Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques

Nagatake, Takahiro; Kishino, Shigenobu; Urano, Emiko; Murakami, Haruka; Kitamura, Nahoko; Konishi, Kana; Ohno, Harumi; Tiwari, Prabha; Morimoto, Sakiko; Node, Eri; Adachi, Jun; Abe, Yuichi; Isoyama, Junko; Sawane, Kento; Honda, Tetsuya; Inoue, Asuka; Uwamizu, Akiharu; Matsuzaka, Takashi; Miyamoto, Yoichi; Hirata, Soichiro; Saika, Azusa; Shibata, Yuki; Hosomi, Koji; Matsunaga, Ayu; Shimano, Hitoshi; Arita, Makoto; Aoki, Junken; Oka, Masahiro; Matsutani, Akira; Tomonaga, Takeshi; Kabashima, Kenji; Miyachi, Motohiko; Yasutomi, Yasuhiro; Ogawa, Jun; Kunisawa, Jun

doi:10.1038/s41385-021-00477-5

Cited by 21 publications

(29 citation statements)

References 73 publications

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“…We did not evaluate the alterations in gut microbiota in the present study. Nonetheless, previous studies performed by ourselves, and by others, revealed that various PUFAs (including GLA) have beneficial actions on gut microbiota [ 95 , 96 , 97 ]. Hence, one distinct possibility by which GLA is beneficial against radiation can be ascribed to its ability to alter gut microbiota (See Figure 18 ).…”

Section: Discussionmentioning

confidence: 94%

Gamma-Linolenic Acid (GLA) Protects against Ionizing Radiation-Induced Damage: An In Vitro and In Vivo Study

Rengachar

Bhatt

Polavarapu³

et al. 2022

Biomolecules

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Radiation is pro-inflammatory in nature in view of its ability to induce the generation of reactive oxygen species (ROS), cytokines, chemokines, and growth factors with associated inflammatory cells. Cells are efficient in repairing radiation-induced DNA damage; however, exactly how this happens is not clear. In the present study, GLA reduced DNA damage (as evidenced by micronuclei formation) and enhanced metabolic viability, which led to an increase in the number of surviving RAW 264.7 cells in vitro by reducing ROS generation, and restoring the activities of desaturases, COX-1, COX-2, and 5-LOX enzymes, TNF-α/TGF-β, NF-kB/IkB, and Bcl-2/Bax ratios, and iNOS, AIM-2, and caspases 1 and 3, to near normal. These in vitro beneficial actions were confirmed by in vivo studies, which revealed that the survival of female C57BL/6J mice exposed to lethal radiation (survival~20%) is significantly enhanced (to ~80%) by GLA treatment by restoring altered levels of duodenal HMGB1, IL-6, TNF-α, and IL-10 concentrations, as well as the expression of NF-kB, IkB, Bcl-2, Bax, delta-6-desaturase, COX-2, and 5-LOX genes, and pro- and anti-oxidant enzymes (SOD, catalase, glutathione), to near normal. These in vitro and in vivo studies suggest that GLA protects cells/tissues from lethal doses of radiation by producing appropriate changes in inflammation and its resolution in a timely fashion.

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Section: Discussionmentioning

confidence: 94%

Gamma-Linolenic Acid (GLA) Protects against Ionizing Radiation-Induced Damage: An In Vitro and In Vivo Study

Rengachar

Bhatt

Polavarapu³

et al. 2022

Biomolecules

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“…In this diet-induced model, male mice are generally used because they are more susceptible to diet-induced weight gain and diabetic pathology 89 , but it is also necessary to examine the sexual differences of the effects of B. wexlerae in the future study including human. As done in previous studies 90,91 , we fasted our mice for 16 h; however, this might have been excessive and thus induced metabolic changes that occur during starvation. Furthermore, although we focused on the metabolism of adipose tissue as a possible mechanism of the control of obesity and diabetes, liver has an even greater role than adipose tissue in energy metabolism, such that more comprehensive studies including assessments using metabolic cages are needed.…”

Section: Discussionmentioning

confidence: 99%

“…Flow cytometry was performed as described previously, with slight modification 91,102 . Cells in the stromal vascular fraction of eAT were Article https://doi.org/10.1038/s41467-022-32015-7…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

“…Samples were analyzed by using BD FACSAria III (BD Biosciences), and data were analyzed by using FlowJo 9.9 (Tree Star, Ashland, Oregon, USA). The CD45 + CD11b + F4/80 + cells were defined as the macrophage population 91 . Among macrophages, the MHC II +/high CD206 -/low cells and MHC II + CD206 high cells were defined as the M1-and M2-like macrophage populations, respectively.…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

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Oral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes via metabolic remodeling of the gut microbiota

et al. 2022

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The gut microbiome is an important determinant in various diseases. Here we perform a cross-sectional study of Japanese adults and identify the Blautia genus, especially B. wexlerae, as a commensal bacterium that is inversely correlated with obesity and type 2 diabetes mellitus. Oral administration of B. wexlerae to mice induce metabolic changes and anti-inflammatory effects that decrease both high-fat diet–induced obesity and diabetes. The beneficial effects of B. wexlerae are correlated with unique amino-acid metabolism to produce S-adenosylmethionine, acetylcholine, and l-ornithine and carbohydrate metabolism resulting in the accumulation of amylopectin and production of succinate, lactate, and acetate, with simultaneous modification of the gut bacterial composition. These findings reveal unique regulatory pathways of host and microbial metabolism that may provide novel strategies in preventive and therapeutic approaches for metabolic disorders.

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“…For example, α-linolenic acid is metabolised by Lactobacillus plantarum AKU 1009a to generate the bioactive metabolite 10-oxo-cis-12-cis-15-octadecadienoic acid (α-Keto acid) [ 77 ]. Interestingly, pioneering research has shown that anti-inflammatory properties are retained by α-Keto acid [ 78 ]. The authors revealed that α-Keto acid was capable of inducing M2 macrophage polarisation in mice administered a high-fat diet.…”

Section: Dietary Approaches For Targeting Macrophage Plasticitymentioning

confidence: 99%

Diet–Microbiota Interplay: An Emerging Player in Macrophage Plasticity and Intestinal Health

O’Mahony

Amamou

Ghosh

2022

IJMS

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Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract with an increasing prevalence worldwide. Targeted therapies for IBD are limited by several factors, including the therapeutic ceiling and the high incidence of non-responders or loss-of-response. In order to improve therapeutic efficacy, there is critical need to decipher disease pathogenesis, currently not well understood. Macrophages, innate immune cells that exhibit high plasticity, perpetuate inflammatory signalling in IBD through excessive release of inflammatory mediators. In recent years, pioneering research has revealed the importance of the interplay between macrophages and gut microbiota in maintaining intestinal homeostasis. Particular attention is focusing on microbiota-derived metabolites, believed to possess immunomodulatory properties capable of manipulating macrophage plasticity. Microbiota-derived short-chain fatty acids (SCFAs) and indole compounds, along with dietary sourced omega-3 (ω-3) polyunsaturated fatty acids (PUFA), exert anti-inflammatory effects, attributable to interactions with macrophages. Before we can effectively incorporate these metabolites into IBD therapies, a deeper understanding of microbiota–macrophage interactions at a molecular level is necessary. Therefore, the aim of this review is firstly to detail current knowledge regarding how diet and microbiota-derived metabolites modify macrophage plasticity. Later, we discuss the concept of therapeutic strategies directed at microbiota–macrophage interactions, which could be highly valuable for IBD therapies in the future.

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Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques

Cited by 21 publications

References 73 publications

Gamma-Linolenic Acid (GLA) Protects against Ionizing Radiation-Induced Damage: An In Vitro and In Vivo Study

Gamma-Linolenic Acid (GLA) Protects against Ionizing Radiation-Induced Damage: An In Vitro and In Vivo Study

Oral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes via metabolic remodeling of the gut microbiota

Diet–Microbiota Interplay: An Emerging Player in Macrophage Plasticity and Intestinal Health

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