Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes
Introduction
Helicobacter pylori is a Gram-negative pathogen colonizing the human gastric epithelium, causing type B gastritis, peptic ulcer disease and gastric cancer [1]. The pathogenesis of this infection is partly due to the immunological response. In the infected gastric mucosa of mice and humans, the immune response is polarized to a Th1 cell-mediated response with release of IFN-γ, which activates phagocytic cell and contributes to mucosal damage [2], [3], [4], [5], [6]. A predominant Th1 response has also been shown in Helicobacter infections of inbred mice, often using Helicobacter felis, a feline gastric Helicobacter more easily infecting mice [7], [8]. An adoptive transfer of T-helper-2 (Th2) T-lymphocytes producing IL-4 to mice subsequently infected with H. felis infected mice leads to a reduction of the bacterial load and gastric inflammation, whereas an adoptive transfer of Th1 cells increased gastric inflammation and bacterial load of subsequently infected animal [7]. Oral immunization of H. felis-infected mice with recombinant urease and cholera toxin induced a shift of T-lymphocyte response from a polarized Th1-response to a mixed Th1/Th2 response and cured the infection [8]. These findings suggest that a polarized Th1-response is associated with the pathogenesis of these gastric diseases and that a Th2 response is associated with control of H. pylori/H. felis infection.
A low dietary intake of antioxidants such as carotenoids and vitamin C has been suggested as an important factor for acquisition of H. pylori by humans [9], [10]. Dietary antioxidants also affect both acquisition of the infection and the bacterial load of H. pylori infected mice [11]. The algae Haematococcus pluvialis is rich in astaxanthin, a carotenoid with strong anti-oxidative and anti-inflammatory properties [12], [13]. Astaxanthin has a number of immuno-modulatory effects in vitro: (i) enhancement of T-cell dependent antibody production by mouse T-lymphocyte clones and unprimed T-lymphocytes; (ii) enhancement of TNF-α and IL-1a release of mouse peritoneal adherent cells and down-regulation of IFN-release by mouse Th1 clones and primed spleen cells [14], [15], [16]. The present study reports the reduction of bacterial load, the decreased gastric inflammation and the changes of the splenocyte cytokine release in response to H. pylori antigens induced by feeding H. pylori-infected Balb/cA mice with an algal meal containing 2–3% astaxanthin, as compared to infected, untreated mice and uninfected untreated mice.
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Mouse experiments
Twenty Balb/cA mice (B&K Universal Company, Stockholm, Sweden), 6–8 weeks old, were inoculated orally with 108 colony forming units (CFU) of the mouse passaged H. pylori strain 119/95p three times at two day intervals and ten mice were inoculated with PBS [11]. Two weeks after inoculation, half of the infected mice were treated orally with a cell extract from the micro algae H. pluvialis containing the antioxidant astaxanthin (200 mg per kg body weight per day) (AstaCarotene AB, Gustavsberg,
Murine gastritis and bacterial load
Inoculation of Balb/cA mice with H. pylori resulted in stable infections of the gastric mucosa characterized by a moderate inflammatory response [11], [18]. Treatment of the infected mice with an algal cell extract containing astaxanthin reduced bacterial load of gastric mucosa in infected mice as compared to untreated, infected mice (mean CFU 101 versus 407, P<0.02) (Fig. 1). Also the gastritis score of infected mice was reduced after treatment with astaxanthin (mean gastritis score 1.85
Discussion
In this study we demonstrate, that H. pylori infected Balb/cA mice treated with the antioxidant astaxanthin show: (i) a decreased bacterial load and a decreased grade of inflammation in the stomach; (ii) the treatment was associated with a shift in the cytokine release profile of cultured splenocytes in vitro. Balb/cA mice infected with H. pylori display a Th1 T-cell response as described in man [2], [3], [4], [5]. However, splenocytes from astaxanthin treated animals showed a significant
Conclusion
Astaxanthin treatment reduced bacterial load and mucosal inflammation in a Balb/cA mouse model of H. pylori infection, and that this was associated with a switch in the systemic T-helper cell response. Further studies are needed to describe the effect of astaxanthin on the T-cell reponse in the inflamed gastric mucosa.
Acknowledgements
This study was supported by grants from The Danish Medical Research Council (9601804), Mimi and Victor Larsens Foundation, Direktør Ib Henriksens Foundation, the Swedish Medical Research Council (16X04723) and AstaCarotene AB, Gustavsberg, Sweden.
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