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 (0–2days), 2) upregulation and activation of messengers (2–3days), 3) signal amplification (2–5days), 4) ulceration with inflammation (5–14days), and 5) healing (14–21days; Fig. 1) (10, 19). Typically, following initiation (0–2days), 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 (2–5days) 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 2–5days 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.

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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 (200mg/kg) single dose	Tumor-free	Weight loss, diarrhea	Apoptosis of villi and increased IL1β expression
Yasuda et al. 2012 (26)	5FU (50mg/kg) 5 consecutive days	Tumor-free	Weight loss, diarrhea	Shortened villi, increased NOX1, ROS, TNFα, and IL1β
Song et al. 2013 (18)	5FU (200mg/kg) single dose	Tumor-free	Weight loss, diarrhea	Decreased occludin and claudin and increased NF-κB and TNFα
Li et al. 2017 (14)	5FU (50mg/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 (40mg/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

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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.

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 250mg twice daily for 4wk. 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 50mg of β-glucan per day for at least a week concomitant with FOLFOX treatment (42). In another study, 1,000mg 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.