Radiation Impacts Microbiota Compositions: History
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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].
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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 10.3390/microbiolres14020048

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