A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling

Yamada, Miki; Takahashi, Naoki; Matsuda, Yukio; Sato, Keisuke; Yokoji, Mai; Sulijaya, Benso; Maekawa, Tomoki; Ushiki, Tatsuo; Mikami, Yohei; Hayatsu, Manabu; Mizutani, Yusuke; Kishino, Shigenobu; Ogawa, Jun; Arita, Makoto; Tabeta, Koichi; Maeda, Takeyasu; Yamazaki, Kazuhisa

doi:10.1038/s41598-018-27408-y

Cited by 46 publications

(46 citation statements)

References 62 publications

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“…For example, mice lacking GPR40 induced inflammation and insulin resistance in the brain [36]. Reportedly, the GPR40 signaling pathway plays a major role in the inhibition of spinal cord nociception after inflammation or nerve injury [37], and GPR40 antagonizes the periodontal inflammation [38]. These phenomena were in agreement with the current experimental results.…”

Section: Discussionsupporting

confidence: 89%

TAK-875 Mitigates β-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-κB Pathway

Xide

Yan

Weng

et al. 2019

Journal of Diabetes Research

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Metabolic inflammatory damage, characterized by Toll-like receptor 4 (TLR4) signaling activation, is a major mechanism underlying lipotoxicity-induced β-cell damage. The present study is aimed at determining whether G protein-coupled receptor 4 (GPR40) agonist can improve β-cell lipotoxicity-induced damage by inhibiting the TLR4-NF-κB pathway. Lipotoxicity, inflammation-damaged β-cells, obese SD, and TLR4KO rat models were used in the study. In vitro, TAK-875 inhibited the lipotoxicity- and LPS-induced β-cell apoptosis in a concentration-dependent manner, improved the insulin secretion, and inhibited the expression of TLR4 and NF-κB subunit P65. Besides, silencing of TLR4 expression enhanced the protective effects of TAK-875, while TLR4 overexpression attenuated this protective effect. Activation of TLR4 or NF-κB attenuated the antagonism of TAK-875 on PA-induced damage. Moreover, the above process of TAK-875 was partially independent of GPR40 expression. TAK-875 reduced the body weight and inflammatory factors, rebalanced the number and distribution of α or β-cells, inhibited the apoptosis of islet cells, and inhibited the expression of TLR4 and NF-κB subunit P65 in obese rats. Further knockout of the rat TLR4 gene delayed the damage induced by the high-fat diet and synergy with the action of TAK-875. These data suggest that GPR40 agonists antagonized the lipotoxicity β-cell damage by inhibiting the TLR4-NF-κB pathway.

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Section: Discussionsupporting

confidence: 89%

TAK-875 Mitigates β-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-κB Pathway

Xide

Yan

Weng

et al. 2019

Journal of Diabetes Research

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“…The induction of periodontitis was performed as previously described . Periodontitis was initiated 1 week after the pretreatment of KetoC or vehicle.…”

Section: Methodsmentioning

confidence: 99%

Antimicrobial function of the polyunsaturated fatty acid KetoC in an experimental model of periodontitis

Sulijaya

Yamada-Hara

Yokoji-Takeuchi

et al. 2019

Journal of Periodontology

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Background The bioactive metabolite KetoC, generated by intestinal bacteria, exerts various beneficial effects. Nevertheless, its function in the pathogenesis of periodontitis remains unclear. Here, we investigated the effect of KetoC in a mouse model of periodontitis and explored the underlying mechanism. Methods Thirty‐one 8‐week‐old male C57BL/6N mice were randomly divided into four groups (non‐ligation, non‐ligation + KetoC, ligation + Porphyromonas gingivalis, and ligation + P. gingivalis + KetoC) (n = 7/8 mice/group) and given a daily oral gavage of KetoC (15 mg/mL) or vehicle for 2 weeks. To induce periodontitis, a 5‐0 silk ligature was placed on the maxillary left second molar on day 7, and P. gingivalis W83 (109 colony‐forming unit [CFU]) was administered orally every 3 days. On day 14, all mice were euthanized. Alveolar bone destruction was determined from the level of the cemento‐enamel junction to the alveolar bone crest. Moreover, bone loss level was confirmed from gingival tissue sections stained with hematoxylin and eosin. The presence of P. gingivalis was quantified using real‐time polymerase chain reaction. In vitro, the bacteriostatic and bactericidal effects of KetoC were assessed by analyzing its suppressive activity on the proliferation of P. gingivalis and using a live/dead bacterial staining kit, respectively. A double‐bond‐deficient metabolite (KetoB) was then used to investigate the importance of double‐bond structure in the antimicrobial activity of KetoC on P. gingivalis. Results In vivo, KetoC attenuated alveolar bone destruction and suppressed P. gingivalis in the periodontitis group. In vitro, KetoC (but not KetoB) downregulated the proliferation and viability of P. gingivalis in a dose‐dependent manner. Conclusions KetoC reduced alveolar bone destruction in a periodontitis model via its antimicrobial function. Therefore, this bioactive metabolite may be valuable in clinical applications to support periodontal therapy.

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“…Emerging research has indicated a role for gut microbial metabolism of linoleic acid to produce postbiotic metabolites with health-promoting effects. For example, a bacterial metabolite of linoleic acid has been shown to prevent the impairment of the epithelial barrier that is caused by periodontopathic bacteria (Yamada et al, 2018). Future research on the targeted delivery of lipids to the colon will determine if this is a successful strategy to influence the production of fatty acid postbiotics with the potential to improve animal health.…”

Section: Fatmentioning

confidence: 99%

“…A study in mice demonstrated that consumption of 10-hydroxy- cis -12-octadecenoic acid reduced clinical symptoms of allergic disease, including scratching behavior, hemorrhage, edema, and dryness ( Kaikiri et al, 2017 ), suggesting it could have similar effects in cats and dogs. This nutritional component, which is found in food-derived polyunsaturated fats, may also be beneficial for other mucosal pathologies, such as oral diseases that stem from decreased epithelial barrier integrity ( Yamada et al, 2018 ). While speculative, emerging postbiotics such as this warrant further research to determine if they can be modulated through nutrition in a way that impacts cat and dog health in a beneficial manner.…”

Section: Emerging Evidence: Role Of Microbiome Function and Postbiotimentioning

confidence: 99%

The Effects of Nutrition on the Gastrointestinal Microbiome of Cats and Dogs: Impact on Health and Disease

et al. 2020

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The gastrointestinal (GI) microbiome of cats and dogs is increasingly recognized as a metabolically active organ inextricably linked to pet health. Food serves as a substrate for the GI microbiome of cats and dogs and plays a significant role in defining the composition and metabolism of the GI microbiome. The microbiome, in turn, facilitates the host's nutrient digestion and the production of postbiotics, which are bacterially derived compounds that can influence pet health. Consequently, pet owners have a role in shaping the microbiome of cats and dogs through the food they choose to provide. Yet, a clear understanding of the impact these food choices have on the microbiome, and thus on the overall health of the pet, is lacking. Pet foods are formulated to contain the typical nutritional building blocks of carbohydrates, proteins, and fats, but increasingly include microbiome-targeted ingredients, such as prebiotics and probiotics. Each of these categories, as well as their relative proportions in food, can affect the composition and/or function of the microbiome. Accumulating evidence suggests that dietary components may impact not only GI disease, but also allergies, oral health, weight management, diabetes, and kidney disease through changes in the GI microbiome. Until recently, the focus of microbiome research was to characterize alterations in microbiome composition in disease states, while less research effort has been devoted to understanding how changes in nutrition can influence pet health by modifying the microbiome function. This review summarizes the impact of pet food nutritional components on the composition and function of the microbiome and examines evidence for the role of nutrition in impacting host health through the microbiome in a variety of disease states. Understanding how nutrition can modulate GI microbiome composition and function may reveal new avenues for enhancing the health and resilience of cats and dogs.

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A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling

Cited by 46 publications

References 62 publications

TAK-875 Mitigates β-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-κB Pathway

TAK-875 Mitigates β-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-κB Pathway

Antimicrobial function of the polyunsaturated fatty acid KetoC in an experimental model of periodontitis

The Effects of Nutrition on the Gastrointestinal Microbiome of Cats and Dogs: Impact on Health and Disease

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