Oral acetate supplementation attenuates N-methyl D-aspartate receptor hypofunction-induced behavioral phenotypes accompanied by restoration of acetyl-histone homeostasis

Singh, Seema; Choudhury, Arnab; Gusain, Priya; Parvez, Suhel; Palit, Gautam; Shukla, Shubha; Ganguly, Shantanu

doi:10.1007/s00213-016-4213-1

Cited by 15 publications

(14 citation statements)

References 47 publications

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“…We have recently demonstrated that the concentration of acetate, the SCFA predominantly produced by microbial fermentation of B-GOS ® 55 , increases in the plasma of male rats following the ingestion of this prebiotic 39 . Furthermore, acetate supplementation itself is not only associated with increased levels of NMDAR subunits 39 , but has also been shown to rescue the behavioural effects of NMDAR blockade in rats 40 . We now show that B-GOS ® intake also increases plasma acetate in female rats (Table 2 ), though GluN2A (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The microbial fermentation of prebiotics, such as Bimuno TM galacto-oligosaccharides (B-GOS ® ), produces the short-chain fatty acids (SCFA) including acetate, butyrate, and propionate 35 , 36 , which themselves influence host physiology 37 . Importantly, the transport of acetate into glial cells is modulated by signal transmissions dependent on the NMDAR 38 , and acetate supplementation itself elevates brain NMDAR subunit levels 39 and rescues NMDAR hypofunction in rodents 40 . Circulating acetate is also an appetite suppressant 41 , and increased hepatic levels of its metabolizing enzyme, acetyl CoA carboxylase (ACC) has been associated with reduced weight gain in olanzapine-injected rats, following antibiotic administration 26 .…”

Section: Introductionmentioning

confidence: 99%

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Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota

et al. 2018

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Olanzapine is an effective antipsychotic drug but since it causes significant weight gain, it is not well tolerated by psychosis patients. The prebiotic, B-GOS®, attenuates metabolic dysfunction in obese subjects, and in rodents, alters central NMDA receptors and may affect serotonin receptors that are relevant in psychosis. We have determined whether B-GOS® influenced olanzapine-associated weight gain and central NMDA and serotonin receptors. Circulating acetate, IL-1β, IL-8 and TNFα, liver acetyl-CoA carboxylase (ACC), white adipose tissue (WAT) acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Adult female Sprague-Dawley rats were administered a B-GOS® (0.5 g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8–21. The intake of B-GOS® significantly attenuated olanzapine-induced weight gain without altering frontal cortex 5-HT2AR blockade. Cortical GluN1 levels were elevated by olanzapine in the presence of B-GOS®. Plasma acetate concentrations increased following B-GOS® or olanzapine administration alone, but reduced when prebiotic and drug were administered in combination. This pattern was paralleled by hepatic ACC mRNA expression. The abundance of WAT GPR43 mRNA was reduced by olanzapine, only in the absence of B-GOS®. Co-administration of B-GOS® and olanzapine also elevated plasma TNFα, which is reported to influence lipid metabolism. Finally, B-GOS® elevated faecal Bifidobacterium spp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOS®, was without effect. These data suggest that inclusion of B-GOS® as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis. The role of acetate in these effects requires further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota

et al. 2018

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“…In a separate study male rats (250–300 g) were gavaged with glyceryl triacetate (GTA, 1 g/ml, Sigma Aldrich, UK) at a final dose of 3 g/kg, or the same volume of water alone (control) daily for 3 weeks. The choice of GTA dose and control was based on a previous studies ( Singh et al, 2016 ).…”

Section: Methodsmentioning

confidence: 99%

“…Fermentation of B-GOS has been shown to produce significant amounts of acetate, and moderate amounts of butyrate ( Grimaldi et al, 2016 , Grimaldi et al, 2017 ). Both of these SCFAs can have central effects, particularly at the epigenetic level where they both influence the expression of brain histone deacetylases (HDACs) ( Soliman et al, 2012 , Han et al, 2014 ), but a link between metabolic acetate and NMDARs has also been demonstrated ( Hirose et al, 2009 , Singh et al, 2016 ). In this regard, if acetate is involved in B-GOS ® mediated changes of NMDAR function, then direct acetate supplementation might be expected to have similar effects on central NMDAR levels as the prebiotic itself.…”

Section: Introductionmentioning

confidence: 99%

Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS®) ingestion

Gronier

Savignac

Miceli

et al. 2018

European Neuropsychopharmacology

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We have previously shown that prebiotics (dietary fibres that augment the growth of indigenous beneficial gut bacteria) such as Bimuno™ galacto-oligosaccharides (B-GOS®), increased N-methyl-D-aspartate (NMDA) receptor levels in the rat brain. The current investigation examined the functional correlates of these changes in B-GOS®-fed rats by measuring cortical neuronal responses to NMDA using in vivo NMDA micro-iontophoresis electrophysiology, and performance in the attentional set-shifting task. Adult male rats were supplemented with B-GOS® in the drinking water 3 weeks prior to in vivo iontophoresis or behavioural testing. Cortical neuronal responses to NMDA iontophoresis, were greater (+30%) in B-GOS® administered rats compared to non-supplemented controls. The intake of B-GOS® also partially hindered the reduction of NMDA responses by the glycine site antagonist, HA-966. In the attentional set-shifting task, B-GOS® -fed rats shifted from an intra-dimensional to an extra-dimensional set in fewer trials than controls, thereby indicating greater cognitive flexibility. An initial exploration into the mechanisms revealed that rats ingesting B-GOS® had increased levels of plasma acetate, and cortical GluN2B subunits and Acetyl Co-A Carboxylase mRNA. These changes were also observed in rats fed daily for 3 weeks with glyceryl triacetate, though unlike B-GOS®, cortical histone deacetylase (HDAC1, HDAC2) mRNAs were also increased which suggested an additional epigenetic action of direct acetate supplementation. Our data demonstrate that a pro-cognitive effect of B-GOS® intake in rats is associated with an increase in cortical NMDA receptor function, but the role of circulating acetate derived from gut bacterial fermentation of this prebiotic requires further investigation.

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“…Depending on the researchers need, this method may offer more comprehensive information compared to commonly used methods for ion concentration measurements. Furthermore, IC units equipped with a splitter for dual ion detection (cations/anions including, small SCFA) provides researchers a means to quantify common ions and difficult SCFA which are altered in pathophysiological states (Christensen et al 1996;Comerford Sarah et al 2014;Drapeau and Nachshen 1988;Jiang et al 2013;Mashimo et al 2014;Perry et al 2016;Rappaport et al 1987;Singh et al 2016;Stocker et al 2015;Watchorn 1933;Yang et al 2006) with minimal sample volume. We anticipate that this new method will be useful to many research groups investigating SCFA and electrolyte concentrations and those effects on: water and electrolyte homeostasis, stroke, cardiovascular disease, hypertension, metabolic processes, cancer, and ethanol metabolism (Chapp et al 2014), to name a few.…”

Section: Perspectivementioning

confidence: 99%

Measurement of cations, anions, and acetate in serum, urine, cerebrospinal fluid, and tissue by ion chromatography

et al. 2018

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Accurate quantification of cations and anions remains a major diagnostic tool in understanding diseased states. The current technologies used for these analyses are either unable to quantify all ions due to sample size/volume, instrument setup/method, or are only able to measure ion concentrations from one physiological sample (liquid or solid). Herein, we adapted a common analytical chemistry technique, ion chromatography and applied it to measure the concentration of cations; sodium, potassium, calcium, and magnesium (Na+, K+, Ca2+, and Mg2+) and anions; chloride, and acetate (Cl−, − OAc) from physiological samples. Specifically, cations and anions were measured in liquid samples: serum, urine, and cerebrospinal fluid, as well as tissue samples: liver, cortex, hypothalamus, and amygdala. Serum concentrations of Na+, K+, Ca2+, Mg2+, Cl−, and − OAc (mmol/L): 138.8 ± 4.56, 4.05 ± 0.21, 4.07 ± 0.26, 0.98 ± 0.05, 97.7 ± 3.42, and 0.23 ± 0.04, respectively. Cerebrospinal fluid concentrations of Na+, K+, Ca2+, Mg2+, Cl−, and − OAc (mmol/L): 145.1 ± 2.81, 2.41 ± 0.26, 2.18 ± 0.38, 1.04 ± 0.11, 120.2 ± 3.75, 0.21 ± 0.05, respectively. Tissue Na+, K+, Ca2+, Mg2+, Cl−, and − OAc were also measured. Validation of the ion chromatography method was established by comparing chloride concentration between ion chromatography with a known method using an ion selective chloride electrode. These results indicate that ion chromatography is a suitable method for the measurement of cations and anions, including acetate from various physiological samples.

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Oral acetate supplementation attenuates N-methyl D-aspartate receptor hypofunction-induced behavioral phenotypes accompanied by restoration of acetyl-histone homeostasis

Abstract: The signature behavioral phenotypes induced by acute and chronic regimen of NMDA receptor antagonists seemed to be attenuated by GTA. This study thus provides a therapeutic paradigm of using dietary acetate supplement in psychiatric disorders.

Cited by 15 publications

References 47 publications

Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota

Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota

Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS®) ingestion

Measurement of cations, anions, and acetate in serum, urine, cerebrospinal fluid, and tissue by ion chromatography

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