Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner

Abstract

BackgroundThe small intestinal epithelium is highly sensitive to radiation and is a major site of injury during radiation therapy and environmental overexposure.ObjectiveTo examine probiotic bacteria as potential radioprotective agents in the intestine.Methods8-week-old C57BL/6 wild-type or knockout mice were administered probiotic by gavage for 3 days before 12 Gy whole body radiation. The intestine was evaluated for cell-positional apoptosis (6 h) and crypt survival (84 h).ResultsGavage of 5×107 Lactobacillus rhamnosus GG (LGG) improved crypt survival about twofold (p<0.01); the effect was observed when administered before, but not after, radiation. Conditioned medium (CM) from LGG improved crypt survival (1.95-fold, p<0.01), and both LGG and LGG-CM reduced epithelial apoptosis particularly at the crypt base (33% to 18%, p<0.01). LGG was detected in the distal ileal contents after the gavage cycle, but did not lead to a detectable shift in bacterial family composition. The reduction in epithelial apoptosis and improved crypt survival offered by LGG was lost in MyD88−/−, TLR-2−/− and cyclo-oxygenase-2−/− (COX-2) mice but not TLR-4−/− mice. LGG administration did not lead to increased jejunal COX-2 mRNA or prostaglandin E2 levels or a change in number of COX-2-expressing cells. However, a location shift was observed in constitutively COX-2-expressing cells of the lamina propria from the villi to a position near the crypt base (villi to crypt ratio 80:20 for control and 62:38 for LGG; p<0.001). Co-staining revealed these COX-2-expressing small intestinal lamina propria cells to be mesenchymal stem cells.ConclusionsLGG or its CM reduce radiation-induced epithelial injury and improve crypt survival. A TLR-2/MyD88 signalling mechanism leading to repositioning of constitutive COX-2-expressing mesenchymal stem cells to the crypt base is invoked.

The Efficacy of Probiotic (Lactobacillus rhamnosus GG) and 5-ASA (Aminosalicylic Acid) in the Treatment of Experimental Radiation Proctitis in Rats

“…LGG or its conditioned medium reduce radiationinduced epithelial injury and improve crypt survival in mice [12]. We preferred to LGG as probiotics because it was shown to be effective especially on the crypts after radiation therapy in experimental studies.…”

“…Probiotic therapies have been clinically evaluated and used as treatment for clinical conditions, such as human inflammatory bowel diseases, pouchitis, and cancer prevention [12,24]. For inflammatory bowel diseases, recent investigations in mice describe antiapoptotic and anti-inflammatory mechanisms for the probiotic LGG.…”

“…Probiotics shows anti-inflammatory effect by several mechanisms [10] and are potential radioprotective agents with improved crypt survival and reduced epithelial apoptosis. Lactobacillus GG (LGG) or its conditioned medium reduce radiation-induced epithelial injury and improve crypt survival [12].…”

A clinical primer of the role of gut microbiome in health and disease

“…113 In summary, while the alterations in gut microbiota between individuals who develop malignancies and those who do not have been well-described, studies exploring the exact pathophysiology of tumorigenesis have been limited. Early, small-scale work has shown that altering the microbiome can decrease the progression to cancer, thus making the microbiota an attractive target in chemoprevention.…”

Correction: Radiation enteropathy—pathogenesis, treatment and prevention

“…On the other hand, it is clear that A) it is impossible to sterilize the bowel in the clinical situation; B) antibiotic use tends to select resistant organisms; and C) certain bacteria are more harmful than others. As with IBD, the potential of probiotics in mitigating gastrointestinal inflammation during radiation therapy has generated substantial interest [61][62][63][64] . New techniques for assessment of bacterial flora in the normal state and after exposure to radiation; the development of powerful new gnotobiotic animal models; and improved understanding of the critical importance of the gut microbiome in health and disease are some of the reasons why this promising area of research is constantly evolving.…”