Pelvic radiotherapy has been frequently reported to cause acute and late onset gastrointestinal (GI) toxicities associated with significant morbidity and mortality. Although the underlying mechanisms of pelvic radiation-induced GI toxicity are poorly understood, they are known to involve a complex interplay between all cell types comprising the intestinal wall. Furthermore, increasing evidence states that the human gut microbiome plays a role in the development of radiation-induced health damaging effects. Gut microbial dysbiosis leads to diarrhea and fatigue in half of the patients. As a result, reinforcement of the microbiome has become a hot topic in various medical disciplines. To counteract GI radiotoxicities, apart from traditional pharmacological compounds, adjuvant therapies are being developed including food supplements like vitamins, prebiotics, and probiotics. Despite the easy, cheap, safe, and feasible approach to protect patients against acute radiation-induced toxicity, clinical trials have yielded contradictory results. In this review, a detailed overview is given of the various clinical, intestinal manifestations after pelvic irradiation as well as the role of the gut microbiome herein. Furthermore, whilst discussing possible strategies to prevent these symptoms, food supplements are presented as auspicious, prophylactic, and therapeutic options to mitigate acute pelvic radiation-induced GI injury by exploring their molecular mechanisms of action.

Pelvic radiotherapy is known to evoke intestinal mucositis and dysbiosis. Currently, there are no effective therapies available to mitigate these injuries, which is partly due to a lack of insight into the events causing mucositis and dysbiosis. Here, the complex interplay between the murine host and its microbiome following pelvic irradiation was mapped by characterizing intestinal mucositis along with extensive 16S microbial profiling. We demonstrated important morphological and inflammatory implications within one day after exposure, thereby impairing intestinal functionality and inducing translocation of intraluminal bacteria into mesenteric lymph nodes as innovatively quantified by flow cytometry. Concurrent 16S microbial profiling revealed a delayed impact of pelvic irradiation on beta diversity. Analysis of composition of microbiomes identified biomarkers for pelvic irradiation. Among them, members of the families Ruminococcaceae, Lachnospiraceae and Porphyromonadaceae were differentially affected. Altogether, our unprecedented findings showed how pelvic irradiation evoked structural and functional changes in the intestine, which secondarily resulted in a microbiome shift. Therefore, the presented in vivo irradiation-gut-microbiome platform allows further research into the pathobiology of pelvic irradiation-induced intestinal mucositis and resultant dysbiosis, as well as the exploration of mitigating treatments including drugs and food supplements.

The radionuclide therapy [¹⁷⁷Lu]Lu-PSMA-617 was recently FDA-approved for treatment of metastatic castration-resistant prostate cancer. Salivary gland toxicity is currently considered as the main dose-limiting side effect. However, its uptake and retention mechanisms in the salivary glands remain elusive. Therefore, our aim was to elucidate the uptake patterns of [¹⁷⁷Lu]Lu-PSMA-617 in salivary gland tissue and cells by conducting cellular binding and autoradiography experiments. Briefly, A-253 and PC3-PIP cells, and mouse kidney and pig salivary gland tissue, were incubated with 5 nM [¹⁷⁷Lu]Lu-PSMA-617 to characterize its binding. Additionally, [¹⁷⁷Lu]Lu-PSMA-617 was co-incubated with monosodium glutamate, ionotropic or metabotropic glutamate receptor antagonists. Low, non-specific binding was observed in salivary gland cells and tissues. Monosodium glutamate was able to decrease [¹⁷⁷Lu]Lu-PSMA-617 in PC3-PIP cells, mouse kidney and pig salivary gland tissue. Kynurenic acid (ionotropic antagonist) decreased the binding of [¹⁷⁷Lu]Lu-PSMA-617 to 29.2 ± 20.6% and 63.4 ± 15.4%, respectively, with similar effects observed on tissues. (RS)-MCPG (metabotropic antagonist) was able to decrease the [¹⁷⁷Lu]Lu-PSMA-617 binding on A-253 cells to 68.2 ± 16.8% and pig salivary gland tissue to 53.1 ± 36.8%. To conclude, we showed that the non-specific binding on [¹⁷⁷Lu]Lu-PSMA-617 could be reduced by monosodium glutamate, kynurenic acid and (RS)-MCPG.

Samarium-153 is a promising theranostic radionuclide, but low molar activities (A_m) resulting from its current production route render it unsuitable for targeted radionuclide therapy (TRNT). Recent efforts combining neutron activation of ¹⁵²Sm in the SCK CEN BR2 reactor with mass separation at CERN/MEDICIS yielded high-A_m ¹⁵³Sm. In this proof-of-concept study, we further evaluated the potential of high-A_m ¹⁵³Sm for TRNT by radiolabeling to DOTA-TATE, a well-established carrier molecule binding the somatostatin receptor 2 (SSTR₂) that is highly expressed in gastroenteropancreatic neuroendocrine tumors. DOTA-TATE was labeled with ¹⁵³Sm and remained stable up to 7 days in relevant media. The binding specificity and high internalization rate were validated on SSTR₂-expressing CA20948 cells. In vitro biological evaluation showed that [¹⁵³Sm]Sm-DOTA-TATE was able to reduce CA20948 cell viability and clonogenic potential in an activity-dependent manner. Biodistribution studies in healthy and CA20948 xenografted mice revealed that [¹⁵³Sm]Sm-DOTA-TATE was rapidly cleared and profound tumor uptake and retention was observed whilst these were limited in normal tissues. This proof-of-concept study showed the potential of mass-separated ¹⁵³Sm for TRNT and could open doors towards wider applications of mass separation in medical isotope production.

Radiotherapy is a commonly employed treatment for colorectal cancer, yet its radiotoxicity-related impact on healthy tissues raises significant health concerns. This highlights the need to use radioprotective agents to mitigate these side effects. This review presents the current landscape of human translational radiobiology, outlining the limitations of existing models and proposing engineering solutions. We delve into radiotherapy principles, encompassing mechanisms of radiation-induced cell death and its influence on normal and cancerous colorectal cells. Furthermore, we explore the engineering aspects of microphysiological systems to represent radiotherapy-induced gastrointestinal toxicity and how to include the gut microbiota to study its role in treatment failure and success. This review ultimately highlights the main challenges and future pathways in translational research for pelvic radiotherapy-induced toxicity. This is achieved by developing a humanized in vitro model that mimics radiotherapy treatment conditions. An in vitro model should provide in-depth analyses of host-gut microbiota interactions and a deeper understanding of the underlying biological mechanisms of radioprotective food supplements. Additionally, it would be of great value if these models could produce high-throughput data using patient-derived samples to address the lack of human representability to complete clinical trials and improve patients’ quality of life.

While dietary supplements can have beneficial effects on the health of the intestine, these effects can come with unresolved issues in terms of therapeutic efficacy and mechanisms of action. In this study, the model probiotic Lacticaseibacillus rhamnosus GG ATCC 53103 and the anciently used dietary supplement Limnospira indica strain PCC 8005 were compared for their effects on murine intestinal ecology. Healthy male mice received either saline or suspensions of living cells of L. indica PCC 8005 or L. rhamnosus GG daily along a two-week intervention period, followed by a two-week washout period. Both bacteria-based solutions appeared able to transiently shift the microbial community, which were characterized by a higher relative abundance of members of the butyrate producing Lachnospiraceae and Porphyromonadaceae families.