| 1. |
- Alin, Rebecca, 1989, et al.
(författare)
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A Preparatory Study for a Randomized Controlled Trial of Dietary Fiber Intake During Adult Pelvic Radiotherapy
- 2021
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Ingår i: Frontiers in Nutrition. - : Frontiers Media SA. - 2296-861X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients undergoing pelvic radiotherapy are often advised to omit fiber-rich foods from their diet to reduce the adverse effects of treatment. Scientific evidence supporting this recommendation is lacking, and recent studies on animals and humans have suggested that there is a beneficial effect of dietary fiber for the alleviation of symptoms. Randomized controlled studies on dietary fiber intake during pelvic radiotherapy of sufficient size and duration are needed. As preparation for such a large-scale study, we evaluated the feasibility, compliance, participation rate, and logistics and report our findings here in this preparatory study. Methods: In this preparatory study of a fiber intervention trial, Swedish gynecological cancer patients scheduled for radiotherapy were recruited between January 2019 and August 2020. During the intervention, the participants filled out questionnaires and used an application. They also consumed a fiber supplement at first in powder form, later in capsules. Blood- and fecal samples were collected. The study is registered in clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT04534075?cond=fidura&draw=2&rank=1). Results: Among 136 approached patients, 57 started the study and the participation rate for primary outcomes was 63% (third blood sample) and 65% (third questionnaire). Barely half of the participants provided fecal samples. Providing concise and relevant information to the patients at the right time was crucial in getting them to participate and stay in the study. The most common reasons for declining participation or dropping out were the expected burden of radiotherapy or acute side effects. Tailoring the ambition level to each patient concerning the collection of data beyond the primary endpoints was an important strategy to keep the dropout rate at an acceptable level. Using capsules rather than psyllium in powder form made it much easier to document intake and to create a control group. During the course of the preparatory study, we improved the logistics and for the last 12 participants included, the participation rate was 100% for the earliest primary outcome. Conclusion: A variety of adjustments in this preparatory study resulted in an improved participation rate, which allowed us to set a final protocol and proceed with the main study.
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| 2. |
- Bandaru, Sashidar, et al.
(författare)
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Targeting filamin A reduces macrophage activity and atherosclerosis. : Filamin A in atherogenesis
- 2019
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Ingår i: Circulation. - 1524-4539. ; 140:1, s. 67-79
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Tidskriftsartikel (refereegranskat)abstract
- The actin-binding protein FLNA (filamin A) regulates signal transduction important for cell locomotion, but the role of macrophage-specific FLNA during atherogenesis has not been explored.We analyzed FLNA expression in human carotid atherosclerotic plaques by immunofluorescence. We also produced mice with Flna-deficient macrophages by breeding conditional Flna-knockout mice ( Flna o/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter ( LC). Atherosclerosis in vivo was studied by transplanting bone marrow from male Flna o/fl/ LC mice to atherogenic low-density lipoprotein receptor-deficient ( Ldlr-/-) mice; and by infecting Flna o/fl and Flna o/fl/ LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Furthermore, C57BL/6 mice were infected with AdPCSK9 and then treated with the calpain inhibitor calpeptin to inhibit FLNA cleavage.We found that macrophage FLNA expression was higher in advanced than in intermediate human atherosclerotic plaques. Flna o/fl/ LC macrophages proliferated and migrated less than controls; expressed lower levels of phosphorylated AKT and ERK1/2; exhibited reduced foam cell formation and lipid uptake; and excreted more lipids. The deficiency of Flna in macrophages markedly reduced the size of aortic atherosclerotic plaques in both Ldlr-/-BMT: Flnao/fl/LC and AdPCSK9-infected Flna o/fl/ LC mice. Intima/media ratios and numbers of CD68-positive macrophages in atherosclerotic plaques were lower in Flna-deficient mice than in control mice. Moreover, we found that STAT3 interacts with a calpain-cleaved carboxyl-terminal fragment of FLNA. Inhibiting calpain-mediated FLNA cleavage with calpeptin in macrophages reduced nuclear levels of phosphorylated STAT3, interleukin 6 secretion, foam cell formation, and lipid uptake. Finally, calpeptin treatment reduced the size of atherosclerotic plaques in C57BL/6 mice infected with AdPCSK9.Genetic inactivation of Flna and chemical inhibition of calpain-dependent cleavage of FLNA impaired macrophage signaling and function, and reduced atherosclerosis in mice, suggesting that drugs targeting FLNA may be useful in the treatment of atherosclerosis.
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| 3. |
- Bull, Cecilia, 1977, et al.
(författare)
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Role of dietary fiber in safeguarding intestinal health after pelvic radiotherapy
- 2021
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Ingår i: Current Opinion in Supportive and Palliative Care. - : Ovid Technologies (Wolters Kluwer Health). - 1751-4258. ; 15:3, s. 180-187
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Tidskriftsartikel (refereegranskat)abstract
- Purpose of review Damage to healthy bowel tissue during pelvic radiotherapy can produce devastating and life-long changes in bowel function. The surging interest in microbiota and its importance for our wellbeing has generated a bulk of research highlighting how the food we consume impacts bowel health and disease. Dietary fiber is known to promote bowel health, yet there is a limited number of studies on dietary fiber in connection to pelvic radiotherapy. Here, we review some of the literature on the subject and present the most recent publications in the field. Recent findings Advice given concerning dietary fiber intake during and after pelvic radiotherapy are inconsistent, with some clinics suggesting a decrease in intake and others an increase. Recent animal studies provide a solid support for a protective role of dietary fiber with regards to intestinal health after pelvic radiotherapy, mainly through its impact on the microbiota. No clinical study has yet provided unambiguous evidence for a similar function of dietary fiber in humans undergoing pelvic radiotherapy. There is a lack of evidence behind the dietary advice given to cancer survivors suffering from radiation-induced bowel dysfunction, and high-quality and well powered studies with long follow-up times are needed.
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| 4. |
- Devarakonda, Sravani, et al.
(författare)
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Dietary Fiber and the Hippocampal Neurogenic Niche in a Model of Pelvic Radiotherapy
- 2021
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522. ; 475, s. 137-147
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Tidskriftsartikel (refereegranskat)abstract
- sought to determine whether radiation to the colorectum had an impact on parameters of hippocampal neurogenesis and, if so, whether it could be modulated by a fiber-rich diet. Male C57BL/6J mice were fed a diet containing bioprocessed oat bran or a fiber-free diet, starting two weeks before colorectal irradiation with 4 fractions of 8 Gray or sham-irradiation. Diets were then continued for 1, 6 or 18 weeks, whereafter parameters of hippocampal neurogenesis were analyzed and correlated to serum cytokine levels. No statistically significant changes in neuronal markers or cell proliferation were found at one week post-irradiation. Six weeks postirradiation there was a decreased cell proliferation in the subgranular zone that appeared slightly more pronounced in irradiated animals on a fiber-free diet and increased numbers of immature neurons per mm2 dentate gyrus in the irradiated mice, with a statistically significant increase in mice on a fiber-rich diet. Microglial abundancy was similar between all groups. 18 weeks post-irradiation, a fiber-free diet had reduced the number of immature neurons, whereas irradiation resulted in an increase. Despite this, the population of mature neurons was stable. Analysis of serum cytokines revealed a negative correlation between MIP1-a and the number of immature neurons one week after irradiation, regardless of diet. Our findings show that pelvic radiotherapy has the potential to cause a long-lasting impact on hippocampal neurogenesis, and dietary interventions may modulate this impact. More in-depth studies on the relationship between irradiation-induced intestinal injury and brain health are warranted. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 5. |
- Devarakonda, Sravani
(författare)
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lntestinal health after pelvic radiotherapy - towards understanding persisting pathophysiological mechanisms
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pelvic cancer survivors struggle with life-long symptoms caused by radiotherapy. Many pelvic cancer survivors live with a constant fear of leaking faeces and the need to always have a toilet within reach. Some of these survivors are forced to retire early and live in social isolation. Radiotherapy saves lives, but radiation-induced damage to intestinal tissue close to, or within, the radiation field causes permanent changes in the cancer survivor’s bowel habits. Our goal was to understand the pathogenic mechanisms that continue to cause symptoms even decades after the treatment. By irradiating the mouse colorectum using the clinic’s linear accelerator for radiotherapy, we have developed a novel model that mimics the human pathophysiological condition in the irradiated colorectal mucosa. The model was used to investigate whether the intake of dietary fiber, known to promote intestinal health, could modulate radiation-induced normal-tissue damage (Paper I). Our findings revealed that dietary fiber modified several intestinal pathophysiological processes and repair mechanisms following irradiation, most notably preventing a late, possibly chronic, bacterial invasion and reducing signs of inflammation. Dietary fiber appeared to also modulate parameters of neurogenesis in the brain following radiotherapy-induced injury to the colorectum, suggesting a connection between intestinal health after radiotherapy and brain health (Paper II). To translate the preclinical findings on inflammation to clinic, a biopsy-study was performed in cancer survivors up to 20 years after pelvic radiotherapy (Paper III). A low-grade chronic intestinal inflammation was observed after pelvic radiotherapy, as evidenced by an elevated neutrophil presence and activity. Inadequate mucus protection was also found, possibly leading to increased pathogen infiltration. These results challenge the notion that pelvic radiotherapy causes acute intestinal inflammation that either heals, or causes tissue to become fibrotic without further inflammation. In conclusion, this thesis demonstrates that the mucosal resilience to radiotherapy may be modulated by quite simple means, such as dietary approaches. Moreover, protecting intestinal health after radiotherapy may also protect brain health. The thesis also demonstrates the presence of a chronic, low-grade inflammation in the intestinal mucosa after pelvic radiotherapy, possibly driven by infiltrating bacteria due to a poor mucus protection. The findings can have implications for future approaches to safeguarding intestinal health while providing effective pelvic cancer therapy.
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| 6. |
- Devarakonda, Sravani, et al.
(författare)
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Low-grade intestinal inflammation two decades after pelvic radiotherapy.
- 2023
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Ingår i: EBioMedicine. - 2352-3964. ; 94
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors.We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection.942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration.Our results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors.This study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow's foundation (MA and VP).
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| 7. |
- Malipatlolla, Dilip, 1990, et al.
(författare)
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A fiber-rich diet and radiation-induced injury in the murine intestinal mucosa
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Dietary fiber is considered a strong intestinal protector, but we do not know whether dietary fiber protects against the long-lasting mucosal damage caused by ionizing radiation. To evaluate whether a fiber-rich diet can ameliorate the long-lasting pathophysiological hallmarks of the irradiated mucosa, C57BL/6J mice on a fiber-rich bioprocessed oat bran diet or a fiber-free diet received 32 Gray in four fractions to the distal colorectum using a linear accelerator and continued on the diets for one, six or 18 weeks. We quantified degenerating crypts, crypt fission, cell proliferation, crypt survival, macrophage density and bacterial infiltration. Crypt loss through crypt degeneration only occurred in the irradiated mice. Initially, it was most frequent in the fiber-deprived group but declined to levels similar to the fiber-consuming group by 18 weeks. The fiber-consuming group had a fast response to irradiation, with crypt fission for growth or healing peaking already at one week post-irradiation, while crypt fission in the fiber-deprived group peaked at six weeks. A fiber-rich diet allowed for a more intense crypt cell proliferation, but the recovery of crypts was eventually lost by 18 weeks. Bacterial infiltration was a late phenomenon, evident in the fiber-deprived animals and intensified manyfold after irradiation. Bacterial infiltration also coincided with a specific proinflammatory serum cytokine profile. In contrast, mice on a fiber-rich diet were completely protected from irradiation-induced bacterial infiltration and exhibited a similar serum cytokine profile as sham-irradiated mice on a fiber-rich diet. Our findings provide ample evidence that dietary fiber consumption modifies the onset, timing and intensity of radiation-induced pathophysiological processes in the intestinal mucosa. However, we need more knowledge, not least from clinical studies, before this finding can be introduced to a new and refined clinical practice.
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| 8. |
- Malipatlolla, Dilip, 1990, et al.
(författare)
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Long-term mucosal injury and repair in a murine model of pelvic radiotherapy
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. A comprehensive understanding of the long-term injury dynamics is prevented in available animal models. With linear accelerators that are used to treat cancer in patients, we irradiated a small volume encompassing the colorectum in mice with four fractions of 8 Gy per fraction. We then determined the long-term dynamics of mucosal injury, repair, and the duration of inflammation. We show that crypt fission, not cell proliferation, is the main long-term mechanism for rescuing crypt density after irradiation, and provides a potentially wide window for clinical interventions. Persisting macrophage aggregations indicate a chronic mucosal inflammation. A better understanding as to how crypt fission is triggered and why it fails to repair fully the mucosa may help restore bowel health after pelvic radiotherapy. Moreover, anti-inflammatory interventions, even if implemented long after completed radiotherapy, could promote bowel health in pelvic cancer survivors.
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| 9. |
- Patel, Piyush, et al.
(författare)
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Dietary oat bran reduces systemic inflammation in mice subjected to pelvic irradiation
- 2020
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- Patients undergoing radiotherapy to treat pelvic-organ cancer are commonly advised to follow a restricted fiber diet. However, reducing dietary fiber may promote gastrointestinal inflammation, eventually leading to deteriorated intestinal health. The goal of this study was to evaluate the influence of dietary fiber on radiation-induced inflammation. C57BL/6J male mice were fed a High-oat bran diet (15% fiber) or a No-fiber diet (0% fiber) and were either irradiated (32 Gy delivered in four fractions) to the colorectal region or only sedated (controls). The dietary intervention started at 2 weeks before irradiation and lasted for 1, 6, and 18 weeks after irradiation, at which time points mice were sacrificed and their serum samples were assayed for 23 cytokines and chemokines. Our analyses show that irradiation increased the serum cytokine levels at all the time points analyzed. The No-fiber irradiated mice had significantly higher levels of pro-inflammatory cytokines than the High-oat irradiated mice at all time points. The results indicate that a fiber-rich oat bran diet reduces the intensity of radiation-induced inflammation, both at an early and late stage. Based on the results, it seems that the advice to follow a low-fiber diet during radiotherapy may increase the risk of decreased intestinal health in cancer survivors. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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| 10. |
- Salimi, Reza, et al.
(författare)
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Blocking the cleavage of filamin A by calpain inhibitor decreases tumor cell growth
- 2018
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Ingår i: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 38:4, s. 2079-2085
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Tidskriftsartikel (refereegranskat)abstract
- Filamin A (FLNA) is the most abundant and widely expressed isoform of filamin in human tissues. It is cleaved by calpain at the hinge 1 and 2 domains, producing a 90-kDa carboxyl-terminal fragment (FLNACT). Recently, it has been shown that FLNACTmediates cell signaling and transports transcription factors into the cell nucleus. However, the significance of cleavage of FLNA by calpain has not been studied in cancer cell growth. Calpeptin is a chemical inhibitor of both calpain 1 and 2 that cleaves FLNA. In this study, we questioned if inhibiting calpain using calpeptin would decrease tumor cell proliferation, migration, invasion, and colony formation.Human melanoma (A7), prostate cancer (PC3), mouse fibrosarcoma (T241) and endothelial (MS1) cells were assayed for proliferation, migration, invasion and colony formation after treatment with calpeptin. Cell lysates were immunoblotted for FLNA and FLNACTResults: Calpeptin treatment of these cells resulted in a decreased production of FLNACTCalpeptin-treated human and mouse tumor cells displayed impaired proliferation, migration, and colony formation.These data suggest that the cleavage of FLNA by calpain is an important cellular event in the regulation of tumor cell growth.
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| 11. |
- Voss, Ulrikke, et al.
(författare)
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Effects of dietary fibers on the tuft cell population in the mouse colon post radiation
- 2019
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1365-2982 .- 1350-1925. ; 31:S4, s. 150-150
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Pelvic radiation therapy is often associated with gastrointestinal dysfunction. Intestinal tuft cell located within the mucosal epithelium have in the small intestine following full body radiation in mice been shown to be essential for epithelial regeneration. Dietary approaches during and after radiation therapy have also been suggested to aid epithelial health and function. Tuft cells are suggested to be important for translation of chemosensory signals in the lumen. This study investigated the effects of dietary fiber composition on tuft cell numbers in the colon at 1, 6 and 18 weeks post radiation.
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| 12. |
- Voss, Ulrikke, et al.
(författare)
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Irradiation Induces Tuft Cell Hyperplasia and Myenteric Neuronal Loss in the Absence of Dietary Fiber in a Mouse Model of Pelvic Radiotherapy
- 2022
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Ingår i: Gastroenterology Insights. - : MDPI AG. - 2036-7422. ; 13:1, s. 87-102
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Tidskriftsartikel (refereegranskat)abstract
- Pelvic radiotherapy is associated with chronic intestinal dysfunction. Dietary approaches, such as fiber enrichment during and after pelvic radiotherapy, have been suggested to prevent or reduce dysfunctions. In the present paper, we aimed to investigate whether a diet rich in fermentable fiber could have a positive effect on radiation-induced intestinal damage, especially focusing on tuft cells and enteric neurons. Male C57BL/6 mice were fed either a purified non-fiber diet or the same purified diet with 5% or 15% oat fiber added, starting two weeks prior to sham-irradiation or irradiation with four fractions of 8 Gray. The animals continued on the diets for 1, 6 or 18 weeks, after which the gross morphology of the colorectum was assessed together with the numbers of enteric neurons, tuft cells and crypt-surface units. The results showed that dietary fiber significantly affected the intestinal morphometrics, both in the short and long-term. The presence of dietary fiber stimulated the re-emergence of crypt-surface unit structures after irradiation. At 18 weeks, the animals fed with the non-fiber diet displayed more myenteric neurons than the animals fed with the dietary fibers, but irradiation resulted in a loss of neurons in the non-fiber fed animals. Irradiation, but not diet, affected the tuft cell numbers, and a significant increase in tuft cells was found 6 and 18 weeks after irradiation. In conclusion, dietary fiber intake has the potential to modify neuronal pathogenesis in the colorectum after irradiation. The long-lasting increase in tuft cells induced by irradiation may reflect an as yet unknown role in the mucosal pathophysiology after pelvic irradiation. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
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