Effect of trimethylamine N-oxide on inflammation and the gut microbiota in Helicobacter pylori-infected mice
Introduction
Helicobacter pylori (H. pylori), an ancient gastrointestinal microorganism, is a major risk factor for chronic gastritis, gastric ulcer and gastric cancer [1], [2]. Although over half of the human population is infected with H. pylori, only 1–2% of persons infected with H. pylori develop gastric cancer [3]. The clinical outcome of H. pylori infection is determined by a combination of virulence among H. pylori strains, duration of infection, host genetic polymorphisms and environmental factors such as diet [4], [5], [6], [7], [8]. Some animal experiments and clinical investigations showed that a synergistic interaction between H. pylori infection and high salt intake accelerated chronic inflammation and the development of gastric cancer [9], [10], [11], [12]. In addition, one study indicated that high-fat diet facilitated corpus atrophic gastritis in Mongolian gerbils [13]. And then research showed that H. pylori infection aggravated high-fat diet-induced inflammation and insulin resistance in association with the gut microbiota in mice, indicating that a potential interaction among H. pylori, the diet and the gut microbiota that dysregulates host metabolic homeostasis [14]. Taken together, these findings suggest that environmental factors such as a high-salt diet and a high-fat diet are associated with increased risk factors for chronic inflammation and cancer. However, the mechanism by which these diets increase the risk of H. pylori-related diseases is not fully understood.
High-salt diets and high-fat diets have been described to increase trimethylamine-N-oxide (TMAO) levels in the serum [15], [16], [17], [18]. TMAO, a microbial metabolite of L-carnitine, choline, red meat and fish, has been identified as a risk factor and prognostic marker for atherosclerosis and cardiovascular diseases (CVDs) [19], [20], [21]. Our preliminary results suggested that TMAO altered H. pylori-induced immune inflammation in human gastric epithelial cells [22]. However, animal or human studies on the acceleratory effects of TMAO on the inflammation and gut microbial dysbiosis induced by H. pylori infection.
In this study, we first examined the effects of TMAO on the viability and virulence of H. pylori in vitro. Moreover, we studied the effect of TMAO intake on the inflammation induced by H. pylori infection in mice. Furthermore, we investigated the effect of TMAO intake on alterations of the gut microbiota in H. pylori-infected mice.
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Bacterial strain and culture conditions
H. pylori strain, a clinical strain from Sichuan Provincial People's Hospital, was isolated from a patient with a gastric ulcer and moderate gastritis. The results of the identification of this strain are shown in Fig. S1. Solid culture: H. pylori strain was grown on 3% (w/v) Columbia blood agar base (Oxoid, UK) mixed with 1.2% (w/v) brain heart infusion (Oxoid, UK) containing 7% (v/v) sheep blood, 10 μg/mL vancomycin, 10 μg/mL amphotericin, 2500 U/L polymyxin B sulfate salt, 5 μg/mL
TMAO facilitated H. pylori growth and viability
To confirm the effect of TMAO on H. pylori growth and metabolism in vitro, H. pylori grown in medium with or without 1% TMAO were used to detect the expression of growth- and metabolism-associated genes and urease activity after 72 h. qRT-PCR results showed that TMAO treatment upregulated the mRNA expression of the growth- and metabolism-associated genes FrdB, Fur, HyuA and TorA (Fig. 1A), which are related to genes involved in the energy metabolism of H. pylori. Fur (ferric uptake regulator),
Discussion
Because complexity of the disease outcome, affected by persistent interactions between bacteria, host factors and environmental factors, most people with H. pylori infection do not have clinical symptoms [35]. Virulence factors of H. pylori such as VacA and CagA not only affect the ability of the organism to colonize and cause disease but also affect inflammation and gastric acid output [35]. In our study, TMAO supplementation increased production of CagA. The presence of CagA gene was linked
Declaration of Competing Interest
We declare that we have no conflict of interest.
Acknowledgements
This work was financially supported by the Sichuan Science and Technology Program (2018RZ0130). This study was also supported by the National Natural Science Foundation of China and by the Program for New Century Excellent Talents in University (31270175, NCET-13-0397).
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Daoyan Wu and Mei Cao contributed equally to this work.