Understanding chemotherapy-induced intestinal mucositis and strategies to improve gut resilience

Abstract

Intestinal mucositis remains one of the most debilitating side effects related to chemotherapy. The onset and persistence of mucositis is an intricate physiological process involving cross-communication between the specific chemotherapeutic drug, the immune system, and gut microbes that results in a loss of mucosal integrity leading to gut-barrier dysfunction. Intestinal mucositis has a severe impact on a patient’s quality of life and negatively influences the outcome of treatment. Most importantly, intestinal mucositis is a major contributor to the decreased survival rates and early onset of death associated with certain chemotherapy treatments. Understanding the pathophysiology and symptomology of intestinal mucositis is important in reducing the negative consequences of this condition. Prophylaxis, early diagnosis, and proper symptom management are essential to improved survival outcomes in patients with cancer. This review focuses on the pathobiology of intestinal mucositis that accompanies chemotherapy treatments. In addition, we will discuss the therapeutic potential of select strategies that have shown promise in mitigating chemotherapies’ off-target effects without hampering their anticancer efficacy.

NEW & NOTEWORTHY Intestinal mucositis, or damage to the intestinal mucosa, is a common side effect of chemotherapy. In this review, we describe the pathobiology of intestinal mucositis that is associated with chemotherapy treatments. In addition, we discuss the efficacy of several potential therapeutic strategies that have shown some potential in alleviating chemotherapies’ off-target effects.

INTRODUCTION

Although the incidence of cancer in the United States remains high, the 5-year survival rate continues to increase given the improved efficacy of modern treatments (1). However, the adverse effects and long-term consequences associated with chemotherapy remain a major source of concern for both patients and healthcare providers. As much as 90% of patients with cancer receiving chemotherapy suffer from gastrointestinal (GI) distress contributing to reduced quality of life, treatment intolerance, and even death (2). Indeed, a 7.5% death rate has been reported in patients receiving chemotherapy as a result of nonselective toxicity rather than the cancer itself (3). Despite this, chemotherapy remains the first-choice treatment for most clinical cases (4–7). Although the nonspecific off-target toxicities of chemotherapeutic drugs span many symptoms across many organ systems, this review will focus primarily on chemotherapy’s impact on gut health related to mucositis—a condition described as inflammation of the mucous membranes lining the digestive tract (4–6).

Intestinal mucositis, or damage to the intestinal mucosa, is a major contributor to the reduced quality of life, decreased survival rates, and early onset of death observed in patients with certain chemotherapeutic agents (4, 5). Chemotherapy-induced mucositis (CIM) has been linked to symptoms such as nausea, vomiting, diarrhea, and pain (2, 6, 8, 9). The onset, timing, and clinical presentation of these symptoms are influenced by patient-specific risk factors such as age, ethnicity, and gender (10). Further, the symptomology of intestinal mucositis depends on the type and progression of cancer that is being treated (11). Moreover, patients with underlying systemic illnesses such as autoimmune diseases (e.g., IgA deficiency) or diabetes are more susceptible to mucosal damage during chemotherapy (10, 12).

In general, chemotherapy drugs work by slowing or stopping the growth of cancer cells; however, the drugs are not specific to cancer cells and consequently lead to off-target side effects. The associated side-effects are typically specific to the mechanism of action of the compounds and can be synergistic based on various combination therapies (9, 11, 13–15). Importantly, these side effects can negatively impact the outcome of chemotherapy treatment schedules and often lead to discontinuation or de-escalation of treatment. Thus, there is an urgent and unmet need to develop strategies to alleviate the off-target effects of chemotherapeutics to improve treatment tolerance and life quality (16). This review will identify and characterize specific pathophysiological consequences that present clinical challenges during chemotherapy treatment and will present strategies that might be used to improve gut resilience during chemotherapy-induced GI distress.

PERTURBATIONS IN GUT HOMEOSTASIS DURING CHEMOTHERAPY

Gut Health

The GI system spans the mouth to the anus and is responsible for digesting and absorbing nutrients. Within the small intestine specifically, brush-border enzymes present on intestinal villi act to break down organic matter into absorbable molecules. Destruction of intestinal villi during intestinal mucositis reduces the small intestine’s absorptive surface area contributing to malabsorption (4, 7, 17–19). Importantly, the intestinal epithelium is one of the most proliferative tissues and antineoplastic compounds such as 5-fluorouracil (5FU) and doxorubicin (DOX) target this otherwise healthy tissue by interrupting DNA synthesis leading to apoptotic cell death. Because of their high-proliferative potential, crypt cells within the epithelium are most susceptible to DNA damage and cell death following chemotherapy. The tumor suppressor gene and transcription factor p53 plays an important role in the regulation of DNA damage-induced cell death. Once p53 is activated, signals induce the creation of the proteins PUMA and p21, which in turn signal cells to begin apoptosis (20). Chemotherapy-induced mucositis ensues, which is characterized by crypt loss, villus atrophy, loss of renewal capacity, and impairment of the gut absorptive and barrier function (7, 15, 19, 21). As a result, the gut-related side effects include nausea, vomiting, diarrhea, and GI pain (2, 6, 8, 9). It has been reported that GI mucositis is present in 20%–50% of patients receiving 5FU (11). For example, in a stage III clinical trial in patients with colorectal cancer (CRC), FOLFOX (folinic acid, 5FU, and oxaliplatin) induced diarrhea in 56% of patients, whereas FOLFIRI (folinic acid, 5FU, and irinotecan) induced diarrhea in 89% of patients with CRC (2). This was typically seen in the first episode of treatment and subsided in most patients in subsequent treatments (2). Importantly, patients who developed chemotherapy-induced diarrhea (CID) reported poorer mean quality of life scores and greater fatigue than those without CID (2). Unfortunately, the occurrence of intestinal mucositis is difficult to quantify given the limited access to the gut mucosa and a lack of reliable tests. The majority of research, therefore, has focused on oral mucositis with relatively fewer studies on intestinal mucositis—at least in humans. Further, current treatments are palliative at best. Nonetheless, it is clear that intestinal mucositis is a common side effect of these chemotherapeutic agents for which we need 1) better diagnostic tools and 2) more effective therapeutic strategies.

Mucositis

Intestinal mucositis can be defined as inflammation of the mucous membranes lining the digestive tract that leads to structural, functional, and immunological changes. Given that it cannot be visually inspected, it is typically diagnosed via clinical symptoms or relevant biomarkers. CIM is commonly described as a five-phase sequence: 1) initiation (0–2 days), 2) upregulation and activation of messengers (2–3 days), 3) signal amplification (2–5 days), 4) ulceration with inflammation (5–14 days), and 5) healing (14–21 days; Fig. 1) (10, 19). Typically, following initiation (0–2 days), generation of reactive oxygen species (ROS) and activation of nuclear factor κ-B (NF-κB) results in an upregulation of ∼200 messengers, most notably the proinflammatory cytokines tumor necrosis factor (TNF) α, interleukin (IL)6, and IL1β, as well as cyclooxygenase-2 (COX2) when signal amplification (2–5 days) is reached (23). In addition, activation of toll-like receptors (TLR) by intestinal bacteria leads to the upregulation of NF-κB through multiple signaling pathways, further compounding the inflammatory response through the generation and amplification of inflammatory cytokines. Production of ROS also mediates activation of the inflammasome during CIM (24). This process is thought to occur through the control of IL-1β and IL-18 release; it was reported that ROS production following irinotecan treatment increased the cleavage of caspase-1 and subsequently IL-1β and IL-18 release (25). Mechanistic studies involving manipulation of IL-1β, IL-18, or caspase-1 provide further support for a role of the inflammasome in mediating tissue injury during chemotherapy treatment in mice (25). Thus, this rapid destruction of the intestinal mucosa has been shown to induce a debilitating cytokine storm that can exacerbate the negative effects of these chemotherapeutics (4, 5, 9). As the increasing release of proinflammatory cytokines increases through 2–5 days after chemotherapy treatment, the increased expression of TNFα and monocyte chemoattractant protein 1 (MCP1) causes recruitment of macrophages and neutrophils to the site of damage (7). The upregulation of TNFα feedback to increase mitogen-activated protein kinase (MAPK) and c-Jun NH₂-terminal kinase (JNK) signaling leading to fibronectin degradation and activation of macrophages, ultimately increasing the mucositis. Ulcerations in the epithelial layer (phase 4) ensue as an end event of tissue injury and stem cell death. This event leads to further increased release of ROS, which exacerbates the damage to the submucosal layer and advances the debilitating effects of chemotherapy-induced damage (26). This is especially worsened in patients receiving multiple doses of chemotherapy. Bacterial colonization at the mucosal ulcers further induces inflammation by stimulating infiltration and activation of proinflammatory macrophages, leading to a vicious cycle of inflammation in the GI tract.

Figure 1.

The pathobiology of mucositis. This model illustrates significant events in the onset and progression of chemotherapy-induced intestinal mucositis. The presented timeline was developed based on analysis of multiple investigations in preclinical and clinical models of intestinal mucositis. Onset of specific biomolecular consequences and immune cell responses may vary based on drug dose and frequency. Simply, at higher dose or greater frequency, chemotherapy is more likely to accelerate the histopathological, biomolecular, and immune cell consequences presented in this figure. Image adapted from Sonis (22). COX2, cyclooxygenase-2; IL1β, interleukin 1β; IL6, interleukin 6; NF-κB, nuclear factor κ-B; ROS, reactive oxygen species; TNFα, tumor necrosis factor α.

Although normally this type of response would result in tissue repair, antineoplastic drugs also target the highly proliferative hematopoietic system causing systemic anemia and lymphocytopenia (27). These events result in a reduced ability for the immune system to properly respond to the tissue insult. Therefore, an imbalance of cytokine responses and healing mechanisms prolongs the physiological disturbances resulting from intestinal tissue destruction; however, our understanding of the long-term consequences of this aberrant healing process is extremely limited. Indeed, understanding the role of specific immune cells in the onset and repair of the intestinal mucosa has emerged as an intriguing area of inquiry, as modulating the inflammatory cascade has shown some promise, at least in preclinical data, in reducing the onset and severity of intestinal mucositis following chemotherapy (28, 29). However, despite the characteristic neutropenia and lymphocytopenia that are associated with chemotherapy (27, 30), it is the local immune response in the GI tract that appears to be driving the initial onset of mucositis. The model of mucositis described in Fig. 1 shows a relative time period (day 0–3) in which resident immune cells are activated to the site of mucosal injury. This sequence of events appears to be driven initially by the local release of proinflammatory cytokines in the GI tract, which activate resident immune cells (7). However, the nonspecific targeting of compounds such as 5FU to the bone marrow that results in lymphocytopenia and anemia does not explain this cytokine response (day 2–3) (8, 21). This phenomenon provokes the question of whether improving immune health or targeting the local inflammatory response will ameliorate the symptoms and pathological consequences of mucositis. Therefore, it is important to investigate the apparent divergences between the “proinflammatory” local environment and an “immunodeficient” systemic environment and tailor pharmacological interventions (e.g., complementary therapeutics) that promote an optimal systemic and local immune cell infiltration to the intestine. Additionally, our understanding of the underlying cancer’s contribution to this inflammatory paradox requires further and specific attention.

In Table 1, we have highlighted select studies investigating the mechanisms described above, in both animal models and human patients. It is important to note that many of the studies describing these cascades utilized large single doses of chemotherapy in animal models rather than translatable dosing cycles (32, 33); thus, the sequence and timing of events described alone may not accurately reflect events that occur in the clinic. Indeed, the sequence of events that occur in the GI system following chemotherapy are likely to be influenced by the cancer type, drug used, dose and timing of drug, as well as inherent individual differences (4, 5, 31). Nonetheless, there is overwhelming evidence that chemotherapeutic drugs cause intestinal mucositis leading to reduced life quality; therefore, effective strategies are urgently needed to prevent interruptions to cancer treatment.

Table 1.

Select investigations indicating possible pathobiological mechanisms of chemotherapy-induced mucositis

Authors	Treatment	Cancer Type	Symptomology	Mechanism
Preclinical Studies
Wu et al. 2011 (29)	5FU (200 mg/kg) single dose	Tumor-free	Weight loss, diarrhea	Apoptosis of villi and increased IL1β expression
Yasuda et al. 2012 (26)	5FU (50 mg/kg) 5 consecutive days	Tumor-free	Weight loss, diarrhea	Shortened villi, increased NOX1, ROS, TNFα, and IL1β
Song et al. 2013 (18)	5FU (200 mg/kg) single dose	Tumor-free	Weight loss, diarrhea	Decreased occludin and claudin and increased NF-κB and TNFα
Li et al. 2017 (14)	5FU (50 mg/kg) 3 consecutive days	Tumor-free	Weight loss, diarrhea, bloody stool	Increased IL22, IL6, MCP1, TNFα, IL1β, VCAM1, ICAM1, JAMA, ZO1, p-ERK1/2, p-JNK, p-p38, iNOS, p-NF-κB, and p-I-κB
Sougiannis et al. 2019 (21)	5FU (40 mg/kg) 5 consecutive days	AOM/DSS (CRC)	Weight loss, diarrhea, bloody stool, fatigue	Shortened villi, increased TNFα, MCP1, NOS2, IL6, IL1β, IL10, and FOXP3
Clinical Studies
Bowen et al. 2005 (31)	Various chemotherapy regimens	Various cancer types	N/A	Acute increases in Bax and Bak expression; decreased Mcl1

AOM, azoxymethane; COX2, cyclooxygenase-2; CRC, colorectal cancer; DSS, dextran sodium sulfate; ICAM1, intercellular adhesion molecule 1; IL1β, interleukin 1β; IL6, interleukin 6; FOXP3, forkhead box P3; JAMA, junctional adhesion molecule-A; MCP1, monocyte chemoattractant protein 1; N/A, not available; NF-κB, nuclear factor κ-B; ROS, reactive oxygen species; TNFα, tumor necrosis factor α; 5FU, 5-fluorouracil; VCAM, vascular cell adhesion protein 1; ZO1, zonula occludens-1.

Microbiome

Gut microbiota have recently been implicated in chemotherapy-associated toxicity as demonstrated by their ability to promote gut dysbiosis (i.e., imbalance of gut microbes contributing to disease/symptomology) (8, 14, 21). For instance, increased toxicity of chemotherapy agents including gemcitabine, cyclophosphamide, irinotecan, cisplatin, and 5FU has been linked to disruption of certain gut microbes (34). The majority of this work to date has been performed in nontumor bearing preclinical models—which allow for a more direct interpretation of the specific chemotherapy effects without the interacting effects of a tumor but may compromise clinical translatability. Preclinical studies have reported a drastic shift from commensal bacteria (i.e., Bifidobacterium and Lactobacillus spp.) to Escherichia, Clostridium, and Enterococcus spp. following even a single intraperitoneal dose of 5-FU (35). Mechanistic support for this relationship is provided by the reduced intestinal mucositis and decreased cytokine levels in 5FU-treated mice after antibiotic-induced depletion of microbes (35). A study by Li et al. reported diminished bacterial community richness and diversity, leading to a relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B) ratio following 5FU treatment (14). 5FU also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria (14). Fecal transplant experiments mechanistically linked these effects to mucositis (14). In C57BL/6 mice presenting with chemically induced colon cancer and receiving three cycles of 5 consecutive days of 5FU (35 mg/kg), a positive correlation between increases in Verrucomicrobia and inflammatory markers in the colon, including TNFα, MCP1, nitric oxide synthase 2 (NOS2), IL6, IL1β, and FOXP3 expression, was reported, which was associated with reduced functional outcomes (21). Indeed, the Verrucomicrobia contain the species Akkermansia muciniphila (A. muciniphila), which has been implicated in the onset of multiple proinflammatory consequences to the gut (36, 37). Additionally, this study documented a positive correlation between Proteobacteria and colonic expression of TNFα, MCP1, IL6, IFNγ, IL1β, IL10, FOXP3, and NOS2 (21). If Verrucomicrobia and Proteobacteria play a role in the promotion of mucositis, targeting these phyla may help lower the adverse toxicities common to chemotherapy treatment. Although the available evidence suggests a link between chemotherapy-induced toxicity and gut microbes, the exact bacterial species driving these unwanted side effects are only beginning to be unearthed. Further, inconsistencies stemming from variable dosages and durations of chemotherapy treatment exist and make it difficult to draw firm conclusions based on the available literature (21). Overall, the role of the microbiota in the onset and progression of CIM requires further investigation. Moreover, future investigations into the mechanisms and treatment of intestinal mucositis should consider the effect of an altered microbiome. Ultimately, gut microbes represent a potential therapeutic target for reducing mucositis following chemotherapy and should be further explored (38, 39).

STRATEGIES TO IMPROVE GUT RESILIENCE

The past several decades has seen significant advances in the treatment of cancer. Although many strategies have been investigated to ameliorate the severity of CIM, the advances have done little to lessen the burden of chemotherapeutic drug toxicity. Currently, there are a limited number of medicines that are used to ameliorate some of the common side effects of chemotherapies with varied effectiveness. For examples, antiemetic palonosetron and metoclopramide are used to reduce vomiting, and diosmectite is used to ameliorate diarrhea; however, these medicines have their own side effects. Recent interest has focused on combination drug therapies, natural compounds, and fecal microbiota transplantation (FMT), which are discussed throughout this mini-review. Further, we highlight recent preclinical and clinical investigations that have shown some promise in reducing chemotherapy associated side effects in Table 2. Although not comprehensive, this table indicates the vast potential of using complementary and alternative medicines to improve gut resilience during chemotherapy treatments.

Table 2.

Recent investigations showing benefits of complementary therapeutics and probiotics in ameliorating symptoms of mucositis

Authors	Treatment	Cancer Type	Intervention	Outcome
Preclinical Studies
Yeung et al. 2015 (40)	5FU (30 mg/kg) 5 consecutive days	Cancer-free	L. casei, L. acidophilus, and B. bifidum 1 × 107 CFU	Reduced villus damage and decreased TNFα, IL1β, and IL6 expression
Wang et al. 2020 (41)	5FU (25 mg/kg) and irinotecan (25 mg/kg) 4 consecutive days	Tumor-free	Dihydrotanshinone I (DHTS)	Reduced histopathological scoring, decreased serum IL6 and TNFα
Chang et al. 2020 (8)	FOLFOX	CT-26 Implant	FMT from control mice	Reduced histopathological scoring; increased goblet cells and ZO1; decreased apoptosis and NF-κB; improved microbial diversity
Clinical trials
Karaca et al. 2014 (42)	FOLOFOX-4	CRC	β-glucan 50 mg/day	Decreased oral mucositis and diarrhea
Michael et al. 2004 (43)	Irinotecan	CRC	Activated charcoal, 1,000 mg	Decreased grade 3/4 diarrhea
Österlund et al. 2007 (44)	5FU and leucovorin	CRC	L. rhamnosus, 1–2 × 10,111 CFU + 11 g guargum	Reduced grade 3/4 diarrhea, reduced abdominal discomfort, fewer treatment interruptions/alterations
Mego et al. 2015 (45)	Irinotecan	CRC	C. dophilus 3 capsules per day containing 10 × 109 CFU	Reduced grade 3/4 diarrhea and reduced incidence of enterocolitis
Lee et al. 2014 (46)	Radiotherapy and chemotherapy	CRC	Lacidofil with L. rhamnosus R0011, L. acidophilus R0052 2 × 109 CFU	Decreased IBS and increased in functional health scores

CFU, colony-forming unit; COX2, cyclooxygenase-2; CRC, colorectal cancer; FOLFOX, folinic acid, 5FU, and oxaliplatin; IL1β, interleukin 1β; IL6, interleukin 6; MCP1, monocyte chemoattractant protein 1; N/A, not available; NF-κB, nuclear factor κ-B; ROS, reactive oxygen species; TNFα, tumor necrosis factor α; 5FU, 5-fluorouracil.

Single-Agent versus Combination Therapies

Since the golden age of chemotherapy, combination therapies have been implemented in clinical medicine in an attempt to synergize the antineoplastic and antimitotic effects of these compounds and potentially reduce the severity of intestinal mucositis (47). The most common of these combination therapies being used for GI malignancies are FOLFIRI (5FU, leucovorin, irinotecan) and FOLFOX (5FU, leucovorin, oxaliplatin). Additional commonly prescribed combination therapies are FCR (fludarabine, cyclophosphamide, and rituximab), FEC-T (5FU, epirubicin, cyclophosphamide, and docetaxel), XELOX (oxaliplatin and capecitabine), and BEP (bleomycin, etoposide, and platinum). Cisplatin and 5FU also are commonly given together as a combination therapy. Combination therapies have been shown to produce significant advantages in improving survival over single agents (47). Unfortunately, these combination regimens have done little to reduce chemotherapy-associated toxicity.

Preclinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may affect the outcome of chemotherapy regimens. Despite some promising preclinical data (28), the available clinical results are contradictory and largely disappointing (48, 49). NSAIDs combined with chemotherapy regimens (celecoxib + 5FU and rofecoxib + 5FU + leucovorin) did not improve efficacy or reduce toxicity (48, 49). In fact, disappointingly, increased GI toxicity was reported when NSAIDs were combined with chemotherapy use compared with chemotherapy alone refuting the hypothesis that NSAIDs may prevent chemotherapy-associated mucositis in the clinic (49). Thus, although combination therapies undoubtedly have contributed to improved survival in patients with cancer, they have done little to alleviate the associated side effects. There is an unmet need to identify drugs that effectively treat the toxicity associated with chemotherapies.

Natural Complementary Compounds

Although herbal medicines are commonly used around the world, there are currently no herbal medicines that are standard practice in United States clinics. This is likely due to the lack of available information from controlled studies regarding the safety and efficacy of natural compounds for use with chemotherapy. Nonetheless, both the National Cancer Institute and the National Center for Complementary and Integrative Health recognize the importance of evidence-based complementary medicine modalities that may be integrated as part of standard cancer care for all patients across the cancer continuum; thus, using natural compounds and probiotics to reduce the severity of chemotherapy-associated mucositis has become an area of increasing interest in clinical medicine. Indeed, many natural compounds possess anti-inflammatory activities that render them potentially useful in treating CIM. For example, turmeric (Curcuma longa) administered as a mouth wash (0.004%) to patients with cancer has been reported to improve wound healing and patient compliance in management of radio-chemotherapy-induced oral mucositis in a pilot study (50). Further, 6-gingerol and 6-shogal, the main ingredients in ginger extract (Zingiber officinale), have been shown to reduce severity of 5FU-induced oral ulcerative mucositis and associated pain (51). Quercetin, a natural flavonoid, was reported to reduce the incidence of oral mucositis, in a pilot study of patients receiving chemotherapy for blood malignancies, when given at a dose of 250 mg twice daily for 4 wk. However, it is important to note that it also was reported that severity of CIM was worse in incident cases receiving quercetin (52). Emodin, a trihydroxy-anthraquinone that is found in several Chinese herbs, including Rheum palmatum and Polygonum multiflorum, has been reported to inhibit gemcitabine-induced NF-κB protein expression—a transcription factor that plays a critical role in promotion of mucositis—that resulted in potentiation of the antitumor effects in pancreatic cancer (53). A significant decrease in the incidence of oral mucositis and diarrhea was reported in patients with CRC that consumed 50 mg of β-glucan per day for at least a week concomitant with FOLFOX treatment (42). In another study, 1,000 mg of activated charcoal given to patients with advanced CRC receiving irinotecan (used in FOLFIRI) reduced the incidence of grade 3 to 4 diarrhea, decreased the consumption of antidiarrheal medication, and increased irinotecan dose intensity (43). Collectively, these studies highlight the promise of natural compounds in attenuating the side effects associated with several cancer treatments. However, given the small sample size in many of these studies, findings should be interpreted with caution. Future work should explore further development of these compounds as complementary strategies for chemotherapy using relevant animal models and in clinical studies with larger sample sizes.

Fecal Microbial Transplantation

Fecal microbial transplantation (FMT) has emerged as a potential avenue for treatment of many diseases, and more specifically GI-based complications (40, 41, 44–46). However, work in this area is also still in its infancy. Interestingly, FMT from healthy untreated mice decreased TLR 1, 2, 3, 4, and 5 as well as myeloid differentiation primary response 88 expression in the jejunum of mice receiving FOLFOX, implicating a role for gut microbes in CIM (8). FMT from healthy mice also increased ZO-1 expression and decreased pathological Claudin-2 expression in the jejunum of these same FOLFOX-treated mice (8). In another study, FMT from 5FU-treated mice was reported to impact immune homeostasis by specifically reducing macrophage recruitment to the colon (21). A study by Li et al. linked chemotherapy-associated mucositis to gut microbes using fecal transplant experiments (14). Our understanding of the impact of chemotherapy on the microbiome and conversely the microbiome’s contribution to CIM requires further investigation. However, there is evidence to suggest that FMT can ameliorate the toxic side effects of chemotherapy treatment by reducing certain immune cell populations and improving gut integrity.

CONCLUSIONS AND FUTURE PERSPECTIVES

In the present review, we highlighted the current literature in CIM and emphasize significant advancements in therapeutic strategies that show promise in ameliorating the initiation and progression of intestinal mucositis and its associated symptoms. Despite improvements in cancer treatments and palliative care, intestinal mucositis remains a significant, common clinical challenge in patients with cancer. Understanding the pathobiology of mucositis is essential to developing new approaches to improve patient outcome and survival. However, our understanding of intestinal mucositis and its clinical manifestations remains incomplete given limited access to the gut mucosa and a lack of reliable tests. Indeed, the accumulation of data on the pathobiology of mucositis in tumor-free animal models has progressed our understanding of side effects associated with chemotherapy; however, it is important to continue these studies in tumor-bearing models to understand the interaction with the tumor. Finally, the current pipeline of potential strategies to treat CIM including combinational therapies, natural compounds, and FMT are promising and should be further explored for efficacy in reducing toxicity of cancer therapies.

GRANTS

This work was supported by National Institutes of Health Grants R41AT009964 (to E. A. Murphy) and F31AT009820 (to A. T. Sougiannis).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

A.T.S. prepared figures; A.T.S., B.N.V., J.M.D., D.F., and E.A.M. drafted manuscript; A.T.S., B.N.V., J.M.D., D.F., and E.A.M. edited and revised manuscript; A.T.S., B.N.V., J.M.D., D.F., and E.A.M. approved final version of manuscript.