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. 2015 Dec 15;6(6):e01358-15.
doi: 10.1128/mBio.01358-15.

Histamine H2 Receptor-Mediated Suppression of Intestinal Inflammation by Probiotic Lactobacillus reuteri

Chunxu Gao  1 , Angela Major  2 , David Rendon  3 , Monica Lugo  4 , Vanessa Jackson  4 , Zhongcheng Shi  4 , Yuko Mori-Akiyama  4 , James Versalovic  5
Affiliations

Histamine H2 Receptor-Mediated Suppression of Intestinal Inflammation by Probiotic Lactobacillus reuteri

Chunxu Gao et al. mBio. .

Abstract

Probiotics and commensal intestinal microbes suppress mammalian cytokine production and intestinal inflammation in various experimental model systems. Limited information exists regarding potential mechanisms of probiotic-mediated immunomodulation in vivo. In this report, we demonstrate that specific probiotic strains of Lactobacillus reuteri suppress intestinal inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model. Only strains that possess the hdc gene cluster, including the histidine decarboxylase and histidine-histamine antiporter genes, can suppress colitis and mucosal cytokine (interleukin-6 [IL-6] and IL-1β in the colon) gene expression. Suppression of acute colitis in mice was documented by diminished weight loss, colonic injury, serum amyloid A (SAA) protein concentrations, and reduced uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG) in the colon by positron emission tomography (PET). The ability of probiotic L. reuteri to suppress colitis depends on the presence of a bacterial histidine decarboxylase gene(s) in the intestinal microbiome, consumption of a histidine-containing diet, and signaling via the histamine H2 receptor (H2R). Collectively, luminal conversion of l-histidine to histamine by hdc(+) L. reuteri activates H2R, and H2R signaling results in suppression of acute inflammation within the mouse colon.

Importance: Probiotics are microorganisms that when administered in adequate amounts confer beneficial effects on the host. Supplementation with probiotic strains was shown to suppress intestinal inflammation in patients with inflammatory bowel disease and in rodent colitis models. However, the mechanisms of probiosis are not clear. Our current studies suggest that supplementation with hdc(+) L. reuteri, which can convert l-histidine to histamine in the gut, resulted in suppression of colonic inflammation. These findings link luminal conversion of dietary components (amino acid metabolism) by gut microbes and probiotic-mediated suppression of colonic inflammation. The effective combination of diet, gut bacteria, and host receptor-mediated signaling may result in opportunities for therapeutic microbiology and provide clues for discovery and development of next-generation probiotics.

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Figures

FIG 1
FIG 1
hdc+ L. reuteri attenuates colonic inflammation in vivo. (A) Time line of the mouse experiments. After 10 days of acclimatization, 8-week-old female BALB/c mice received 5 × 109 CFU of bacteria in MRS or MRS medium only by orogastric gavage daily for 7 days. Acute colitis was induced by intrarectal instillation of TNBS-ethanol before the sixth gavage, and colitis severity was evaluated in 2 days. (B to D) Weight loss (B), Wallace scores (C), and SAA concentrations (D) of mice challenged with or without TNBS and gavaged with or without L. reuteri 6475. (E and F) Representative microscopic colonic images (hematoxylin and eosin stained) (E) and Ameho scores (F) from mice in the healthy control group (MRS/PBS), the colitis control group (MRS/TNBS), and the L. reuteri-treated group (L. reuteri 6475/TNBS).
FIG 2
FIG 2
Detection of colitis attenuation by PET imaging. (A) Time line of the PET imaging experiments. Fasted (for 6 h) mice were anesthetized with isoflurane and received 200 µCi [18F]FDG by intraperitoneal (IP) injection. One hour later, these mice received 200 µl MD-Gastroview rectally immediately before scan initiation. Computed tomography (CT) scanning was performed for 10 min followed by PET scanning for 20 min using the Inveon PET-CT multimodality system. Mice were kept sedated during the scanning process by constant isoflurane inhalation. The images were recorded, and FDG standardized uptake values (SUVs) were analyzed blindly using Inveon Research Workplace software. (B) Representative mouse images captured by PET-CT scanning in each group. The color code bar represents FDG signal intensity. (C) Quantification of FDG signals in mouse colon using SUVs in different groups.
FIG 3
FIG 3
L. reuteri administration increases hdc gene expression in vivo. (A) Relative abundance of hdcA gene in mouse gut microbiome was significantly increased in mice gavaged with L. reuteri 6475 compared to control mice gavaged with MRS. The relative abundance was determined by qPCR and normalized to the bacterial housekeeping gene rpoB. (B and C) Both hdcA (B) and hdcP (C) gene expression levels were significantly increased in colonic luminal contents of mice receiving L. reuteri compared to control mice receiving MRS. The relative gene expression was determined by qPCR and normalized to the bacterial housekeeping gene rpoB. n = 6 per group. ****, P < 0.0001.
FIG 4
FIG 4
Inactivation of the L. reuteri histidine decarboxylase gene diminishes its ability to suppress intestinal inflammation. The anti-inflammatory effects of hdcA within an isogenic mutant which does not produce histamine were compared with those of wild-type L. reuteri 6475 using the TNBS colitis model. The wild-type strain attenuated colitis compared with the medium-control group (MRS/TNBS), whereas the hdcA mutant yielded diminished effects in terms of weight loss (A), Wallace scores (B), and SAA concentrations (C).
FIG 5
FIG 5
l-histidine deficiency diminishes anti-inflammatory effects. The anti-inflammatory effects of L. reuteri 6475 were compared in mice fed with different diets using the TNBS colitis model. Mice fed a regular diet or an amino acid defined diet showed decreased Wallace scores (A) and plasma SAA concentrations (B) when receiving L. reuteri 6475 compared to the MRS medium control. When mice were fed an l-histidine-deficient diet, L. reuteri 6475 showed diminished anti-inflammatory effects in terms of Wallace scores and SAA concentrations.
FIG 6
FIG 6
Activation of H2R is required for the anti-inflammatory effects. (A) Immunohistochemistry studies using H2R-specific antibody showed that H2R was expressed in 9-week-old BALB/c mice, with high intensity in the villi and crypts (red arrows). (B to D) Mice that received pyrilamine (Pyr) did not show an effect on the anti-inflammatory effects of L. reuteri 6475, while mice that received ranitidine (Ran) showed a diminished ability for L. reuteri 6475 to attenuate colitis, as indicated by weight loss (B), Wallace scores (C), and plasma SAA concentrations (D).
FIG 7
FIG 7
L. reuteri administration affects cytokine gene expression in the colon. Gene expression of IL-1β (A) and IL-6 (B) in the colons of healthy mice, colitic mice challenged with TNBS, and L. reuteri 6475-treated colitic mice was measured by reverse transcription-quantitative PCR using GAPDH as the internal standard. n = 10 per group. The P values are indicated in the figure.
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Comment in

  • IBD: Probiotics for IBD: a need for histamine?
    Thomas H. Thomas H. Nat Rev Gastroenterol Hepatol. 2016 Feb;13(2):62-3. doi: 10.1038/nrgastro.2016.2. Epub 2016 Jan 13. Nat Rev Gastroenterol Hepatol. 2016. PMID: 26758785 No abstract available.

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