Dietary oat bran can offset chronic gastrointestinal damage caused by radiotherapy

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Loved or hated, the humble oat could be the new superfood for cancer patients as international research shows a diet rich in fiber could significantly reduce radiation-induced gut inflammation.

Conducted by the University of Gothenburg, Lund University and the University of South Australia, the preclinical study found that dietary oat bran can offset chronic gastrointestinal damage caused by radiotherapy, contradicting long-held clinical recommendations.

Gastroenterology and oncology researcher UniSA’s Dr. Andrea Stringer says the research provides critical new insights for radiology patients.

“Cancer patients are often advised to follow a restricted fiber diet. This is because a diet high in fiber is believed to exacerbate bloating and diarrhea – both common side effects of radiotherapy,” Dr. Stringer says.

“Yet, this advice is not unequivocally evidence-based, with insufficient fiber potentially being counterproductive and exacerbating gastrointestinal toxicity.

Our study compared the effects of high-fiber and no-fiber diets, finding that a fiber-free diet is actually worse for subjects undergoing radiotherapy treatment.

A diet without fiber generates inflammatory cytokines which are present for a long time following radiation, resulting in increased inflammation of the digestive system.

Conversely, a fiber-rich diet decreases the presence of cytokines to reduce radiation-induced inflammation, both in the short and the long term.”

Intestinal issues following radiotherapy are problematic for many cancer survivors.

“In Europe, approximately one million pelvic-organ cancer survivors suffer from compromised intestinal health due to radiation-induced gastrointestinal symptoms,” Dr. Stringer says.

“This is also commonplace in Australia and around the world with no immediate cure or effective treatment. If we can prevent some of inflammation resulting from radiation simply by adjusting dietary fiber levels, we could improve long-term, and possibly life-long, intestinal health among cancer survivors.”


Radiotherapy plays an important role in cancer treatments with curative or palliative intent. In many countries, more than half of cancer patients undergo radiotherapy at some point during the disease trajectory [1,2].

Despite the fact that new conformal technologies have improved radiotherapy treatment, the dose of ionizing radiation delivered to the normal surrounding tissues is still substantial. Therefore, as cure rates for cancer have improved, the number of cancer survivors who experience radiation-induced gastrointestinal symptoms has also increased manyfold [3].

In Europe, roughly one million pelvic-organ cancer survivors suffer from compromised intestinal health due to radiation-induced gastrointestinal symptoms. Acute gastrointestinal symptoms are experienced at 1 to 2 weeks after the commencement of radiotherapy [4].

The acute side effects are usually transient, and some of the symptoms subside within 2–6 weeks from the end of the radiotherapy. Diarrhea and uncomfortable flatulence are the most common acute gastrointestinal side effects experienced by the patients undergoing pelvic radiotherapy [5,6].

Chronic side effects occur months to years or even decades after radiotherapy and are characterized by diarrhea, intestinal dysmotility, fecal incontinence, malabsorption, tenesmus, steatorrhea, urgency, blood discharge, mucus discharge, and excessive production of odorous gases [7,8].

Radiation-induced acute side effects may be due to the disruption of the epithelial barrier, crypt cell death, mucosal inflammation, and the accumulation of inflammatory cells [9,10]. Several studies have shown that ionizing radiation induces the synthesis of various pro-inflammatory and fibrogenic cytokines by several different tissues, including the intestines [11,12,13,14,15,16].

Cytokines regulate the immune system and inflammation via a complex and highly coordinated signaling cascade. Resident immune cells are the first immune cells to respond to irradiation by producing pro-inflammatory cytokines, chemokines, and growth factors [17].

The early immune response is mediated through the secretion of the pro-inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, which in turn activate the resident immune cells, e.g., macrophages and lymphocytes [18]. Increased levels of IL-1, IL-6, and TNF-α are found in the plasma samples of patients soon after irradiation [19,20].

Chemokines also play important roles in recruiting circulating neutrophils, macrophages, lymphocytes, and eosinophils to the radiation-damaged site [17]. This further enhances the ongoing inflammatory processes. It has been shown that the cascade of pro-inflammatory and pro-fibrotic cytokines that is produced immediately after irradiation may persist for weeks to months until the tissue becomes fibrotic [16,21,22].

Molecular evidence also indicates that a “cytokine cascade” with a distinct temporal pattern exists between the early and late effects of irradiation [16].

The health benefits of dietary fiber have been acknowledged for decades [23,24]. Studies have shown that dietary fiber may increase the number of crypts in the colon, thereby decreasing intestinal atrophy and increasing intestinal mass [25].

Dietary fiber increases the nutritional status of the colonic mucosa by increasing the levels of short-chain fatty acids (SCFAs) produced by the gut microbiota [26]. Dietary fiber has also been shown to decrease the permeability of the intestinal mucus and to decrease the levels of serum pro-inflammatory cytokines [27,28].

Despite the known health benefits of dietary fiber, patients may be advised to follow a low-fiber diet during the course of radiotherapy [29,30]. This advice, which is aimed at reducing the frequency of diarrhea and other acute gastrointestinal symptoms, is not unequivocally evidence-based [30].

Hence, the recommendation made to the patients to lower their fiber intake may be counterproductive and may exacerbate gastrointestinal toxicity in these patients. The underlying pathophysiological processes responsible for the beneficial effects of dietary fibers are not completely understood.

Apart from health benefits, fibers from oat bran have also been shown to have immunomodulatory effects [31]. Therefore, we measured serum cytokine levels in an experimental mouse model of pelvic radiotherapy to investigate the influence of a fiber-rich bioprocessed oat bran diet on radiation-induced inflammation.

Discussion
Preclinical and clinical studies have shown that pelvic radiotherapy increases cytokine levels soon after irradiation, and that this plays an important role in radiation-induced gastrointestinal toxicity [38,39,40]. However, long-term studies of post-irradiation cytokine profiles are scarce.

The main goal of the present study was to evaluate whether a fiber-rich bioprocessed oat bran diet can modify radiation-induced inflammation. We show that a No-fiber diet generates an abundance of circulating pro-inflammatory cytokines for at least 18 weeks after the irradiation, indicating an exacerbation of radiation-induced inflammation. In contrast, a fiber-rich bioprocessed oat bran diet causes decreased levels of pro-inflammatory cytokines, indicating the mitigation of radiation-induced inflammation.

Our data also indicate that radiation-induced inflammation is a long-term phenomenon that, at least in mice, persists for several months without resolving.

With the advent of new technologies, a high dose of radiation can be delivered to the tumor site. Our experimental model of pelvic radiotherapy is unique in that we irradiated the mice with the same clinical linear accelerator (LINAC) that is used to irradiate cancer patients [41].

Thus, high-energy photons can be delivered to a highly defined area, thereby avoiding undesirable irradiation of non-target organs. Our previous study showed that irradiation with 8 Gy × 4 fractions was best suited for our model as it inflicted similar pathologic changes in the mouse intestinal mucosa, notably crypt degeneration, as seen in a cancer survivor’s intestinal mucosa irradiated at the pelvic region [41,42].

Furthermore, these mice appear to maintain their overall health and a normal lifespan despite having received high doses of irradiation. Therefore, our model is suitable for studying the long-term effects of irradiation, given that radiation-induced symptoms in patients may persist for decades after the initial radiotherapy [43,44].

At all-time points, the metrics concerning cytokines and chemokines are consistent with the notion of an irradiation effect. At 1 week post-irradiation, increased levels of IL-1α were seen in the mice subjected to irradiation, as compared to their respective control group.

Similar results have been shown in previous studies, where increased levels of IL-1α have been reported in both mice and rats subjected to irradiation [9,16]. IL-1α is a pro-inflammatory cytokine that is mainly produced by activated macrophages, neutrophils, epithelial cells, and endothelial cells.

It is also involved in the acute-phase response to radiation-induced injury and plays an important role in tissue remodeling by inducing fibrosis, as IL-1α has key activities in the regulation of fibroblast proliferation and connective tissue production [20,45].

Irradiation also caused increased IL-2 levels in the mice fed the No-fiber diet. Increased levels of IL-2 have been reported in patients with radiation-induced proctitis [46]. IL-2 is secreted by activated T lymphocytes and is involved in T-helper cell proliferation.

The increased levels of IL-2 in the No-fiber irradiated mice are an indication that the cytotoxic T cell-mediated immune mechanism may have a role in the pathogenesis of radiation-induced inflammation.

At 6 weeks post-irradiation, increased levels of G-CSF were observed in the irradiated mice fed a No-fiber diet, as compared to the non-irradiated control mice. G-CSF is a potent hematopoietic factor that enhances the survival and differentiation of myeloid lineage cells [47].

It is known to act in the generation, mobilization, and function of neutrophils, which are key innate immune cells that protect against invading microbes [48,49,50]. In accordance with our results, the levels of G-CSF have been found to be increased during radiotherapy in patients with prostate cancer [51].

At 18 weeks post-irradiation, increased levels of GM-CSF were seen in the mice fed the No-fiber diet and subjected to irradiation, as compared to the control mice. Similarly, increased levels of IL-1α, IL-3, IL-12p40, IL-12p70, MIP-1β, and TNF-α were observed in both the irradiated groups, as compared to their respective control groups.

These findings indicate that radiation-induced inflammation is a long-term process, contradicting the notion that radiation-induced inflammation is an acute process that gets resolved within a short period [40].

The health benefits of oat bran have been recognized for decades [52,53]. The bioprocessed oat bran used in the present study contains 52% fiber, of which 28% is β-glucan having a molecular weight of around 100 kDa. Beta-glucan can modulate both adaptive and innate immunity.

Beta-glucan is a potent activator of the innate immune system including macrophages, neutrophils and cytotoxic lymphocytes such as natural killer (NK) cells. Oat beta-glucan enhances resistance towards various bacterial, protozoal, and viral infections by its ability to activate macrophages, thereby enhancing host immune defense [54,55].

Dietary fiber may alter the microbiota composition and increase the production of beneficial short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate. Butyrate is known to exert anti-inflammatory effects through the modulation of NF-κB activation [56]. Apart from dietary fiber, oat bran also contains a large variety of bioactive components, including phenolic acids and avenanthramides, which may also contribute to its physiological effects.

Mice fed with a fiber-rich bioprocessed oat bran diet had lower levels of cytokines and chemokines compared to the mice fed a No-fiber diet, even in the absence of ionizing irradiation. The effects of dietary fiber on the non-irradiated animals were examined at the 1-week time point.

The High-oat control group had lower levels of pro-inflammatory cytokines and chemokines, such as IL-1β, IL-12p70, KC, MIP-1α, and MIP-1β, and the anti-inflammatory cytokine IL-10, as compared to the No-fiber control group. Oat bran has been previously shown to decrease the levels of IL-1β, KC, MIP-1α, and IL-10 [57,58,59,60].

Oat beta-glucan has also been previously shown to decrease the mRNA and protein expression of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in mice suffering from dextran sulfate sodium (DSS)-induced ulcerative colitis [57]. IL-12p70, mainly produced by dendritic cells, macrophages, neutrophils, and B cells, is important for the growth and differentiation of B and T cells, as well as in the proliferation of natural killer (NK) cells.

The IL-12 level is an indicator of the intensity of colonic inflammation [61]. KC is predominantly secreted by macrophages, neutrophils, and epithelial cells and has neutrophil chemoattractant activity. MIP-1α is a chemoattractant for macrophages, monocytes, and neutrophils, while MIP-1β attracts NK cells, monocytes, and a variety of immune cells.

IL-10, which is produced by Th2 cells, cluster of differentiation (CD) 8+ T cells and B cells, and macrophages, is a potently immunosuppressive cytokine, repressing the expression of cytokines, such as TNF-α, IL-6, and IL-1 by activated macrophages [62].

At 6 weeks post-irradiation, there were no clear differences in cytokine levels between the non-irradiated control groups. However, at 18 weeks post-irradiation, the High-oat control group showed decreased levels of IL-17 and MCP-1, when compared to the No-fiber control group.

IL-17 is mainly produced by Th17 cells and is involved in both acute and chronic inflammation. Patients with inflammatory bowel disease (IBD) have increased levels of IL-17 [63]. High-fiber diet has previously been shown to decrease the serum IL-17 levels in a murine model of autoimmune hepatitis [64].

MCP-1 is a chemokine that promotes the recruitment of immune cells, such as monocytes, T cells, and dendritic cells, to sites of inflammation that appear following either tissue injury or infection. Wheat arabinoxylan has been previously shown to decrease the production of MCP-1 by dendritic cells [59].

Bioprocessed oat bran diet decreased the levels of cytokines in the irradiated mice at all time points. At 1 week post-irradiation, the High-oat irradiated group had lower levels of IL-3 and IL-13, as compared to the No-fiber irradiated group. IL-3 is produced by activated T cells and basophils. The level of IL-3 has been correlated with fatigue in patients with prostate cancer who were receiving radiotherapy [65]. IL-13, which is secreted mainly by Th2 cells, is upregulated by irradiation and is a key factor in the progression of radiation-induced fibrosis [66,67].

At 6 weeks post-irradiation, the High-oat irradiated group had lower levels of IL-12p40 than the No-fiber irradiated group. The main source of IL-12p40 is T cells, and it activates both T and NK cells. At 18 weeks post-irradiation, the High-oat irradiated group had lower levels of IL-1β, GM-CSF, IFN-γ, eotaxin, IL-4, IL-9, and IL-10, as compared to the No-fiber irradiated group.

IL-1β is secreted primarily by monocytes and macrophages, as well as by non-immune cells, such as fibroblasts and endothelial cells. Several studies have shown that IL-1β is a major mediator of radiation-induced intestinal damage, and that the administration of an IL-1 receptor antagonist leads to reduced intestinal injury [68,69].

IL-1β is also responsible for exacerbating mucositis by causing the disruption of tight junctions in the intestines of mice [70]. GM-CSF is secreted by macrophages, T cells, mast cells, NK cells, endothelial cells, and fibroblasts.

The level of serum GM-CSF has been shown to increase post-irradiation [71]. IFN-γ is mainly produced by NK cells and Th1 cells as part of the innate immune response. Irradiation increases the levels of IFN-γ, whereas cereal fiber has been shown to decrease IFN-γ levels [72,73]. Eotaxin is a chemokine that is responsible for the chemotaxis of eosinophils. Abdominal irradiation has been shown to increase the expression of eotaxin, which plays a critical role in radiation-induced fibrosis [74].

IL-4 is a pleiotropic cytokine that is mainly produced by activated Th2 cells, mast cells, and basophils. It has been shown that the levels of IL-4 increases post-irradiation in patients with prostate cancer, and has been implicated in radiation-induced fibrosis [75,76].

Similar to our results, cereal fiber has been shown to decrease the levels of IL-4 in the sera of healthy persons [73]. Arabinoxylan extracted from rice bran has also been shown to inhibit the production of IL-4 by bone marrow-derived mast cells [77]. IL-9 is predominantly secreted by a subset of CD4+ T cells called Th9 cells and is involved in the pathogenesis of IBD. It causes disruption of the intestinal barrier, thereby enhancing bacterial translocation into the mucosa, and inhibits intestinal wound healing [78].

Overall, the levels of 5/23, 1/23, and 13/23 cytokines were found to be significantly lower in the High-oat irradiated group than in the No-fiber irradiated group at 1, 6, and 18 weeks post-irradiation, respectively.

These results indicate that a fiber-rich diet helps to decrease radiation-induced inflammation not only acutely, but also in the longer term, and thereby might help in reducing late radiation-induced toxicity. Moreover, we also show that a lack of dietary fiber increases the levels of pro-inflammatory cytokines in animals that have not been subjected to irradiation.

This is important when one considers that patients with already aggravated inflammatory states are at extremely high risk of developing severe acute and late toxicities after pelvic radiotherapy [79]. Thus, reducing an already existing inflammatory state through dietary interventions is of potential interest.

In addition, the chronic effects of inflammation are associated with high morbidity and mortality in patients receiving radiotherapy. Similar results emerged from our IPA analysis, in which the canonical pathways and biological functions or diseases that are upregulated by irradiation appear to be downregulated by the High-oat diet, as compared to the No-fiber diet.

The IPA data from all the time points reveal that the oat bran diet downregulated high mobility group box 1 (HMGB1) and triggering receptor expressed on myeloid cells-1 (TREM1) signaling pathways compared to No-fiber diet after irradiation. Both HMGB1 and TREM1 signaling pathways have been shown to promote inflammatory responses.

HMGB1 acts as an inducer to activate macrophages and leukocytes and promotes the production of inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 [80]. TREM1 can activate myeloid cells to release inflammatory cytokines including TNF-α, IL-1β, and IL-6 [81]. Taken together, our mouse model data indicate that an oat bran-containing diet protects against the harmful effects of irradiation by reducing radiation-induced inflammation, which in contrast may be exacerbated by the No-fiber diet.

Conclusions
Elevated serum cytokine levels were found in mice at 1, 6, and 18 weeks after irradiation, indicating that radiation-induced inflammation is a long-term phenomenon.

A diet without fiber increased the production of pro-inflammatory cytokines for many months after the irradiation.

In contrast, a fiber-rich oat bran diet resulted in decreased cytokine levels, thereby appearing to reduce the acute, intermediate, and chronic radiation-induced inflammation.

Moreover, the fiber-rich diet appeared to downregulate the canonical pathways and biological functions or diseases that were upregulated by the irradiation, as compared to the fiber-free diet. Therefore, a diet high in fiber could help to reduce radiation-induced inflammation, whereas the absence of it may exacerbate radiation-induced inflammation. Based on these results in mice, it could be advisable to conduct clinical dietary interventions to confirm if patients undergoing radiotherapy would also benefit from a high-fiber diet during their treatment.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468988/


More information: Piyush Patel et al. Dietary Oat Bran Reduces Systemic Inflammation in Mice Subjected to Pelvic Irradiation, Nutrients (2020). DOI: 10.3390/nu12082172

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