, radiation proctitis, and radiation cystitis post treatment (4, 11). As these patients with pelvic cancers live longer, an increasing number of them suffer for decades with RT-related gastrointestinal (GI) symptoms and toxicities, all of which can significantly decrease the patients’ quality of life (QOL).

Current knowledge has delineated the microbiome-host interactions as an integrative point in the pathogenesis of GI symptoms and toxicities among cancer patients receiving RT (12, 13). The human microbiotas and their genomes in the GI tract are collectively called the gut microbiome (14), which varies among different hosts and across different parts of the GI tract within a single host (15, 16). The gut microbiome is a dynamic ecosystem and is highly susceptible to a variety of environmental factors (e.g., diet and physical activity) and host-driven factors (e.g., cancer diagnosis and tolerance of RT) (17, 18). The pathogenesis of the gut microbiome for cancer treatment-related symptoms and GI toxicities may be related to the following pathways: inflammatory cytokines, intestinal permeability, bacteria translocation; changes in the epithelial surface microbiota pattern, intestinal protection from noxious stimuli, epithelial repair mechanisms; and the release of immune cells and molecules (19). Thus, pelvic RT can lead to a dysbiotic gut microbiome, potentially increasing intestinal permeability, thereby causing GI symptoms and toxicities.

Recently, research has started to investigate the interaction of the gut microbiome with pelvic RT and its associations with RT-related GI toxicities. Both animal models and clinical studies have corroborated decreases in diversity and disturbance of the gut microbial communities across cancer treatments (12, 13). Based on male C57/Bl6 mice, Johnson et al. found that radiation led to significant decreases in anaerobic Enterobacteriaceae and Lactobacillus genera (20); Kim and colleagues found a significant increase in Alistipes and a decrease in Mucispirillum genera when characterizing the mouse gut microbiome during radiation (21). Among human cancer populations, gynecological cancer patients with pelvic RT showed a higher abundance of Actinobacteria but a lower abundance of Fusobacteria compared to healthy individuals (22). Patients with pelvic tumors who experienced acute post-RT diarrhea showed a decrease in microbial diversity compared to both healthy volunteers and patients who received pelvic RT but without diarrhea; patients with diarrhea exhibited an increased abundance of Actinobacteria and Bacilli but a decreased abundance of Clostridia compared to patients without diarrhea (23). All these studies seem to indicate that patients receiving RT exhibit marked changes in their gut microbiome, and these changes may be associated with GI symptoms and toxicities, such as diarrhea and radiation enteritis.

Although evidence has shown the potential role of the gut microbiome in GI symptoms and toxicities during cancer treatments, current literature has primarily focused on the impact of chemotherapy and immunotherapy on the gut microbiome (12, 13). Some animal studies have proposed the potential role of the gut microbiome as a protection against RT toxicities, suggesting a higher abundance of Lachnospiraceae and Enterococcaceae associated with less RT side effects in mice models (24). Although some evidence has shown the potential associations of the gut microbiome with symptoms and GI toxicities in cancer patients, findings of studies are inconsistent, and the role of pelvic RT on the gut microbiome and resulted symptoms remain obscure (12, 13).

Radiation enteritis and symptoms experienced by cancer patients treated with RT is a global challenge. Understanding the impact of pelvic RT on the gut microbiome and its associations with symptoms and GI toxicities may provide a precise target to relieve symptoms and decrease patients’ suffering. The current literature reviews primarily focused on preclinical and clinical studies to elucidate the underlying mechanisms of gut microbiome dysbiosis in relation to RT (8, 25). Also, to date, no systematic review was conducted with a robust methodology to evaluate the quality of the included studies using a valid tool (25). Thus, a systematic review was needed to synthesize current research regarding the impact of pelvic RT on the gut microbiome and its relationship with symptoms and GI toxicities in adult cancer patients with pelvic cancers.

A systematic review was conducted to examine: 1) the influence of pelvic RT on the gut microbiome in adult patients with pelvic cancers receiving RT; and 2) the associations between the gut microbiome and clinician-reported and patient-reported GI toxicities and symptoms among adult patients treated with pelvic RT.

Thirteen studies were systematically synthesized to describe the role pelvic RT plays in influencing the gut microbiome and its associations with symptoms and GI toxicities among patients with various pelvic cancers. These studies indicated that pelvic RT could lead to dysbiosis by altering the diversity and abundance of the gut microbiome. A lower alpha diversity, dissimilarity in beta diversity, and decreased relative abundance of the healthy-associated gut microbes seemed to be associated with GI toxicities such as diarrhea and radiation enteritis. However, these studies have very specific limitations, including small sample size, using different tools to measure toxicities, diversity of patient populations, combination of multiple pelvic cancers at different stages, RT dose, use of concurrent chemotherapy as another systematic treatment, the use of diverse DNA sequencing approaches (e.g., 16S rRNA V1-V9 gene regions), and using different methodologies to describe the gut microbiome diversity and composition (i.e., definition of operational taxonomic unit (OTU), and sequencing read processing), all of which further complicate the interpretation of inconsistent findings. Moreover, cofounding factors such as diet, body mass index (BMI), physical activity, changes in BMI pre- to post-treatment, and use of antibiotics, were not systematically measured in the included studies, which may affect the results.

RT is a core modality used to treat pelvic cancers (41). Pelvic RT can disrupt the gut microbiome and lead to marked changes (e.g., promoting dysbiosis) in the gut microbiome (8, 13). Pre-clinical studies (via animal models) found that RT causes significant changes in the diversity and abundance of the gut microbiome (21), including a significant decrease in Enterobacteriaceae and Lactobacillus groups (20). Current findings were inconsistent in human populations. This systematic review found a lower alpha diversity (e.g., Chao1 index, Shannon index, and observed OTUs) among cancer patients with pelvic RT (22, 30, 33, 38) and significant differences in beta diversity (e.g., Jaccard distance metric) between patients with and without pelvic RT (37, 38); however, these findings were inconsistent with other studies (31, 32, 37). These differences in results can be explained due to small sample size (with a range between 5 and 134), studying various different pelvic cancers (e.g., gynecologic cancers, colorectal cancers, prostate cancer, and other GI cancers), and the use of multiple treatment modalities (e.g., RT alone and CRT). Importantly, the use of various 16S rRNA gene regions (i.e., V1-V9) for the microbiome data sequencing may further explain the discrepancies in these results.

Pelvic RT can lead to a dysbiosis of gut microbiome taxa, with a larger average variation of the relative abundance during RT compared to before RT and after RT (22). Specifically, cancer patients with pelvic RT showed decreased Firmicutes (the phylum level) (22), Eubacteriaceae (the family level) (22), Clostridiales (the order level) (38), Faecalibacterium (the genus level) (30), and increased Fusobacteria (the phylum level) (22), Fusobacteriaceae (the family level) (22), Streptococcaceae (the family level) (22), Pseudomonas (the genus level) (34), Veillonella (the genus level) (34), Megamonas (the genus level) (34), Bacteroides (the genus level) (30), Clostridium_XIVa (the genus level) (30), and Lactobacillus (the genus level) (32) across pelvic RT. These significant changes in the gut microbiome are associated with cytotoxic chemotherapy or RT (8). For example, pelvic RT could lead to a significant change in the health status of the GI tract, including chronic inflammation or abnormal function of the epithelial cells, which might directly affect the gut microbial community. Although previous study has concluded that pelvic RT leads to increases in Bacteroides and Enterobacteriaceae, and decreases in Bifidobacterium, Faecalibacterium prausnitzii, and Clostridium cluster XIVa (13), this study suggested a variety of gut microbial taxa are disrupted during pelvic RT, such as Bifidobacterium, Lactobacillus, and Faecalibacterium prausnitzii, all of which have been examined as probiotics to treat a dysbiotic gut microbiome (8, 42, 43). Due to the limitations of study methodology and study design for this review, these probiotic studies would benefit from a future review.

RT-induced diarrhea affects more than 80% of cancer patients with pelvic RT (44), and this can cause significant treatment delays or dose reductions and diminish patients’ QOL (45, 46). The gut microbiome can impact RT-associated GI toxicity and diarrhea through two primary mechanisms: microbial translocation and dysbiosis (8). Specifically, a dysbiotic gut microbiome can promote the pathogenesis of radiation-induced GI mucositis (inflammation) (13) via modulating the oxidative stress and inflammatory processes, intestinal permeability, mucus layer composition, epithelial repair and ability to resist harmful stimuli, and expression and release of immune effector molecules in the intestine (19). In this study, our findings showed a lower alpha diversity (e.g., Shannon index) of the gut microbiome to be associated with worse diarrhea and radiation enteritis before and after RT (30, 34), as well as a significant difference in beta diversity between patients with low and high GI toxicities after RT (38). Findings of our study further indicated that a higher abundance of Bacteroides, Phascolarctobacterium, and Roseburia was associated with higher GI toxicities while Clostridium XI, XIVa and XVIII, and Faecalibacterium were associated with lower GI toxicities (30, 33, 38). Phascolarctobacterium and Roseburia are short chain fatty acid (SCFA) producers that promote GI homeostasis and whose depletion has been associated with irritable bowel disease; this seems to contradict the findings of our review. One potential hypothesis is that these bacteria are part of an intestinal mucosa–associated community, and increased competition by potentially pathogenic bacteria leads to increased shedding in the stools of patients at risk of RT-induced GI toxicities (33, 47). Clostridia cluster groups (P. 48, 49) and Faecalibacterium genus ( 50 ) are potential probiotics with leading roles in the maintenance of gut homeostasis. For example, Clostridia cluster XVIII was linked to promotion of regulatory T-cell expansion and protection from colitis and allergic diarrhea, and this group was significantly less abundant in patients who developed diarrhea (51). Similarly, Faecalibacterium genus includes a protective commensal bacteria, such as Faecalibacterium prausnitzii (50). Therefore, depletion of protective commensal bacteria during pelvic RT can promote much more severe GI toxicities among patients with pelvic cancers.

Pelvic RT for pelvic cancers has frequently been found to increase the risk of radiation enteritis, and this may lead to longer hospitalizations and interruptions to the treatment plans of cancer patients (52). Previous work has examined the impact of RT on the gut microbiome by assuming that changes in the gut microbiome may affect the developmental course of radiation enteropathy (20, 53). Particularly, a linkage between the gut microbiome and RT-induced enteritis has been reported in germ-free animals (54). It is known that inflammatory pathways such as the NF-kB signaling pathway could be activated in response to RT (55), and commensal bacteria may regulate inflammatory responses as well. For instance, Bacteroides thetaiotaomicron and Bifidobacterium infantis are able to suppress NF-kB activation, whereas gut microbes in the Clostridium XIVa group have been reported to attenuate inflammation of the gut epithelium (56, 57). With respect to these promising microbial relationships, strategies such as FMT (35), prebiotics (39), and probiotics (58–60), used for increasing bacterial diversity and promoting the protective commensal bacteria in patients at risk for radiation enteritis, should be tested to understand whether they modify the course of RT-induced enteropathy.

This study has several limitations. According to our results, it is not possible to causatively link any of those significantly identified taxa to the etiology of RT-induced enteropathy. The current study synthesized data related to both acute and late toxicities related to RT. These promising findings should be further examined in a large sample size by considering confounding factors, such as diet, and using standard methods to measure symptoms and gut microbiome profiles so that confirmed findings can be used to improve the clinical practice among patients with cancer receiving pelvic RT. Secondly, radiation enteropathy has multiple causes, which are likely to have differential contributions from the gut microbiome. So far, no objective markers of radiation enteropathy have been defined, and there is no option but to rely on abnormal outcomes, primarily measured by clinician-reported toxicities or patient-reported symptoms. Finally, this study systematically reviewed all the articles using next generation sequencing and published in English only, which may lead to some data selection biases.

Pelvic RT can disrupt the diversity and abundance of commensal gut microorganisms. A dysbiotic gut microbiome showed promising associations with pelvic radiation enteropathy and toxicities through alterations of intestinal barrier function, innate immunity, and intestinal repair mechanisms. The conflicting reports on microbial diversity and abundance may be attributed to cofounding factors within the complicated relationship between the gut microbiome and RT enteropathy. This may limit our ability to clearly define the unique contribution of the gut microbiome in RT enteropathy, and this important relationship warrants further investigations. A better understanding of the role of the gut microbiome in RT-induced symptoms and GI toxicities may lead to new therapeutic approaches and the identification of predictive markers of RT-induced GI toxicities.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

JB: conception of the study, methodology, developing the search strategy, supervision, drafting and editing the article, and funding acquisition. ZB: conception of the study, methodology, screening and extracting data, developing the search strategy, drafting, and editing the article. CR: methodology, screening and extracting data, developing the search strategy, drafting and editing the article. RM: drafting and editing the article. DT: methodology, screening and extracting data, assessing the risk of bias, and completing data synthesis. DB: conception of the study, drafting and editing the article. All authors contributed to the article and approved the submitted version.

This work was partially supported by the National Institutes of Health/National Institute of Nursing Research (1K99NR017897-01 and 4R00NR017897-03).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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