Supporting gut health with medicinal cannabis in people with advanced cancer: potential benefits and challenges.

The side effects of cancer therapy continue to cause significant health and cost burden to the patient, their friends and family, and governments. A major barrier in the way in which these side effects are managed is the highly siloed mentality that results in a fragmented approach to symptom control. Increasingly, it is appreciated that many symptoms are manifestations of common underlying pathobiology, with changes in the gastrointestinal environment a key driver for many symptom sequelae. Breakdown of the mucosal barrier (mucositis) is a common and early side effect of many anti-cancer agents, known to contribute (in part) to a range of highly burdensome symptoms such as diarrhoea, nausea, vomiting, infection, malnutrition, fatigue, depression, and insomnia. Here, we outline a rationale for how, based on its already documented effects on the gastrointestinal microenvironment, medicinal cannabis could be used to control mucositis and prevent the constellation of symptoms with which it is associated. We will provide a brief update on the current state of evidence on medicinal cannabis in cancer care and outline the potential benefits (and challenges) of using medicinal cannabis during active cancer therapy.

Autologous Faecal Microbiota Transplantation to Improve Outcomes of Haematopoietic Stem Cell Transplantation: Results of a Single-Centre Feasibility Study.

Haematopoietic stem cell transplantation (HSCT) is a curative approach for blood cancers, yet its efficacy is undermined by a range of acute and chronic complications. In light of mounting evidence to suggest that these complications are linked to a dysbiotic gut microbiome, we aimed to evaluate the feasibility of faecal microbiota transplantation (FMT) delivered during the acute phase after HSCT. Of note, this trial opted for FMT prepared using the individual's own stool (autologous FMT) to mitigate the risks of disease transmission from a donor stool. Adults (>18 years) with multiple myeloma were recruited from a single centre. The stool was collected prior to starting first line therapy. Patients who progressed to HSCT were offered FMT via 3 × retention enemas before day +5 (HSCT = day 0). The feasibility was determined by the recruitment rate, number and volume of enemas administered, and the retention time. Longitudinally collected stool samples were also collected to explore the influence of auto-FMT using 16S rRNA gene sequencing. n = 4 (2F:2M) participants received auto-FMT in 12 months. Participants received an average of 2.25 (1-3) enemas 43.67 (25-50) mL total, retained for an average of 60.78 (10-145) min. No adverse events (AEs) attributed to the FMT were identified. Although the minimum requirements were met for the volume and retention of auto-FMT, the recruitment was significantly impacted by the logistical challenges of the pretherapy stool collection. This ultimately undermined the feasibility of this trial and suggests that third party (donor) FMT should be prioritised.

The Role of the Innate Immune Response in Oral Mucositis Pathogenesis.

Oral mucositis (OM) is a significant complication of cancer therapy with limited management strategies. Whilst inflammation is a central feature of destructive and ultimately ulcerative pathology, to date, attempts to mitigate damage via this mechanism have proven limited. A relatively underexamined aspect of OM development is the contribution of elements of the innate immune system. In particular, the role played by barriers, pattern recognition systems, and microbial composition in early damage signaling requires further investigation. As such, this review highlights the innate immune response as a potential focus for research to better understand OM pathogenesis and development of interventions for patients treated with radiotherapy and chemotherapy. Future areas of evaluation include manipulation of microbial-mucosal interactions to alter cytotoxic sensitivity, use of germ-free models, and translation of innate immune-targeted agents interrogated for mucosal injury in other regions of the alimentary canal into OM-based clinical trials.

The Association between the Gut Microbiome and Development and Progression of Cancer Treatment Adverse Effects.

Adverse effects are a common consequence of cytotoxic cancer treatments. Over the last two decades there have been significant advances in exploring the relationship between the gut microbiome and these adverse effects. Changes in the gut microbiome were shown in multiple clinical studies to be associated with the development of acute gastrointestinal adverse effects, including diarrhoea and mucositis. However, more recent studies showed that changes in the gut microbiome may also be associated with the long-term development of psychoneurological changes, cancer cachexia, and fatigue. Therefore, the aim of this review was to examine the literature to identify potential contributions and associations of the gut microbiome with the wide range of adverse effects from cytotoxic cancer treatments.

Advanced statistics identification of participant and treatment predictors associated with severe adverse effects induced by fluoropyrimidine-based chemotherapy.

PURPOSE: Adverse effects following fluoropyrimidine-based chemotherapy regimens are common. However, there are no current accepted diagnostic markers for prediction prior to treatment, and the underlying mechanisms remain unclear. This study aimed to determine genetic and non-genetic predictors of adverse effects. METHODS: Genomic DNA was analyzed for 25 single nucleotide polymorphisms (SNPs). Demographics, comorbidities, cancer and fluoropyrimidine-based chemotherapy regimen types, and adverse effect data were obtained from clinical records for 155 Australian White participants. Associations were determined by bivariate analysis, logistic regression modeling and Bayesian network analysis. RESULTS: Twelve different adverse effects were observed in the participants, the most common severe adverse effect was diarrhea (12.9%). Bivariate analysis revealed associations between all adverse effects except neutropenia, between genetic and non-genetic predictors, and between 8 genetic and 12 non-genetic predictors with more than 1 adverse effect. Logistic regression modeling of adverse effects revealed a greater/sole role for six genetic predictors in overall gastrointestinal toxicity, nausea and/or vomiting, constipation, and neutropenia, and for nine non-genetic predictors in diarrhea, mucositis, neuropathy, generalized pain, hand-foot syndrome, skin toxicity, cardiotoxicity and fatigue. The Bayesian network analysis revealed less directly associated predictors (one genetic and six non-genetic) with adverse effects and confirmed associations between six adverse effects, eight genetic predictors and nine non-genetic predictors. CONCLUSION: This study is the first to link both genetic and non-genetic predictors with adverse effects following fluoropyrimidine-based chemotherapy. Collectively, we report a wealth of information that warrants further investigation to elucidate the clinical significance, especially associations with genetic predictors and adverse effects.

Whey-based diet containing medium chain triglycerides modulates the gut microbiota and protects the intestinal mucosa from chemotherapy while maintaining therapy efficacy.

Cytotoxicity (i.e. cell death) is the core mechanism by which chemotherapy induces its anti-cancer effects. Unfortunately, this same mechanism underpins the collateral damage it causes to healthy tissues. The gastrointestinal tract is highly susceptible to chemotherapy's cytotoxicity, resulting in ulcerative lesions (termed gastrointestinal mucositis, GI-M) that impair the functional capacity of the gut leading to diarrhea, anorexia, malnutrition and weight loss, which negatively impact physical/psychological wellbeing and treatment adherence. Preventing these side effects has proven challenging given the overlapping mechanisms that dictate chemotherapy efficacy and toxicity. Here, we report on a novel dietary intervention that, due to its localized gastrointestinal effects, is able to protect the intestinal mucosal from unwanted toxicity without impairing the anti-tumor effects of chemotherapy. The test diet (containing extensively hydrolyzed whey protein and medium chain triglycerides (MCTs)), was investigated in both tumor-naïve and tumor-bearing models to evaluate its effect on GI-M and chemo-efficacy, respectively. In both models, methotrexate was used as the representative chemotherapeutic agent and the diet was provided ad libitum for 14 days prior to treatment. GI-M was measured using the validated biomarker plasma citrulline, and chemo-efficacy defined by tumor burden (cm3/g body weight). The test diet significantly attenuated GI-M (P = 0.03), with associated reductions in diarrhea (P < 0.0001), weight loss (P < 0.05), daily activity (P < 0.02) and maintenance of body composition (P < 0.02). Moreover, the test diet showed significant impact on gut microbiota by increasing diversity and resilience, whilst also altering microbial composition and function (indicated by cecal short and brained chain fatty acids). The test diet did not impair the efficacy of methotrexate against mammary adenocarcinoma (tumor) cells. In line with the first model, the test diet minimized intestinal injury (P = 0.001) and diarrhea (P < 0.0001). These data support translational initiatives to determine the clinical feasibility, utility and efficacy of this diet to improve chemotherapy treatment outcomes.

Baseline gut microbiota composition is associated with oral mucositis and tumour recurrence in patients with head and neck cancer: a pilot study.

PURPOSE: Mounting evidence suggests that the gut microbiome influences radiotherapy efficacy and toxicity by modulating immune signalling. However, its contribution to radiotherapy outcomes in head and neck cancer (HNC) is yet to be investigated. This study, therefore, aimed to uncover associations between an individual's pre-therapy gut microbiota and (i) severity of radiotherapy-induced oral mucositis (OM), and (ii) recurrence risk in patients with HNC. METHODS: In this prospective pilot study, 20 patients with HNC scheduled to receive radiotherapy or chemoradiotherapy were recruited. Stool samples were collected before treatment and microbial composition was analysed using 16S rRNA gene sequencing. OM severity was assessed using the NCI-CTCAE scoring system. Patients were also followed for 12 months of treatment completion to assess tumour recurrence. RESULTS: Overall, 80% of the patients were male with a median age of 65.5 years. Fifty-three percent experienced mild/moderate OM while 47% developed severe OM. Furthermore, 18% experienced tumour relapse within 1 year of treatment completion. A pre-treatment microbiota enriched of Eubacterium, Victivallis, and Ruminococcus was associated with severe OM. Conversely, a higher relative abundance of immunomodulatory microbes Faecalibacterium, Prevotella, and Phascolarctobacterium was associated with a lower risk of tumour recurrence. CONCLUSION: Our results indicate that a patient's gut microbiota composition at the start of treatment is linked to OM severity and recurrence risk. We now seek to validate these findings to determine their ability to predict treatment outcomes in HNC, with the goal of using this data to inform second-generation microbial therapeutics to optimise treatment outcomes for patients with HNC.

Investigation of TLR4 Antagonists for Prevention of Intestinal Inflammation.

Activation of toll-like receptor 4 (TLR4) has been shown to be a major influence on the inflammatory signalling pathways in intestinal mucositis (IM), as demonstrated by TLR4 knock-out mice. Pharmacological TLR4 inhibition has thus been postulated as a potential new therapeutic approach for the treatment of IM but specific TLR4 inhibitors have yet to be investigated. As such, we aimed to determine whether direct TLR4 antagonism prevents inflammation in pre-clinical experimental models of IM. The non-competitive and competitive TLR4 inhibitors, TAK-242 (10 µM) and IAXO-102 (10 µM), respectively, or vehicle were added to human T84, HT-29, and U937 cell lines and mouse colonic explants 1 h before the addition of lipopolysaccharide (LPS) (in vitro: 100 µg/mL; ex vivo: 10 µg/mL), SN-38 (in vitro: 1 µM or 1 nM; ex vivo: 2 µM), and/or tumour necrosis factor-alpha (TNF-α) (5 µg/mL). Supernatant was collected for human IL-8 and mouse IL-6 enzyme-linked immunosorbent assays (ELISAs), as a measure of inflammatory signalling. Cell viability was measured using XTT assays. Explant tissue was used in histopathological and RT-PCR analysis for genes of interest: TLR4, MD2, CD14, MyD88, IL-6, IL-6R, CXCL2, CXCR1, CXCR2. SN-38 increased cytostasis compared to vehicle (P < 0.0001). However, this was not prevented by either antagonist (P > 0.05) in any of the 3 cell lines. Quantitative histological assessment scores showed no differences between vehicle and treatment groups (P > 0.05). There were no differences in in vitro IL-8 (P > 0.05, in all 3 cells lines) and ex vivo IL-6 (P > 0.05) concentrations between vehicle and treatment groups. Transcript expression of all genes was similar across vehicle and treatment groups (P > 0.05). TLR4 antagonism using specific inhibitors TAK-242 and IAXO-102 was not effective at blocking IM in these pre-clinical models of mucositis. This work indicates that specific epithelial inhibition of TLR4 with these compounds is insufficient to manage mucositis-related inflammation. Rather, TLR4 signalling through immune cells may be a more important target to prevent IM.

Structural insight and analysis of TLR4 interactions with IAXO-102, TAK-242 and SN-38: an in silico approach.

Introduction: Toll-like receptor 4 (TLR4) has attracted interest due to its role in chemotherapy-induced gastrointestinal inflammation. This structural study aimed to provide in silico rational of the recognition and potential binding of TLR4 ligands IAXO-102, TAK-242, and SN-38 (the toxic metabolite of the chemotherapeutic irinotecan hydrochloride), which could contribute to rationale development of therapeutic anti-inflammation drugs targeting TLR4 in the gastrointestinal tract. Methods: In silico docking was performed between the human TLR4-MD-2 complex and ligands (IAXO-102, TAK-242, SN-38) using Autodock Vina, setting the docking grids to cover either the upper or the lower bound of TLR4. The conformation having the lowest binding energy value (kcal/mol) was processed for post-hoc analysis of the best-fit model. Hydrogen bonding was calculated by using ChimeraX. Results: Binding energies of IAXO-102, TAK-242 and SN-38 at the upper bound of TLR4-MD-2 ranged between - 3.8 and - 3.1, - 6.9 and - 6.3, and - 9.0 and - 7.0, respectively. Binding energies of IAXO-102, TAK-242 and SN-38 at the lower bound ranged between - 3.9 and - 3.5, - 6.5 and - 5.8, and - 8.2 and - 6.8, respectively. Hydrogen bonding at the upper bound of TLR4/MD-2 with IAXO-102, TAK-242 and SN-38 was to aspartic acid 70, cysteine 133 and serine 120, respectively. Hydrogen bonding at the lower bound of TLR4-MD-2 with IAXO-102, TAK-242 and SN-38 was to serine 528, glycine 480 and glutamine 510, respectively. Conclusion: The in silico rational presented here supports further investigation of the binding activity of IAXO-102 and TAK-242 for their potential application in the prevention of gastrointestinal inflammation caused by SN-38.

5-Fluorouracil Induces an Acute Reduction in Neurogenesis and Persistent Neuroinflammation in a Mouse Model of the Neuropsychological Complications of Chemotherapy.

The neuropsychological symptoms associated with chemotherapy treatment remain a major challenge with their prevention hampered by insufficient understanding of pathophysiology. While long-term neuroimmune changes have been identified as a hallmark feature shared by neurological symptoms, the exact timeline of mechanistic events preceding neuroinflammation, and the relationship between the glial cells driving this neuroinflammatory response, remain unclear. We therefore aimed to longitudinally characterize the neuroimmunological changes following systemic 5-fluorouracil (5-FU) treatment to gain insight into the timeline of events preceding the well-documented chronic neuroinflammation seen following chemotherapy. Eighteen female C57Bl/6 mice received a single intraperitoneal dose of 5-FU and groups were killed at days 1 and 2 (acute timepoint), days 4 and 8 (subacute timepoint), and days 16 and 32 (chronic timepoint). A further six mice were administered with vehicle control with tissues collected from three mice on day 1 and day 32 of the study. The expression of key genes of interest, BCL2, BDNF, TIMP1, MMP-9, MMP-2, TNFα, IL-1ß, and IL-6R were assessed using real time polymerase chain reaction. Levels of neurogenesis were determined through immunofluorescent staining of doublecortin (DCX). The density of microglia and astrocytes were assessed using immunofluorescence staining of Iba1 and GFAP respectively. 5-FU treatment caused significant decreases to DCX staining at acute timepoints (p = 0.0030) which was positively correlated with BCL2 expression levels. An increase to microglial density was observed in the prefrontal cortex (p = 0.0256), CA3 region (p = 0.0283), and dentate gyrus (p = 0.0052) of the hippocampus at acute timepoints. 5-FU caused increases to astrocyte density, across multiple brains regions, at subacute and chronic timepoints which were positively correlated with TNFα, TIMP-1, MMP-2, and IL-6R expression. This study has identified acute objective neuroinflammatory changes suggesting that the role of early intervention should be explored to prevent the development of neuropsychological deficits in the longer-term following chemotherapy.

Contribution of TLR4 to colorectal tumor microenvironment, etiology and prognosis.

PURPOSE: Toll-like receptor 4 (TLR4) is increasingly recognized for its ability to govern the etiology and prognostic outcomes of colorectal cancer (CRC) due to its profound immunomodulatory capacity. Despite widespread interest in TLR4 and CRC, no clear analysis of current literature and data exists. Therefore, translational advances have failed to move beyond conceptual ideas and suggestions. METHODS: We aimed to determine the relationship between TLR4 and CRC through a systematic review and analysis of published literature and datasets. Data were extracted from nine studies that reported survival, CRC staging and tumor progression data in relation to TLR4 expression. Primary and metastatic tumor samples with associated clinical data were identified through the Cancer Genome Atlas (TCGA) database. RESULTS: Systematic review identified heterogeneous relationships between TLR4 and CRC traits, with no clear theme evident across studies. A total of 448 datasets were identified through the TCGA database. Analysis of TCGA datasets revealed TLR4 mRNA expression is decreased in advanced CRC stages (P < 0.05 for normal vs Stage II, Stage III and Stage IV). Stage-dependent impact of TLR4 expression on survival outcomes were also found, with high TLR4 expression associated with poorer prognosis (stage I vs III (HR = 4.2, P = 0.008) and stage I vs IV (HR = 11.3, P < 0.001)). CONCLUSION: While TLR4 mRNA expression aligned with CRC staging, it appeared to heterogeneously regulate survival outcomes depending on the stage of disease. This underscores the complex relationship between TLR4 and CRC, with unique impacts dependent on disease stage.

Gut Microbiota-Derived Short-Chain Fatty Acids: Impact on Cancer Treatment Response and Toxicities.

The gut microbiota has emerged as a key modulator of cancer treatment responses in terms of both efficacy and toxicity. This effect is clearly mediated by processes impacting the activation and modulation of immune responses. More recently, the ability to regulate chemotherapeutic drug metabolism has also emerged as a key driver of response, although the direct mechanisms have yet to be fully elucidated. Through fermentation, the gut microbiota can produce several types of metabolites, including short-chain fatty acids (SCFAs). SCFAs play an important role in maintaining epithelial barrier functions and intestinal homeostasis, with recent work suggesting that SCFAs can modulate response to cancer treatments and influence both anti-tumor immune response and inflammatory-related side effects. In this review, we will discuss the importance of SCFAs and their implications for cancer treatment response and toxicities.

Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity.

INTRODUCTION: Gastrointestinal mucositis (GIM) is a side effect of high-dose irinotecan (CPT-11), causing debilitating symptoms that are often poorly managed. The role of TLR4 in the development of GIM has been clearly demonstrated. We, therefore, aimed to investigate the potential of the TLR4 antagonist, IAXO-102, to attenuate gastrointestinal inflammation as well as supress tumour activity in a colorectal-tumour-bearing mouse model of GIM induced by CPT-11. METHODS: 24 C57BL/6 mice received a vehicle, daily i.p. IAXO-102 (3 mg/kg), i.p. CPT-11 (270 mg/kg) or a combination of CPT-11 and IAXO-102. GIM was assessed using validated toxicity markers. At 72 h, colon and tumour tissue were collected and examined for histopathological changes and RT-PCR for genes of interest; TLR4, MD-2, CD-14, MyD88, IL-6, IL-6R, CXCL2, CXCR1, and CXCR2. RESULTS: IAXO-102 prevented diarrhoea in mice treated with CPT-11. Tumour volume in IAXO-102-treated mice was lower compared to vehicle at 48 h (P < 0.05). There were no differences observed in colon and tumour weights between the treatment groups. Mice who received the combination treatment had improved tissue injury score (P < 0.05) in the colon but did not show any improvements in cell proliferation or apoptotic rate. Expression of all genes was similar across all treatment groups in the tumour (P > 0.05). In the colon, there was a difference in transcript expression in vehicle vs. IAXO-102 (P < 0.05) and CPT-11 vs. combination (P < 0.01) in MD-2 and IL-6R, respectively. CONCLUSION: IAXO-102 was able to attenuate symptomatic parameters of GIM induced by CPT-11 as well as reduce tissue injury in the colon. However, there was no effect on cell proliferation and apoptosis. As such, TLR4 activation plays a partial role in GIM development but further research is required to understand the specific inflammatory signals underpinning tissue-level changes.

Compound Kushen injection reduces severity of radiation-induced gastrointestinal mucositis in rats.

Mucositis, or damage/injury to mucous membranes of the alimentary, respiratory, or genitourinary tract, is the major side effect associated with anticancer radiotherapies. Because there is no effective treatment for mucositis at present, this is a particular issue as it limits the dose of therapy in cancer patients and significantly affects their quality of life. Gastrointestinal mucositis (GIM) occurs in patients receiving radiotherapies to treat cancers of the stomach, abdomen, and pelvis. It involves inflammation and ulceration of the gastrointestinal (GI) tract causing diarrhea, nausea and vomiting, abdominal pain, and bloating. However, there is currently no effective treatment for this debilitating condition. In this study, we investigated the potential of a type of traditional Chinese medicine (TCM), compound Kushen injection (CKI), as a treatment for GIM. It has previously been shown that major groups of chemical compounds found in CKI have anti-inflammatory effects and are capable of inhibiting the expression of pro-inflammatory cytokines. Intraperitoneal administration of CKI to Sprague Dawley (SD) rats that concurrently received abdominal irradiation over five fractions resulted in reduced severity of GIM symptoms compared to rats administered a vehicle control. Histological examination of the intestinal tissues revealed significantly less damaged villus epithelium in CKI-administered rats that had reduced numbers of apoptotic cells in the crypts. Furthermore, it was also found that CKI treatment led to decreased levels of inflammatory factors including lower levels of interleukin (IL)-1ß and IL-6 as well as myeloperoxidase (MPO)-producing cells in the intestinal mucosa. Together, our data indicate a novel effect of CKI to reduce the symptoms of radiation-induced GIM by inhibiting inflammation in the mucosa and apoptosis of epithelial cells.

Role of ErbB1 in the Underlying Mechanism of Lapatinib-Induced Diarrhoea: A Review.

Lapatinib, an orally administered small-molecule tyrosine kinase inhibitor (SM-TKI), is an effective treatment for ErbB2-positive breast cancer. However, its efficacy as one of the targeted cancer therapies has been hampered by several adverse effects, especially gastrointestinal toxicity, commonly manifested as diarrhoea. Although it can be generally tolerated, diarrhoea is reported as the most common and most impactful on a patient's quality of life and associated with treatment interruption. Severe diarrhoea can result in malabsorption, leading to dehydration, fatigue, and even death. ErbB1 is an epidermal growth factor profoundly expressed in normal gut epithelium while lapatinib is a dual ErbB1/ErbB2 tyrosine kinase inhibitor. Thus, ErbB1 inhibition by lapatinib may affect gut homeostasis leading to diarrhoea. Nevertheless, the underlying mechanisms remain unclear. This review article provides evidence of the possible mechanisms of lapatinib-induced diarrhoea that may be related to/or modulated by ErbB1. Insight regarding the involvement of ErbB1 in the pathophysiological changes such as inflammation and intestinal permeability as the underlying cause of diarrhoea is covered in this article.

Antibiotic treatment targeting gram negative bacteria prevents neratinib-induced diarrhea in rats.

BACKGROUND: Neratinib is a pan-ErbB tyrosine kinase inhibitor used for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the main adverse event associated with neratinib treatment. We aimed here to determine whether antibiotic-induced gut microbial shifts altered development of neratinib-induced diarrhea. METHODS: Female Albino Wistar rats (total n = 44) were given antibiotics (vancomycin, neomycin, or a cocktail of vancomycin, neomycin and ampicillin) in drinking water for four weeks, and then treated daily with neratinib (50 mg/kg) for 28 days. Diarrhea, along with markers of gastrointestinal damage and microbial alterations were measured by histopathology and 16S sequencing, respectively. RESULTS: Rats treated with vancomycin or neomycin had significantly lower levels of diarrhea than rats treated with neratinib alone. In the distal ileum, neratinib was associated with a statistically significant increase in histological damage in all treatment groups expect the antibiotic cocktail. Key features included villous blunting and fusion and some inflammatory infiltrate. Differences in microbial composition at necropsy in vehicle control, neratinib and neratinib + neomycin groups, were characterized by a neratinib-induced increase in gram-negative bacteria that was reversed by neomycin. Neomycin shifted bacterial composition so that Blautia become the dominant genus. CONCLUSIONS: Narrow spectrum antibiotics reduced neratinib-induced diarrhea. This suggests that the microbiome may play a key role in the development and prolongation of diarrhea following neratinib treatment, although further research is required to understand the key bacteria and mechanisms by which they reduce diarrhea, as well as how this may impact presentation of diarrhea in clinical cohorts.

Oral-Gut Microbiome Axis in the Pathogenesis of Cancer Treatment-Induced Oral Mucositis.

Oral mucositis (OM) is one of the most common and debilitating oral complications of cancer treatments including chemotherapy, radiotherapy, and hematopoietic stem cell transplantation. It is associated with severe pain and difficulties in chewing, swallowing, and speech. This leads to impairment of basic oral functions and could result in unplanned treatment interruption or modification. As such, OM negatively impacts both patients' quality of life as well as tumor prognostic outcomes. Understanding pathways underlying OM pathogenesis help identify new targets for intervention or prevention. The pathophysiology of OM has been widely studied over past decades with several pathways related to oxidative stress, inflammation, and molecular and cellular signaling being implicated. In this mini-review, we will discuss the emerging role of the oral-gut microbiome axis in the development of OM. Particularly, we will elaborate on how the alterations in the oral and gut microbiota as well as intestinal dysfunction caused by cancer treatments could contribute to the pathogenesis of OM. Further, we will briefly discuss the potential methods for targeting the oral-gut microbiome axis to improve OM outcomes.

Antibiotic-Induced Gut Microbiota Depletion Accelerates the Recovery of Radiation-Induced Oral Mucositis in Rats.

PURPOSE: Due to its pivotal role in the modulation of immune and inflammatory responses, the gut microbiota has emerged as a key modulator of cancer treatment-induced gastrointestinal mucositis. However, it is not clear yet how it affects radiation therapy-induced oral mucositis (OM). As such, this study aimed to explore the gut microbiota's role in the pathogenesis of radiation-induced OM in rats. METHODS AND MATERIALS: Male Sprague Dawley rats were treated with 20 Gy x-ray radiation (Rx) delivered to the snout, with or without antibiotic-induced microbiota depletion (AIMD). OM severity was assessed, and tongue tissues were collected on day 9 and 15 postradiation for tissue injury and inflammatory markers assessment. RESULTS: AIMD+Rx had a significantly shorter duration of severe OM compared with Rx alone group. Macroscopically, the tongue ulcer-like area was smaller in AIMD+Rx compared with the Rx group. Microscopically, a smaller percentage of the mucosal ulcer was observed in the dorsal tongue of AIMD+Rx compared with the Rx group. AIMD+Rx also had significantly lower levels of interleukin 6, interleukin 1 beta, and toll like receptor 4 in the tongue tissues than the Rx group. CONCLUSIONS: The gut microbiota plays a role in OM pathogenesis, mainly in the recovery phase, through the modulation of proinflammatory pathways. Future microbiota-targeted interventions may improve OM in clinical settings.

Smart design approaches for orally administered lipophilic prodrugs to promote lymphatic transport.

Challenges to effective delivery of drugs following oral administration has attracted growing interest over recent decades. Small molecule drugs (<1000 Da) are generally absorbed across the gastrointestinal tract into the portal blood and further transported to the systemic circulation via the liver. This can result in a significant reduction to the oral bioavailability of drugs that are metabolically labile and ultimately lead to ineffective exposure and treatment. Targeting drug delivery to the intestinal lymphatics is attracting increased attention as an alternative route of drug transportation providing multiple benefits. These include bypassing hepatic first-pass metabolism and selectively targeting disease reservoirs residing within the lymphatic system. The particular physicochemical requirements for drugs to be able to access the lymphatics after oral delivery include high lipophilicity (logP>5) and high long-chain triglyceride solubility (> 50 mg/g), properties required to enable drug association with the lipoprotein transport pathway. The majority of small molecule drugs, however, are not this lipophilic and therefore not substantially transported via the intestinal lymph. This has contributed to a growing body of investigation into prodrug approaches to deliver drugs to the lymphatic system by chemical manipulation. Optimised lipophilic prodrugs have the potential to increase lymphatic transport thereby improving oral pharmacokinetics via a reduction in first pass metabolism and may also target of disease-specific reservoirs within the lymphatics. This may provide advantages for current pharmacotherapy approaches for a wide array of pathological conditions, e.g. immune disease, cancer and metabolic disease, and also presents a promising approach for advanced vaccination strategies. In this review, specific emphasis is placed on medicinal chemistry strategies that have been successfully employed to design lipophilic prodrugs to deliberately enable lymphatic transport. Recent progress and opportunities in medicinal chemistry and drug delivery that enable new platforms for efficacious and safe delivery of drugs are critically evaluated.