Microbial influences on the small intestinal response to radiation injury

Abstract

Purpose of review: Injury to the small bowel from ionizing radiation occurs commonly in patients undergoing cancer therapy and less commonly in instances of accidental radiation overexposure. Several lines of evidence now suggest that dynamic interactions between the host's enteric microbiota and innate immune system are important in modulating the intestinal response to radiation. Here, we will review recent developments in the area of acute radiation enteropathy and examine the current state of knowledge regarding the impact of host-microbial interactions in the process.

Recent findings: There is promise in the development and testing of new clinical biomarkers including serum citrulline. Toll-like receptor agonists and innate immune system signaling pathways including nuclear factor-kappa B profoundly alter intestinal epithelial cell apoptosis and crypt survival after radiation exposure. Germ-free conditions, probiotics and antibiotics are each identified as modifiers of disease development and course. A human study suggested that luminal microbiota composition may influence the host's intestinal response to radiation and may change in those developing postradiation diarrhea.

Summary: New knowledge implies that investigations aimed at deciphering the microbiome-host interactions before and after small bowl radiation injury may eventually allow prediction of disease course and offer opportunities for the development of novel therapeutic or prophylactic strategies.

Figure 1. Modifiers of acute small intestinal radiation injury

The small intestinal response to radiation is altered by signaling induced by luminal bacteria or bacterial-based products. Experimental models and human trials suggest Lactobacillus species or their soluble secreted proteins alone may protect intestinal crypts against damage from radiation exposure [26•,27]. Flagellin, a TLR5 ligand that activates the NF-κB pathway, protected IECs from radiation-induced apoptosis and increased host survival when injected into mice before lethal doses of radiation [25••]. LPS, a TLR4 ligand that is found in the outer membrane of Gram-negative bacteria, increased both endogenous intestinal prostaglandin production and intestinal crypt survival in mice exposed to 14-Gy radiation when injected parenterally 2–24 h prior to exposure [20]. Endogenous PGE₂ has been shown to decrease murine IEC apoptosis and increase IEC proliferation in response to radiation [23]. Conversely, blocking pathways that are activated by bacterial products have been shown to have detrimental effects on the ability of IECs and crypts to survive radiation insults. The E. coli STa is a ligand for GC-C, an IEC transmembrane receptor. UGN is a peptide hormone that binds to and activates GC-C. Mice in which GC-C or UGN is knocked out have increased jejunal IEC apoptosis 3 h after 5-Gy radiation as compared with wild-type counterparts [19•]. Indomethacin blocks PGE₂ production by inhibiting COX-1 and COX-2, thereby increasing IEC apoptosis and intestinal crypt ablation [22]. Similarly, irradiated COX-1^−/− mice have diminished PGE₂ synthesis, leading to increased crypt epithelial apoptosis and decreased clonogenic stem cell survival [21]. Irradiated EP₂ receptor^−/− mice also have decreased intestinal crypt survival and a 1.6-fold increase in IEC apoptosis [24]. Blocking NF-κB activation by deleting the p50 subunit of the NF-κB complex [18] or the canonical NF-κB activation kinase [17] results in increased radiation-induced IEC apoptosis in mice. Although debate still exists as to the degree of importance of endothelial apoptosis in acute intestinal outcomes after high-dose radiation exposure [14,15], endothelial apoptosis is shown to be lower in germ-free than conventionally raised mice [16]. COX, cyclooxygenase; E. coli STa, heat-stable enterotoxin of Escherichia coli; GC-C, guanylate cyclase C; IEC, intestinal epithelial cell; KO, knocked out; LPS, lipopolysaccharide; NF-κB, nuclear factor-kappa B; PGE₂, prostaglandin E₂; TLR, Toll-like receptor; UGN, uroguanylin. Limits acute intestinal injury from radiation, contributes to acute intestinal injury from radiation.