Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

Maslowski, Kendle M.; Vieira, Angélica T.; Ng, Aylwin; Kranich, Jan; Sierro, Frédéric; Yu, Di; Schilter, Heidi; Rolph, Michael S.; Mackay, Fabienne; Artis, David; Xavier, Ramnik J.; Teixeira, Mauro Martins; Mackay, Charles R.

doi:10.1038/nature08530

Cited by 2,656 publications

(2,430 citation statements)

References 42 publications

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“…Other than HDAC inhibition, butyrate has two effects in the cell; it is a fatty acid that can be used as an energy source, and it can bind G‐protein‐coupled receptors that are involved in the resolution of inflammation in the gut (Maslowski et al ., 2009). Whether these receptors have a function in skeletal muscle needs to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Butyrate is a general HDAC inhibitor and protects against high‐fat diet‐induced metabolic changes (Gao et al ., 2009), has anti‐inflammatory properties (Maslowski et al ., 2009) and extends lifespan in a mouse model of progeria (Krishnan et al ., 2011) and Drosophila (Zhao et al ., 2005). Thus, we hypothesized that butyrate would improve metabolism and prevent muscle atrophy in mice during aging.…”

Section: Introductionmentioning

confidence: 99%

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The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Walsh¹,

et al. 2015

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SummarySarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with loss of motor neuron innervation, we investigated the potential for the histone deacetylase (HDAC) inhibitor butyrate to modulate age‐related muscle loss. Consistent with previous studies, we found significant loss of hindlimb muscle mass in 26‐month‐old C57Bl/6 female mice fed a control diet. Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hindlimb muscles. Butyrate increased muscle fiber cross‐sectional area and prevented intramuscular fat accumulation in the old mice. In addition to the protective effect on muscle mass, butyrate reduced fat mass and improved glucose metabolism in 26‐month‐old mice as determined by a glucose tolerance test. Furthermore, butyrate increased markers of mitochondrial biogenesis in skeletal muscle and whole‐body oxygen consumption without affecting activity. The increase in mass in butyrate‐treated mice was not due to reduced ubiquitin‐mediated proteasomal degradation. However, butyrate reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity. Our data is the first to show a beneficial effect of butyrate on muscle mass during aging and suggests HDACs contribute to age‐related muscle atrophy and may be effective targets for intervention in sarcopenia and age‐related metabolic disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Walsh¹,

et al. 2015

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“…Experimentally induced obesity is known to decrease 5HT levels 44. Inflammation associated with changes in the gut microbiota is considered to decrease 5HT availability during obesity 43, 45. Studies have yielded inconsistent data on the composition of the gut microbiota in obese subjects 8, 18, 46.…”

Section: Discussionmentioning

confidence: 99%

Association of Obesity with Serum Leptin, Adiponectin, and Serotonin and Gut Microflora in Beagle Dogs

Park

Lee

Kim

et al. 2014

Veterinary Internal Medicne

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BackgroundSerotonin (5‐hydroxytryptamine, 5HT) is involved in hypothalamic regulation of energy consumption. Also, the gut microbiome can influence neuronal signaling to the brain through vagal afferent neurons. Therefore, serotonin concentrations in the central nervous system and the composition of the microbiota can be related to obesity.ObjectiveTo examine adipokine, and, serotonin concentrations, and the gut microbiota in lean dogs and dogs with experimentally induced obesity.AnimalsFourteen healthy Beagle dogs were used in this study.MethodsSeven Beagle dogs in the obese group were fed commercial food ad libitum, over a period of 6 months to increase their weight and seven Beagle dogs in lean group were fed a restricted amount of the same diet to maintain optimal body condition over a period of 6 months. Peripheral leptin, adiponectin, 5HT, and cerebrospinal fluid (CSF‐5HT) levels were measured by ELISA. Fecal samples were collected in lean and obese groups 6 months after obesity was induced. Targeted pyrosequencing of the 16S rRNA gene was performed using a Genome Sequencer FLX plus system.ResultsLeptin concentrations were higher in the obese group (1.98 ± 1.00) compared to those of the lean group (1.12 ± 0.07, P = .025). Adiponectin and 5‐hydroytryptamine of cerebrospinal fluid (CSF‐5HT) concentrations were higher in the lean group (27.1 ± 7.28) than in the obese group (14.4 ± 5.40, P = .018). Analysis of the microbiome revealed that the diversity of the microbial community was lower in the obese group. Microbes from the phylum Firmicutes (85%) were predominant group in the gut microbiota of lean dogs. However, bacteria from the phylum Proteobacteria (76%) were the predominant group in the gut microbiota of dogs in the obese group.Conclusions and Clinical ImportanceDecreased 5HT levels in obese group might increase the risk of obesity because of increased appetite. Microflora enriched with gram‐negative might be related with chronic inflammation status in obese dogs.

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“…Germ-free mice, which lack an intestinal microbiota, exhibit altered inflammatory responses (10)(11)(12). We have shown recently that a normal gut microbiota is essential for the host to mount inflammatory responses, both local and systemic, in germ-free mice (12)(13)(14).…”

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confidence: 99%

A Role for Gut Microbiota and the Metabolite‐Sensing Receptor GPR43 in a Murine Model of Gout

Vieira

Macia

Galvão

et al. 2015

Arthritis & Rheumatology

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Objective Host–microbial interactions are central in health and disease. Monosodium urate monohydrate (MSU) crystals cause gout by activating the NLRP3 inflammasome, leading to interleukin‐1β (IL‐1β) production and neutrophil recruitment. This study was undertaken to investigate the relevance of gut microbiota, acetate, and the metabolite‐sensing receptor GPR43 in regulating inflammation in a murine model of gout. Methods Gout was induced by the injection of MSU crystals into the knee joints of mice. Macrophages from the various animals were stimulated to determine inflammasome activation and production of reactive oxygen species (ROS). Results Injection of MSU crystals caused joint inflammation, as seen by neutrophil influx, hypernociception, and production of IL‐1β and CXCL1. These parameters were greatly decreased in germ‐free mice, mice treated with antibiotics, and GPR‐43–deficient mice. Recolonization or administration of acetate to germ‐free mice restored inflammation in response to injection of MSU crystals. In vitro, macrophages produced ROS and assembled the inflammasome when stimulated with MSU. Macrophages from germ‐free animals produced little ROS, and there was little inflammasome assembly. Similar results were observed in macrophages from GPR‐43–deficient mice. Treatment of germ‐free mice with acetate restored in vitro responsiveness of macrophages to MSU crystals. Conclusion In the absence of microbiota, there is decreased production of short‐chain fatty acids that are necessary for adequate inflammasome assembly and IL‐1β production in a manner that is at least partially dependent on GPR43. These results clearly show that the commensal microbiota shapes the host's ability to respond to an inflammasome‐dependent acute inflammatory stimulus outside the gut.

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Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

Cited by 2,656 publications

References 42 publications

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Association of Obesity with Serum Leptin, Adiponectin, and Serotonin and Gut Microflora in Beagle Dogs

A Role for Gut Microbiota and the Metabolite‐Sensing Receptor GPR43 in a Murine Model of Gout

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