Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy

Ferreira, Ana Rita da Silva; Aa, Stijn A.J. van der; Wehkamp, Tjalling; Wardill, Hannah R.; Klooster, Jean Paul ten; Garssen, Johan; Harthoorn, Lucien F.; Hartog, Anita; Harmsen, Hermie J. M.; Tissing, Wim J. E.; Bergenhenegouwen, Jeroen van

doi:10.1038/s41598-021-02308-w

Cited by 6 publications

(4 citation statements)

References 49 publications

(45 reference statements)

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“…In contrast to SCFAs, which have well documented effects on mucosal integrity, immune function and other mechanisms related to GI-M, BCFAs have not been well studied in the context of chemotherapy-side effects, or mucosal integrity. In the context of MTX-induced GI-M, exogenous administration of butyrate mitigated tissue damage by upregulating efflux pathways ( Abcc1 ) to reduce cytotoxic drug load in enterocytes [ 60 ]. Whether this same effect is seen for iso-butyrate remains unclear and warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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“… 174 , 175 Vitamin A and its metabolite, retinoic acid, enhance ISC stemness and promote ISC differentiation, respectively, 176 , 177 whereas vitamin B9 rescues the reduction in cell metabolic activity in small intestinal organoids caused by the chemotherapeutic agent methotrexate. 178 The effects of 1,25-dihydroxyvitamin D3 (vitamin D3) on ISC function are controversial, with studies reporting contrasting impacts. 179 , 180 Vitamin D receptor in enterocytes in the intestine of Drosophila is essential for ISC proliferation and enteroendocrine cell differentiation.…”

Section: Interplay Between Host and Microbiota In Isc Homeostasismentioning

confidence: 99%

Host-microbiota interaction in intestinal stem cell homeostasis

Wu,

Mu,

et al. 2024

Gut Microbes

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Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host–microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.

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“…Since then, several studies have investigated the protective effect of SCFA in both in vitro and in vivo GIM models of several chemotherapeutic agents as well as radiotherapy. For instance, in an in vitro study, SCFAs, mainly butyrate, attenuated methotrexate-induced toxicity in a 3D intestinal organoids model [ 68 ]. In mice treated with 5-FU, Ferreira et al demonstrated that the administration of mixed SCFAs reduced intestinal injury; however, it did not impact intestinal permeability.…”

Section: Scfas and Cancer Treatment Toxicitiesmentioning

confidence: 99%

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

et al. 2022

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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.

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Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy

Cited by 6 publications

References 49 publications

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

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

Host-microbiota interaction in intestinal stem cell homeostasis

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

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