Your browser does not fully support modern features. Please upgrade for a smoother experience.
Radiation Impacts Microbiota Compositions: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor: Irene Maier

The composition of the gut microbiota represents an early indicator of chronic post-radiation side-effects in elderly bone and immunogenic traits of the gastrointestinal homeostasis. Fecal microbiota analyses revealed that the relative abundances of Bacteroides massiliensis, Muribaculum sp., or Prevotella denticola were different between conventional microbiota (CM) and anti-inflammatory restricted microbiota (RM). The murine RM was found conditional on mucosa-associated dysbiosis under both, disturbances of interleukin (IL)-17 signaling, and exposure to radiation alone. The hypothesis that intestinal microbiota induced alterations in DNA repair and expressed transforming growth factor (TGF)-β in the small intestine is discussed, thereby impacting bone microstructure and osteoblast dysfunction in silicon ion (1.5 Gy 28Si ions of 850 MeV/u) irradiated mice. Bacterial microbiota compositions influenced therapeutic approaches, correlated with clinical outcomes in radiotherapy and were associated with alterations of the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infections during the last global pandemics.

  • TGF-beta
  • radiation
  • small intestine
  • enteropathy
  • antitumor immunity

1. Introduction

Bacterial indicator phylotypes (BIPs), which were associated with double-stranded DNA breaks in peripheral blood, were depleted in CM mucosa cells and increased in irradiated CM mice after exposure to sub-lethal dose of high-linear energy transfer (high-LET) radiation [1]. Contrarily, two of the bacteria which researchers identified in RM were enhanced by particle-beam radiation, namely Muribaculum intestinale and an unidentified Gram-negative bacterium. An unidentified Bacteroidetes was directly correlated with trabecular thickness (Tb.Th) in anti-IL-17 neutralized and radiation-exposed mice, but inversely decreased with body weight in anti-IL-17 treated sham mice [2][3], thus reflecting tibiae bone microarchitecture and cell immunity (Scheme 1). Moreover, microbiota restriction reduced inflammatory tumor necrosis factor (TNF) in bone marrow, and chemokine (C-C motif) ligand 20 (CCL20) in marrow compared to small intestine upon anti-IL-17 treatment. Double-stranded DNA breaks in blood lymphocytes were associated with the anti-inflammatory intestinal microbiota in both, wild-type RM mice and aged RM mice deficient of ataxia-telangiectasia-mutated [2], in which kynurenic acid (a tryptophan metabolite) was found elevated in feces [4]. Treatment with anti-IL-17 antibodies revealed TGF-β in their bone marrow, but not in irradiated RM mice, indicating reprogrammed immune suppression by activated regulatory T cells (Tregs) in RM. These findings indicated a key role of intestinal microbiota in bearing autoantigens that were inductive for rheumatoid arthritis [5][6], bone loss [7], and osteoporosis [8].
Microbiolres 14 00048 sch001 550
Scheme 1. Microbiota Restriction Improved Bone Micro-architecture.
Prior research confirmed antitumor innate immunity in RM mice and a phenotype which was indicative of hypoxia-inducible factor (HIF)-1 mediated effects [9], IL-12 activation, and macrophage polarization [10]. The naïve CD4+ T cell subset was functionally distinguished in restricted flora mice from specific pathogen-free (SPF) mice by increased activation-induced cell death [11]. Gut microbiota restrictions (restricted flora was defined as RM in the immune-genotoxicity model [12] and compared with SPF) revealed similar memory CD4+ and CD8+ T cell levels, whereas IL-12-expressing CD11chigh dendritic cells (DC) were 2.7-fold increased in RM versus SPF mice; attributable with certain commensal bacteria in RM in comparison to the immunity of SPF mice [12][13]. Fujiwara, D. and colleagues compared the low effect of SPF versus RM on the systemic status of DC populations. Due to commensal bacteria, plasmacytoid DC (pDC) were selectively deficient in spleen and mesenteric lymph nodes (MLN), accompanied by an increased prevalence of myeloid DC (mDC) and T cells with a proinflammatory phenotype. These data provide evidence that, through direct action on newly differentiated mDC, RM stimulated mDC maturation and IL-12 production [13]. Memory, and also activated, CD8+ T cells were expanded in restricted flora mice and suspected to induce depleted invariant natural killer T (iNKT) cells [14]. The pDC deficiency in restricted flora mice was reversed by depletion of CD8+ T cells and in mice lacking perforin function [13][14]. Indeed, iNKT cell numbers were restored in restricted flora mice bearing the CD8α(−/−) genotype; or in adult wild-type mice bearing RM, acutely depleted with anti-CD8 antibodies [14]. However, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)–induced activation of splenic effector CD4+ T cells was significantly suppressed in mice reared under germ-free conditions. The same reduced activation of effector CD4+ T cells was achieved when mice were treated with broad-spectrum antibiotics, compared with mice having conventional microflora, and a phenotype with reduced intratumoral accumulation of CD3+ tumor-infiltrating lymphocytes (TIL), T-helper(h)1 cells, and cytotoxic T lymphocytes (CTLs). As a result, interventions with anti-CTLA-4 monoclonal antibodies (mAb) lost therapeutic efficacy against established sarcomas, melanomas, and colon cancers in mice with a change of intestinal microbiota [15]. Next, cytotoxic CD8+ cells were experimentally blocked with antibodies, and the mucosal compartment in the murine colon then analyzed for higher abundance of certain species of Bacteroides and Turicibacter, and of Barnesiella in the small intestine [16]. A ‘T cell receptor-like’ activation of autoimmunity was stimulated via receptor activator of nuclear factor-κB ligand (RANKL) by subsequent activation of bone marrow osteoclasts [17].

2. Different Gut Microbiota Can Both Negatively and Positively Impact Radiation-Induced Bone Loss

Gut bacterium Bacteroides massiliensis correlated higher relative bone volume in tibiae in IL-17 suppressed RM mice . Whereas Bacteroidetes was found directly correlated with trabecular thickness (Tb.Th) in anti-IL-17 neutralized and radiation-exposed mice, Turicibacter sp. was found directly correlated with trabecular spacing (Tb.Sp) in solely anti-IL-17 treated mice [3]. Only Lachnospiraceae correlated systemic genotoxicity in female irradiated RM [2], whose increased activity was seen in cigarette smoke-exposed mice along with altered immune factors [18] but were not changed in abundance in CM due to ionizing radiation. Neutralizing anti-IL-17 antibodies revealed high levels of TGF-β in the bone marrow of RM mice that were reduced by heavy ion radiation, delivered as a single fraction of 1.5 Gy (28Si ions, 850 MeV/u). Likewise, IL-17 in CM mice was reduced by irradiation in the small intestine. Anti-IL-17 treated adult mice showed hardly any micronuclei formation in normochromatic erythroblasts at six hours postirradiation (CM < RM) [2]. The expression of pro-osteoclastogenic TNF genes, however, was interrogated and reported to be enhanced by radiation-induced genotoxicity [19]. Yu M, et al. confirmed TNF being relevant for the bone catabolic activity of parathyroid hormone and demonstrated that low-calcium diet led to bone resorption, high bone turnover, and impaired bone trabecular microarchitecture in bones [8], such as the hard palate, mandible, vertebrae, femur, and proximal tibia [8][20]. Blocking IL-1 [21] showed that IL-1β was a major driver of radiation bone sensitivity [3], as well as IL-1 was associated with tissue damage [21], and microbiota with enhanced expression of TNF-α in irradiated bone marrow. By contrast, particle radiation reduced TGF-β in the absence of peripheral IL-17 in RM mice, particularly in females [2] — to prevent pro-osteoclastogenic IL-17 in chronic inflammation-associated cancer [22]. TGF-β controlled osteoblast-specific gene expression in cooperation of runt-related transcription factor 2 (Runx2) and mothers against decapentaplegic homolog 5 (Smad5) signaling with bone morphogenic protein 2 [23].
CM mice (females) showed higher expression of interferon (IFN)-γ in the small intestine and a lower level in blood [2]. Relative to tibiae basal thickness, researchers measured differences in the mean cortical thickness in irradiated CM mice (−15%) versus irradiated RM mice (−9.2%) by ex vivo micro-computed tomography [2][3]. Higher trabecular bone volume fraction and improved bone morphologies were assessed in anti-IL-17 treated RM mice compared with anti-IL-17 treated CM mice. Researchers showed a direct impact of antibody intervention at the early timepoints within two days postirradiation; but the resulting feedback upregulation of IL-17 in non-irradiated control mice at the time of three weeks after anti-IL-17 treatment suspected significantly reduced TGF-β by irradiation in mice with intestinal microbiota restriction. Increased TGF-β was measured in peripheral blood in RM and higher gene expression of proinflammatory cytokines in the small intestine in irradiated RM mice [2], along the lines of protected small intestinal crypt stem cells [24][25][26] or matrilysin expression [27]. Studies explored gain-in-function mutations for structural interactions among proteins of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family and TGF-β signaling genes to promote colorectal adenocarcinomas. Feces from mice with defects in TGF-β signaling had increased abundance of Clostridium septicum and decreased abundance of beneficial bacteria, such as B. vulgatus and Parabacteroides distasonis [28]. More recently, Mucispirillum and Clostridium species were demonstrated being adaptively modified with the rather low radiation-induced genotoxicity in blood lymphocytes in CM males, or the downregulated TGF-β level in blood [2]. Taken together, crucial roles of RM have been considered which made mice radiation susceptible, whereas higher trabecular numbers and bone volume parameters were detected in both non-radiated and irradiated mice. Colonization of mice by a defined mix of Clostridium strains provided an environment rich in TGF-β and affected Foxp3+ Treg numbers and function in the colon [2][29]. Oral inoculation of Clostridium during the early life challenged conventionally reared mice and resulted in resistance to colitis and systemic immunoglobulin (Ig) E responses in adult mice [29].

3. SARS-CoV-2 Infections Impact Radio-Immunogenic Responses of the Gastrointestinal Tract

Given the high risk of the worldwide coronavirus spread to reinforce COVID-19 disease, low-dose radiation which has been described for the determination of relative biological effectiveness (RBE) on thoracic [30] and intestinal radiation [31], was tested on thirty COVID-19 pneumonia patients as low-dose radiotherapy (LDRT, <0.5 Gy) [32] that induced anti-inflammatory effects [33][34]. Paraoxonase-1 (PON1)-related variables and cytokines were analyzed in serum samples and reported concerning their relationship with the clinical and radiological characteristics of patients with COVID-19 pneumonia. One week after LDRT, 83% of patients had lower PON1 and TGF-β1 concentrations compared with 24-h after LDRT, PON1 specific activity increased, lactate dehydrogenase, and C-reactive protein decreased, and CD4+ and CD8+ cells increased after one week, whereas respiratory function improved [32]. In Japanese cancer patients compared with health care workers, the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies did not differ between the cancer patients and health care worker groups; however, findings suggested that systemic therapies, including chemotherapy and immune checkpoint inhibitors, lowered N (nucleocapsid)-IgG or S (spike)-IgG levels against SARS-CoV-2 in cancer patients, with immune checkpoint inhibitor treatment showing less impact on the infection immune response [35]. Across 34 human cancers, interferon-stimulated genes and T cell-inflamed interferon signatures in tumor and normal tissues correlated with angiotensin-converting enzyme 2 (ACE2) [36], the cell receptor for SARS-CoV and SARS-CoV-2 [37], which itself was negatively correlated with angiogenesis and TGF-β [36]. For various types of cancers, including lung cancer [38], ACE2 expression increased with the potential risk of cancers to SARS-CoV-2 infection [39] and correlated bacterial microbiota, but were inconsistent in associations between ACE2 and type II transmembrane serine protease (TMPRSS2) in the presence of viruses (HPV, Epstein-Barr virus, and hepatitis B virus) or tissue microbiota [36]. Collectively, the SARS-CoV-2 infection was associated with human enterocytes' pathology [40] as well as reduced bacterial diversity and virus-specific lower relative abundance of beneficial symbionts in gut microbiota [41]. Lately, for colon adenocarcinoma and stomach adenocarcinoma, 1093 commensal microbiotas were correlated; and these cancers assessed as the two tumor types with the strongest and most prevalent positive correlation of ACE2 and TMPRSS2 gene expression with abundance of specific bacteria taxa, respectively. Chlamydia was the top microbiota among 75 taxa that positively correlated with ACE2 in colon adenocarcinoma (p = 0.81, FDR-adjusted p < 0.0001), and also kidney cancers correlated with ACE2 and microbiota [36]. Taken together, various tumor types and tissues were susceptible to SARS-CoV-2 [39] and immunotherapy aggravated SARS-CoV-2 antibody responses among cancer patients [35]. Another immune-related response SARS-CoV-2 with possible variation due to tumors, is antibody-dependent cellular cytotoxicity (ADCC) [42] addressing glycan targeting [43]. The activated subset of effector cells, mostly NK cells [44][45], was known for antitumor activity [46].
There is currently no data available if a combined effect between ADCC to virus-infected cells and radiation was achieved after conventional radiotherapy (RT), or supported by LDRT and microbiota changes after SARS-CoV-2 infection [47][48][49]. Tissue TGF-β expression followed conventional RT and pulsed low-dose rate radiation [50]. Coupled complex photobiomodulation, applying low-level light therapy, and probiotic interventions controlled the microbiome [51][52], improved viral clearance [53], as well as the activity of the immune system, the release of chemokines, and thus saved the lives of people with immune imbalances. In general, the last COVID-19 pandemics urged for the development of innovative treatments to successfully interact with the microbiota and the human immune system in the coronavirus crisis [51]. In the sense of reducing the risk for secondary cancers after RT, most bacterial strains that were mentioned to function anti-inflammatory or to reduce infection cytokines and chemokine CXCL8, were tested positive for medical antiviral effects on one of the viruses infecting the respiratory tract [54][55]. Gut, lung [56] and oral microbiota [57] composition influenced and reflected the severity of COVID-19 [49][56][58]. The probiotics mixture VSL#3 dampened proinflammatory and chemokine production, but accelerated restitution in the absence of a functional mucus layer and regeneration. Gut permeability mediated by the short-chain fatty acid (SCFA) acetate was remarkedly improved in the colons of these mice [59]. Consistently, SARS-CoV-2 impaired SCFA acetate and L-Isoleucine biosynthesis [60], whereas SARS-CoV-2-associated gut microbiota alteration promoted pathogenesis of colorectal cancer [61][62], predominantly through lower abundance of Faecalibacterium, Clostridium, and Eubacterium [62].
Taken together, it remains uncertain how intestinal homeostasis maintains physiological integrity or prevents gastrointestinal tumorigenesis: Reduced abundances of members of the bacterial taxa Bacteroidales, the commensal Muribaculum intestinale, and an expansion in Lactobacilli in the ileal microbiome were most notably investigated with the onset of Crohn’s disease and inflammatory bowel disease [63], implying that those were bacteria that impart a proinflammatory protection of cellular metabolism and redox homeostasis to acquire reducing agents for DNA-biosynthesis [64]. TGF-β1, a radiation injury marker [65] and mitigator [66], and glutamine were shown to promote secretory IgA independently from the method of B cell activation [67] and through intestinal microbiota [68], respectively.

This entry is adapted from the peer-reviewed paper https://doi.org/10.3390/microbiolres14020048

References

  1. Maier, I.; Berry, D.M.; Schiestl, R.H. Intestinal microbiota reduces genotoxic endpoints induced by high-energy protons. Radiat. Res. 2014, 181, 45–53.
  2. Maier, I.; Liu, J.; Ruegger, P.M.; Deutschmann, J.; Patsch, J.M.; Helbich, T.H.; Borneman, J.; Schiestl, R.H. Intestinal bacterial indicator phylotypes associate with impaired DNA double-stranded break sensors but augmented skeletal bone micro-structure. Carcinogenesis 2020, 41, 483–489.
  3. Maier, I.; Ruegger, P.M.; Deutschmann, J.; Helbich, T.H.; Pietschmann, P.; Schiestl, R.H.; Borneman, J. Particle Radiation Side-Effects: Intestinal Microbiota Composition Shapes Interferon-γ-Induced Osteo-Immunogenicity. Radiat. Res. 2022, 197, 184–192.
  4. Cheema, A.K.; Maier, I.; Dowdy, T.; Wang, Y.; Singh, R.; Ruegger, P.M.; Borneman, J.; Fornace, A.J., Jr.; Schiestl, R.H. Chemopreventive Metabolites Are Correlated with a Change in Intestinal Microbiota Measured in A-T Mice and Decreased Carcinogenesis. PLoS ONE 2016, 11, e0151190.
  5. Maeda, Y.; Kurakawa, T.; Umemoto, E.; Motooka, D.; Ito, Y.; Gotoh, K.; Hirota, K.; Matsushita, M.; Furuta, Y.; Narazaki, M.; et al. Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine. Arthritis Rheumatol. 2016, 68, 2646–2661.
  6. Sato, K.; Suematsu, A.; Okamoto, K.; Yamaguchi, K.; Morishita, Y.; Kadono, Y.; Tanaka, S.; Kodama, T.; Akira, S.; Iwakura, Y.; et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 2006, 203, 2673–2682.
  7. Sjogren, K.; Engdahl, C.; Henning, P.; Lerner, U.H.; Tremaroli, V.; Lagerquist, M.K.; Bäckhed, F.; Ohlsson, C. The gut microbiota regulates bone mass in mice. J. Bone Miner. Res. 2012, 27, 1357–1367.
  8. Yu, M.; Tyagi, A.M.; Li, J.-Y.; Adams, J.; Denning, T.L.; Weitzmann, N.M.; Jones, R.M.; Pacifici, R. PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells. Nat. Commun. 2020, 11, 468.
  9. Masoud, G.N.; Wang, J.; Chen, J.; Miller, D.; Li, W. Design, Synthesis and Biological Evaluation of Novel HIF1α Inhibitors. Anticancer Res. 2015, 35, 3849–3859.
  10. Wynn, T.A.; Barron, L. Macrophages: Master regulators of inflammation and fibrosis. Semin. Liver Dis. 2010, 30, 245–257.
  11. Huang, T.; Wei, B.; Velazquez, P.; Borneman, J.; Braun, J. Commensal microbiota alter the abundance and TCR responsiveness of splenic naïve CD4+ T lymphocytes. Clin. Immunol. 2005, 117, 221–230.
  12. Yamamoto, M.L.; Maier, I.; Dang, A.T.; Berry, D.; Liu, J.; Ruegger, P.M.; Yang, J.I.; Soto, P.A.; Presley, L.L.; Reliene, R.; et al. Intestinal bacteria modify lymphoma incidence and latency by affecting systemic inflammatory state, oxidative stress, and leukocyte genotoxicity. Cancer Res. 2013, 73, 4222–4232.
  13. Fujiwara, D.; Wei, B.; Presley, L.L.; Brewer, S.; McPherson, M.; Lewinski, M.A.; Borneman, J.; Braun, J. Systemic control of plasmacytoid dendritic cells by CD8+ T cells and commensal microbiota. J. Immunol. 2008, 180, 5843–5852.
  14. Wei, B.; Wingender, G.; Fujiwara, D.; Chen, D.Y.H.; McPherson, M.; Brewer, S.; Borneman, J.; Kronenberg, M.; Braun, J. Commensal microbiota and CD8+ T cells shape the formation of invariant NKT cells. J. Immunol. 2010, 184, 1218–1226.
  15. Vetizou, M.; Pitt, J.M.; Daillère, R.; Lepage, P.; Waldschmitt, N.; Flament, C.; Rusakiewicz, S.; Routy, B.; Roberti, M.P.; Duong, C.P.; et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015, 350, 1079–1084.
  16. Presley, L.L.; Wei, B.; Braun, J.; Borneman, J. Bacteria associated with immunoregulatory cells in mice. Appl. Environ. Microbiol. 2010, 76, 936–941.
  17. Takayanagi, H.; Kim, S.; Koga, T.; Nishina, H.; Isshiki, M.; Yoshida, H.; Saiura, A.; Isobe, M.; Yokochi, T.; Inoue, J.; et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 2002, 3, 889–901.
  18. Allais, L.; Kerckhof, F.M.; Verschuere, S.; Bracke, K.R.; De Smet, R.; Laukens, D.; Van den Abbeele, P.; De Vos, M.; Boon, N.; Brusselle, G.G.; et al. Chronic cigarette smoke exposure induces microbial and inflammatory shifts and mucin changes in the murine gut. Environ. Microbiol. 2016, 18, 1352–1363.
  19. Alwood, J.S.; Shahnazari, M.; Chicana, B.; Schreurs, A.S.; Kumar, A.; Bartolini, A.; Shirazi-Fard, Y.; Globus, R.K. Ionizing Radiation Stimulates Expression of Pro-Osteoclastogenic Genes in Marrow and Skeletal Tissue. J. Interferon Cytokine Res. 2015, 35, 480–487.
  20. Shen, V.; Birchman, R.; Xu, R.; Lindsay, R.; Dempster, D.W. Short-term changes in histomorphometric and biochemical turnover markers and bone mineral density in estrogen-and/or dietary calcium-deficient rats. Bone 1995, 16, 149–156.
  21. Gerassy-Vainberg, S.; Blatt, A.; Danin-Poleg, Y.; Gershovich, K.; Sabo, E.; Nevelsky, A.; Daniel, S.; Dahan, A.; Ziv, O.; Dheer, R.; et al. Radiation induces proinflammatory dysbiosis: Transmission of inflammatory susceptibility by host cytokine induction. Gut 2018, 67, 97–107.
  22. Hemdan, N.Y. Anti-cancer versus cancer-promoting effects of the interleukin-17-producing T helper cells. Immunol. Lett. 2013, 149, 123–133.
  23. Lee, K.S.; Kim, H.J.; Li, Q.L.; Chi, X.Z.; Ueta, C.; Komori, T.; Wozney, J.M.; Kim, E.G.; Choi, J.Y.; Ryoo, H.M.; et al. Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol. Cell Biol. 2000, 20, 8783–8792.
  24. Ruifrok, A.C.; Mason, K.A.; Lozano, G.; Thames, H.D. Spatial and temporal patterns of expression of epidermal growth factor, transforming growth factor alpha and transforming growth factor beta 1-3 and their receptors in mouse jejunum after radiation treatment. Radiat. Res. 1997, 147, 1–12.
  25. Booth, D.; Haley, J.D.; Bruskin, A.M.; Potten, C.S. Transforming growth factor-B3 protects murine small intestinal crypt stem cells and animal survival after irradiation, possibly by reducing stem-cell cycling. Int. J. Cancer 2000, 86, 53–59.
  26. Potten, C.S.; Booth, D.; Haley, J.D. Pretreatment with transforming growth factor beta-3 protects small intestinal stem cells against radiation damage in vivo. Br. J. Cancer 1997, 75, 1454–1459.
  27. Polistena, A.; Johnson, L.B.; Röme, A.; Wittgren, L.; Bäck, S.; Osman, N.; Molin, G.; Adawi, D.; Jeppsson, B. Matrilysin expression related to radiation and microflora changes in murine bowel. J. Surg. Res. 2011, 167, e137–e143.
  28. Gu, S.; Zaidi, S.; Hassan, M.I.; Mohammad, T.; Malta, T.M.; Noushmehr, H.; Nguyen, B.; Crandall, K.A.; Srivastav, J.; Obias, V.; et al. Mutated CEACAMs Disrupt Transforming Growth Factor Beta Signaling and Alter the Intestinal Microbiome to Promote Colorectal Carcinogenesis. Gastroenterology 2020, 158, 238–252.
  29. Atarashi, K.; Tanoue, T.; Shima, T.; Imaoka, A.; Kuwahara, T.; Momose, Y.; Cheng, G.; Yamasaki, S.; Saito, T.; Ohba, Y.; et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011, 331, 337–341.
  30. Gueulette, J.; Slabbert, J.P.; Böhm, L.; De Coster, B.M.; Rosier, J.F.; Octave-Prignot, M.; Ruifrok, A.; Schreuder, A.N.; Wambersie, A.; Scalliet, P.; et al. Proton RBE for early intestinal tolerance in mice after fractionated irradiation. Radiother. Oncol. 2001, 61, 177–184.
  31. Gueulette, J.; Bohm, L.; Slabbert, J.P.; De Coster, B.M.; Rutherfoord, G.S.; Ruifrok, A.; Octave-Prignot, M.; Binns, P.J.; Schreuder, A.N.; Symons, J.E.; et al. Proton relative biological effectiveness (RBE) for survival in mice after thoracic irradiation with fractionated doses. Int. J. Radiat. Oncol. Biol. Phys. 2000, 47, 1051–1058.
  32. Rodríguez-Tomàs, E.; Acosta, J.C.; Torres-Royo, L.; De Febrer, G.; Baiges-Gaya, G.; Castañé, H.; Jiménez, A.; Vasco, C.; Araguas, P.; Gómez, J.; et al. Effect of Low-Dose Radiotherapy on the Circulating Levels of Paraoxonase-1-Related Variables and Markers of Inflammation in Patients with COVID-19 Pneumonia. Antioxidants 2022, 11, 1184.
  33. Algara, M.; Arenas, M.; Marin, J.; Vallverdu, I.; Fernandez-Letón, P.; Villar, J.; Fabrer, G.; Rubio, C.; Montero, A. Low dose anti-inflammatory radiotherapy for the treatment of pneumonia by covid-19: A proposal for a multi-centric prospective trial. Clin. Transl. Radiat. Oncol. 2020, 24, 29–33.
  34. Montero, M.; Arenas, M.; Algara, M. Low-dose radiation therapy: Could it be a game-changer for COVID-19? Clin. Transl. Oncol. 2021, 23, 1–4.
  35. Yazaki, S.; Yoshida, T.; Kojima, Y.; Yagishita, S.; Nakahama, H.; Okinaka, K.; Matsushita, H.; Shiotsuka, M.; Kobayashi, O.; Iwata, S.; et al. Difference in SARS-CoV-2 Antibody Status Between Patients With Cancer and Health Care Workers During the COVID-19 Pandemic in Japan. JAMA Oncol. 2021, 7, 1141–1148.
  36. Bao, R.; Hernandez, K.; Huang, L.; Luke, J.J. ACE2 and TMPRSS2 expression by clinical.; HLA.; immune.; and microbial correlates across 34 human cancers and matched normal tissues: Implications for SARS-CoV-2 COVID-19. J. Immunother. Cancer 2020, 8, e001020.
  37. Xu, J.; Chu, M.; Zhong, F.; Tan, X.; Tang, G.; Mai, J.; Lai, N.; Guan, C.; Liang, Y.; Liao, G. Digestive symptoms of COVID-19 and expression of ACE2 in digestive tract organs. Cell Death Discov. 2020, 6, 76.
  38. Subbarayan, K.; Ulagappan, K.; Wickenhauser, C.; Seliger, B. Expression and Clinical Significance of SARS-CoV-2 Human Targets in Neoplastic and Non-Neoplastic Lung Tissues. Curr. Cancer Drug Targets 2021, 21, 428–442.
  39. Dai, Y.J.; Hu, F.; Li, H.; Huang, H.Y.; Wang, D.W.; Liang, Y. A profiling analysis on the receptor ACE2 expression reveals the potential risk of different type of cancers vulnerable to SARS-CoV-2 infection. Ann. Transl. Med. 2020, 8, 481.
  40. Lamers, M.M.; Beumer, J.; van der Vaart, J.; Knoops, K.; Puschhof, J.; Breugem, T.I.; Ravelli, R.B.G.; Paul van Schayck, J.; Mykytyn, A.Z.; Duimel, H.Q.; et al. SARS-CoV-2 productively infects human gut enterocytes. Science 2020, 369, 50–54.
  41. Gu, S.; Chen, Y.; Wu, Z.; Chen, Y.; Gao, H.; Lv, L.; Guo, F.; Zhang, X.; Luo, R.; Huang, C.; et al. Alterations of the Gut Microbiota in Patients With Coronavirus Disease 2019 or H1N1 Influenza. Clin. Infect. Dis. 2020, 71, 2669–2678.
  42. Yu, Y.; Wang, M.; Zhang, X.; Li, S.; Lu, Q.; Zeng, H.; Hou, H.; Li, H.; Zhang, M.; Jiang, F.; et al. Antibody-dependent cellular cytotoxicity response to SARS-CoV-2 in COVID-19 patients. Signal Transduct. Target Ther. 2021, 6, 346.
  43. Pinto, D.; Park, Y.J.; Beltramello, M.; Walls, A.C.; Tortorici, M.A.; Bianchi, S.; Jaconi, S.; Culap, K.; Zatta, F.; De Marco, A.; et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 2020, 583, 290–295.
  44. Hagemann, K.; Riecken, K.; Jung, J.M.; Hildebrandt, H.; Menzel, S.; Bunders, M.J.; Fehse, B.; Koch-Nolte, F.; Heinrich, F.; Peine, S.; et al. Natural killer cell-mediated ADCC in SARS-CoV-2-infected individuals and vaccine recipients. Eur. J. Immunol. 2022, 52, 1297–1307.
  45. Di Vito, C.; Calcaterra, F.; Coianiz, N.; Terzoli, S.; Voza, A.; Mikulak, J.; Della Bella, S.; Mavilio, D. Natural Killer Cells in SARS-CoV-2 Infection: Pathophysiology and Therapeutic Implications. Front. Immunol. 2022, 13, 888248.
  46. Flexman, J.P.; Shellam, G.R.; Mayrhofer, G. Natural cytotoxicity, responsiveness to interferon and morphology of intra-epithelial lymphocytes from the small intestine of the rat. Immunology 1983, 48, 733–741.
  47. Zuo, T.; Zhang, F.; Lui, G.C.Y.; Yeoh, Y.K.; Li, A.Y.L.; Zhan, H.; Wan, Y.; Chung, A.C.K.; Cheung, C.P.; Chen, N.; et al. Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology 2020, 159, 944–955.e8.
  48. Li, K.; Methé, B.A.; Fitch, A.; Gentry, H.; Kessinger, C.; Patel, A.; Petraglia, V.; Swamy, P.; Morris, A. Gut and oral microbiota associations with viral mitigation behaviors during the COVID-19 pandemic. Front. Cell Infect. Microbiol. 2022, 12, 966361.
  49. De Maio, F.; Ianiro, G.; Coppola, G.; Santopaolo, F.; Abbate, V.; Bianco, D.M.; Del Zompo, F.; De Matteis, G.; Leo, M.; Nesci, A.; et al. Improved gut microbiota features after the resolution of SARS-CoV-2 infection. Gut Pathog. 2021, 13, 62.
  50. Meyer, J.E.; Finnberg, N.K.; Chen, L.; Cvetkovic, D.; Wang, B.; Zhou, L.; Dong, Y.; Hallman, M.A.; Ma, C.C.; El-Deiry, W.S. Tissue TGF-β expression following conventional radiotherapy and pulsed low-dose-rate radiation. Cell Cycle 2017, 16, 1171–1174.
  51. Harper, A.; Vijayakumar, V.; Ouwehand, A.C.; Ter Haar, J.; Obis, D.; Espadaler, J.; Binda, S.; Desiraju, S.; Day, R. Viral Infections, the Microbiome, and Probiotics. Front. Cell Infect. Microbiol. 2021, 10, 596166.
  52. Ailioaie, L.M.; Litscher, G. Probiotics, Photobiomodulation, and Disease Management: Controversies and Challenges. Int. J. Mol. Sci. 2021, 22, 4942.
  53. Gutiérrez-Castrellón, P.; Gandara-Martí, T.; Abreu Y Abreu, A.T.; Nieto-Rufino, C.D.; López-Orduña, E.; Jiménez-Escobar, I.; Jiménez-Gutiérrez, C.; López-Velazquez, G.; Espadaler-Mazo, J. Probiotic improves symptomatic and viral clearance in Covid19 outpatients: A randomized.; quadruple-blinded.; placebo-controlled trial. Gut Microbes 2022, 14, 2018899.
  54. Nayebi, A.; Navashenaq, J.G.; Soleimani, D.; Nachvak, S.M. Probiotic supplementation: A prospective approach in the treatment of COVID-19. Nutr. Health 2022, 28, 163–175.
  55. Baindara, P.; Chakraborty, R.; Holliday, Z.M.; Mandal, S.M.; Schrum, A.G. Oral probiotics in coronavirus disease 2019: Connecting the gut-lung axis to viral pathogenesis.; inflammation.; secondary infection and clinical trials. New Microbes New Infect. 2021, 40, 100837.
  56. Sokol, H.; Contreras, V.; Maisonnasse, P.; Desmons, A.; Delache, B.; Sencio, V.; Machelart, A.; Brisebarre, A.; Humbert, L.; Deryuter, L.; et al. SARS-CoV-2 infection in nonhuman primates alters the composition and functional activity of the gut microbiota. Gut Microbes 2021, 13, 1–19.
  57. Scarpellini, E.; Fagoonee, S.; Rinninella, E.; Rasetti, C.; Aquila, I.; Larussa, T.; Ricci, P.; Luzza, F.; Abenavoli, L. Gut Microbiota and Liver Interaction through Immune System Cross-Talk: A Comprehensive Review at the Time of the SARS-CoV-2 Pandemic. J. Clin. Med. 2020, 9, 2488.
  58. Sencio, V.; Machelart, A.; Robil, C.; Benech, N.; Hoffmann, E.; Galbert, C.; Deryuter, L.; Heumel, S.; Hantute-Ghesquier, A.; Flourens, A.; et al. Alteration of the gut microbiota following SARS-CoV-2 infection correlates with disease severity in hamsters. Gut Microbes 2022, 14, 2018900.
  59. Kumar, M.; Kissoon-Singh, V.; Coria, A.L.; Moreau, F.; Chadee, K. Probiotic mixture VSL#3 reduces colonic inflammation and improves intestinal barrier function in Muc2 mucin-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2017, 312, G34–G45.
  60. Zhang, F.; Wan, Y.; Zuo, T.; Yeoh, Y.K.; Liu, Q.; Zhang, L.; Zhan, H.; Lu, W.; Xu, W.; Lui, G.C.Y.; et al. Prolonged Impairment of Short-Chain Fatty Acid and L-Isoleucine Biosynthesis in Gut Microbiome in Patients With COVID-19. Gastroenterology 2022, 162, 548–561.e4.
  61. Howell, M.C.; Green, R.; McGill, A.R.; Dutta, R.; Mohapatra, S.; Mohapatra, S.S. SARS-CoV-2-Induced Gut Microbiome Dysbiosis: Implications for Colorectal Cancer. Cancers 2021, 13, 2676.
  62. Mozaffari, S.A.; Salehi, A.; Mousavi, E.; Zaman, B.A.; Nassaj, A.E.; Ebrahimzadeh, F.; Nasiri, H.; Valedkarimi, Z.; Adili, A.; Asemani, G.; et al. SARS-CoV-2-associated gut microbiome alteration; A new contributor to colorectal cancer pathogenesis. Pathol. Res. Pract. 2022, 239, 154131.
  63. Dobranowski, P.A.; Tang, C.; Sauvé, J.P.; Menzies, S.C.; Sly, L.M. Compositional changes to the ileal microbiome precede the onset of spontaneous ileitis in SHIP deficient mice. Gut Microbes 2019, 10, 578–598.
  64. Yi, W.; Clark, P.M.; Mason, D.E.; Keenan, M.C.; Hill, C.; Goddard, W.A., 3rd; Peters, E.C.; Driggers, E.M.; Hsieh-Wilson, L.C. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 2012, 337, 975–980.
  65. Richter, K.K.; Langberg, C.W.; Sung, C.C.; Hauer-Jensen, M.; Increased transforming growth factor β (TGF-β) immunoreactivity is independently associated with chronic injury in both consequential and primary radiation enteropathy. Int. J. Radiat. Oncol. Biol. Phys. 1997, 39, 187-195, .
  66. Haydont, V.; Mathé, D.; Bourgier, C.; Abdelali, J.; Aigueperse, J.; Bourhis, J.; Vozenin-Brotons, M.C.; Induction of CTGF by TGF-beta1 in normal and radiation enteritis human smooth muscle cells: Smad/Rho balance and therapeutic perspectives. Radiother. Oncol. 2005, 76, 219-225, .
  67. Ehrhardt, R.O.; Strober, W.; Harriman, G.R. Effect of transforming growth factor (TGF)-beta 1 on IgA isotype expression. TGF-beta 1 induces a small increase in sIgA+ B cells regardless of the method of B cell activation. J. Immunol. 1992, 148, 3830–3836.
  68. Wu, M.; Xiao, H.; Liu, G.; Chen, S.; Tan, B.; Ren, W.; Bazer, F.W.; Wu, G.; Yin, Y. Glutamine promotes intestinal SIgA secretion through intestinal microbiota and IL-13. Mol. Nutr. Food Res. 2016, 60, 1637–1648.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Academic Video Service
Feedback