Abstract
The ability of Helicobacter pylori to evade the host immune system allows the bacterium to colonize the host for a lifetime. Long-term infection with H. pylori causes chronic inflammation, which is the major risk factor for the development of gastric ulcers and gastric cancer. Lactobacilli are part of the human microbiota and have been studied as an adjunct treatment in H. pylori eradication therapy. However, the molecular mechanisms by which lactobacilli act against H. pylori infection have not been fully characterized. In this study, we investigated the anti-inflammatory effects of Lactobacillus strains upon coincubation of host macrophages with H. pylori. We found that Lactobacillus gasseri Kx110A1 (L. gas), a strain isolated from a human stomach, but not other tested Lactobacillus species, blocked the production of the proinflammatory cytokines TNF and IL-6 in H. pylori-infected macrophages. Interestingly, L. gas also inhibited the release of these cytokines in LPS or LTA stimulated macrophages, demonstrating a general anti-inflammatory property. The inhibition of these cytokines did not occur through the polarization of macrophages from the M1 (proinflammatory) to M2 (anti-inflammatory) phenotype or through the altered viability of H. pylori or host cells. Instead, we show that L. gas suppressed the release of TNF and IL-6 by reducing the expression of ADAM17 (also known as TNF-alpha-converting enzyme, TACE) on host cells. Our findings reveal a novel mechanism by which L. gas prevents the production of the proinflammatory cytokines TNF and IL-6 in host macrophages.
Highlights
The human-adapted bacterial pathogen, Helicobacter pylori, colonizes the stomach of more than half of the world’s population
To investigate the anti-inflammatory activity of lactobacilli, we quantified the levels of tumor necrosis factor (TNF) and IL-6 produced upon stimulation of THP-1-derived macrophages with H. pylori alone or in the presence of different strains of Lactobacillus
With the exception of Lactobacillus rhamnosus GG (LGG), which suppressed TNF production at 8 h, there was no significant reduction in the secretion of TNF and IL-6 when cells were coincubated with H. pylori in combination with the other Lactobacillus species tested
Summary
The human-adapted bacterial pathogen, Helicobacter pylori, colonizes the stomach of more than half of the world’s population. Infection with H. pylori is often acquired early in childhood and persists throughout the lifetime of the host, if left untreated. Upon H. pylori infection, the host mounts a vigorous inflammatory response but often fails to eradicate the pathogen leading to persistent infection [3]. The majority of H. pylori-infected individuals are asymptomatic, but some develop overt diseases. Differences in host genetics are one of the reasons why only certain individuals develop serious infections. The continuous production of cytokines, chemokines, reactive oxygen species (ROS), and reactive nitrogen species (RNS) from recruited immune cells causes oxidative stress, tissue injury, and DNA damage, which in turn predisposes the host to develop gastric cancer later in life [5, 7, 8]
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