Med. Nutr. PLoS. Frye, R. E. Biomarkers of Abnormal Energy Metabolism in Children with Autism Spectrum Disorder. 3e, f). Infect. 2017 May;66(5):1405-1418.doi: 10.2337/db16-0924. Clin. 4d). 2022 May 19. doi: 10.1111/jcmm.17342. Glob. Of note, a unique pattern of biomarkers of mitochondrial dysfunction found in the PPA rodent model is found in 1724% of the children with ASD37,64. Kratsman, N., Getselter, D. & Elliott, E. Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model. et al. Given the positive modulation of BT on mitochondrial function, we hypothesized that BT would have a preferential positive effect on AD-A LCLs. Ther. Provided by the Springer Nature SharedIt content-sharing initiative, Translational Psychiatry (Transl Psychiatry) If material is not included in the articles Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism. PGC1 also has the effect of upregulating ETC complex genes as well as mitochondrial DNA transcription. Curr. Le Poul, E. et al. & MacFabe, D. F. Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome. J. Neurosci. Thomas, R. H. et al. To determine the change in mitochondrial response to BT in the context of oxidative stress, LCLs were exposed to 0M or 10M of 2,3-dimethoxy-1,4-napthoquinone (DMNQ; Sigma-Aldrich, St. Louis, MO, USA) for 1h at 37C in a non-CO2 incubator prior to the Seahorse assay, similar to our previous studies (See Fig. Behav. Behav. Rev. PDF Butyrate Ameliorates Mitochondrial Respiratory Capacity of The Motor Rane, P. et al. This effect was believed to occur due to the recruitment of mitoplasticity pathways, resulting in the upregulation of genes to improve mitochondrial function during times of physiological stress such as the ones identified to be upregulated in this study. Towards a multidisciplinary approach to understand and manage obesity and related diseases. (a) Oxygen consumption rate (OCR) is measured to determine the mitochondrial activity. Res. In fact, there was a slight increase in reserve capacity at 1mM BT (Fig. Finegold, S. M., Downes, J. Biochem. GSK3beta, CREB, and BDNF in peripheral blood of patients with Alzheimers disease and depression. Table S2 provides the F-values for the effect of the mixed model in this section. Invest. The potential mechanisms are discussed below. Whiteley, P. et al. ATP-linked respiration was higher than baseline for AD-A at 0.1mM BT as compared to AD-N and at 1mM BT as compared to CNT (Fig. CNT LCLs were obtained from Coriell Cell Repository (Camden, NJ, USA). PLoS. Psychiatry 17, 389401 (2012). Finegold, S. M. Therapy and epidemiology of autismclostridial spores as key elements. Cunningham, M. W. & Cox, C. J. Autoimmunity against dopamine receptors in neuropsychiatric and movement disorders: a review of Sydenham chorea and beyond. Tailor, D., Hahm, E. R., Kale, R. K., Singh, S. V. & Singh, R. P. Sodium butyrate induces DRP1-mediated mitochondrial fusion and apoptosis in human colorectal cancer cells. 817, 373403 (2014). Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. 279, 1326 (2016). 625, 5663 (2016). Health Dis. Thank you for visiting nature.com. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. The result for the 48h BT exposure can be found in the Supplementary Materials. Resulting graphs display individual LCLs response to BT based on predicted curves using the model parameters and individual LCLs data. 26, 26878 (2015). Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism Transl Psychiatry. We applied our LCL model of mitochondrial dysfunction in ASD to help understand the role of BT in modulating mitochondrial function. Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort. Three of the four genes associated with energy metabolism increased expression, specifically mTOR, AMPK, and SIRT3. 185, 108112 (2011). (b) Timeline for the experiment. Clin. The outlined methods. 2b). Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure The significant drop in glycolytic rate found at 1mM BT concentration without DMNQ exposure was not seen when the CNT LCLs were exposed to DMNQ, resulting in a DMNQ by BT concentration interaction. Lymphoblastoid cell lines are pretreated with 10M of 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) for 1h to increase the intracellular reactive oxygen species before the mitochondrial assay after BT has been washed from the cell culture. Mitochondrial functional analysis is a novel tool to explore the relationship between IEC energetics and functional consequences within the contexts of health and disease. Pharmacol. BT significantly increased the expression of many genes at 1mM, but not at 0.1mM (Fig. The analysis of individual LCLs provides some insight into the effect of oxidative stress on the mitochondria in the CNT LCLs. Butyrate - The Surprising Ingredient for Gut and Brain Communication Kesli, R., Gokcen, C., Bulug, U. Med. Previ The liver plays a pivotal role in maintaining euglycemia. However, the same bacteria which produce PPA also produce BT, the relative production of which may be dependent upon the dietary substrate. Additionally, BT has been found to modulate the ASD-related genes in cell line models33. PubMed Biochim. Macfabe, D. Autism: metabolism, mitochondria, and the microbiome. 4a). Levison, M. E. Effect of colon flora and short-chain fatty acids on growth in vitro of Pseudomonas aeruginsoa and Enterobacteriaceae. Psychiatry 50, 8393 (2014). Butyrate (BT) is a ubiquitous short-chain fatty acid (SCFA) principally derived from the enteric microbiome. PubMed Central Acta 1745, 318329 (2005). Butyrate, produced by fermentation in the large intestine by gut microbiota, and its synthetic derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide, FBA, have been Butyrate Regulates Liver Mitochondrial Function, Efficiency, and Dynamics in Insulin-Resistant Obese Mice Diabetes. Pol. Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. The mixed model allowed data from the matched samples on each Seahorse plate to be compared to one another. & Joyce, D. A. Uncoupling protein-2 accumulates rapidly in the inner mitochondrial membrane during mitochondrial reactive oxygen stress in macrophages. Frye, R. E., Melnyk, S. & Macfabe, D. F. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Hypotheses 70, 508511 (2008). 5c). Mitochondria - intracellular organelles - are our organism's "powerhouse", the main oxygen sensors that play the . BT decreased the excitatory and increased the inhibitory neurotransmitter genes in the prefrontal cortex and had a positive effect on behavior by increasing social behavior and decreasing repetitive behavior through modulating the excitatoryinhibitory balance of the brain67. BT resulted in an increase in the expression of genes associated with mitochondrial dynamics, particularly mitochondrial fission and mitophagy (Fig. This explains the mean data in Fig. We approach the comparison between CNT and ASD cell lines and the differences between the two types of ASD cell lines (AD-N, AD-A) in a systematic fashion. These LCLs were obtained from the Autism Genetic Resource Exchange (Los Angeles, CA, USA) and the National Institutes of Mental Health (Bethesda, MD, USA) center for collaborative genomic studies on mental disorders. Authors Shannon Rose 1 , Sirish C Bennuri 1 , Jakeira E Davis 1 , Rebecca Wynne 1 , John C Slattery 1 Gen. Physiol. Turnbaugh, P. J. & Terzi, Y. Maximal oxidative to glycolytic capacity ratio (OCR/ECAR) was significantly higher for AD-A as compared to AD-N (Fig. Expert. 14, 2533 (2015). Li, L. X., Skorpen, F., Egeberg, K., Jorgensen, I. H. & Grill, V. Uncoupling protein-2 participates in cellular defense against oxidative stress in clonal beta-cells. Statistical significance levels: *p0.05, **p0.01, ***p0.001, ****p0.0001. volume8, Articlenumber:42 (2018) These are a subject of further inquiry. J. Lipid Res. Many of these mitoplastic processes may occur through PGC1 as PGC1 upregulates genes important for mitochondrial metabolism, including nuclear respiratory factors (NRF-1, NRF-2), UCP, and genes essential for redox metabolism, including superoxide dismutase, catalase, and glutathione peroxidase-1 and decreases expression of genes that inhibit ETC function (AKT)92,93. It should be noted that the findings in this study may or may not relate to other tissue types (i.e., brain, colon), doses, or critical time periods in development. Song, Y., Liu, C. & Finegold, S. M. Real-time PCR quantitation of clostridia in feces of autistic children. Butyrate may also protect the mitochondria from other forms of oxidative stress, but its potential against radiation poisoning is especially encouraging . The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. The bars adjacent to the data lines represent the overall significant difference. J. The observed difference between LCFA and SCFA likely reflects the ability of butyrate to bypass the highly regulated LCFA transport mechanisms of the mitochondria which are altered in chronic heart failure. 33, 139146 (2000). Proton leak respiration was significantly higher for AD-A at 1mM BT as compared to CNT (Fig. B., Agarwal, R., MacFabe, D. F. & La Gamma, E. F. Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells--possible relevance to autism spectrum disorders. Acta 1777, 118129 (2008). Annu. What is Butyrate? BT demonstrated a concentration-dependent effect on CNT LCLs such that the highest BT concentration influenced mitochondrial function with this effect independent of the exposure time. 15, 201211 (2016). These metabolic groupings have been shown to be consistent and repeatable in our previous studies65,80,81,82,83,84. For the AD-A LCLs, BT regulated reserve capacity to an overall higher set-point at higher BT concentration (~0.9mM). The human body houses a diverse ecosystem of microbes collectively referred to as the human microbiome. Studies have shown that butyrate, a natural gut-bacteria product, alleviates the disease progression of ALS mice overexpressing a human ALS-associated mutation, hSOD1G93A. 126, 4349 (2014). Brown, C. T. et al. Welcome to GutBites, Here is your go-to destination for reliable and evidence-based information on gut health, fiber, butyrate, mitochondria, and the fascinating world of the microbiome.Authored by a knowledgeable gastro doctor, this platform serves as your trusted resource to unravel the mysteries of your gut and empower you with valuable insights into optimizing your digestive well-being. In fact, germ-free mice demonstrate a specific deficit in bioenergetics in colon tissue with this deficiency rescued by the BT-producing bacteria Butyrivibrio fibrisolvens. Med. Pellizzaro, C., Coradini, D. & Daidone, M. G. Modulation of angiogenesis-related proteins synthesis by sodium butyrate in colon cancer cell line HT29. Streptozotocin-induced type-1-diabetes disease onset in Sprague-Dawley rats is associated with an altered intestinal microbiota composition and decreased diversity. Neuroimage 40, 18881901 (2008). 245, E253E260 (1983). Pharmacol. J. Biol. Foley, K. A., MacFabe, D. F., Vaz, A., Ossenkopp, K. P. & Kavaliers, M. Sexually dimorphic effects of prenatal exposure to propionic acid and lipopolysaccharide on social behavior in neonatal, adolescent, and adult rats: implications for autism spectrum disorders. 31, 904909 (2017). Conn, A. R., Fell, D. I. Gene expression was analyzed similarly, although only two BT concentrations for 24h exposure without DMNQ exposure were examined. A Seahorse Extracellular Flux (XF) 96 Analyzer (Seahorse Bioscience, Inc., North Billerica, MA, USA) measured the oxygen consumption rate (OCR), an indicator of mitochondrial respiration, in live intact LCLs in real-time. Article Sodium butyrate prevented mice from developing non-alcoholic steatohepatitis (NASH), an inflammatory disease caused by fat building up in the liver . The color of the stars and bars represents the specific comparisons. Microbiol. BT has positive effects in biological models of several important human diseases, including diabetes43,44, neurodegenerative disorders18,45, leukemia46, lymphoma47, and colorectal48,49, breast50,51, and pancreatic52 cancers. Health Dis. J. Dent. Transl. Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism. PubMed Central 2018 Feb 2;8(1):42.doi: 10.1038/s41398-017-0089-z. ONE 9, e87072 (2014). 10, 4356 (2016). In the meantime, to ensure continued support, we are displaying the site without styles There are many lines of evidence that BT may be helpful in normalizing the behavior and physiological abnormalities in ASD. J. Int. https://doi.org/10.1038/s41398-017-0089-z, DOI: https://doi.org/10.1038/s41398-017-0089-z. J. Physiol. Portal vein concentrations are about twice the hepatic vein concentrations due to the metabolism of BT in the liver, and peripheral blood concentrations are about one-third the hepatic vein concentrations87. J. Dev. J. Med. J. Alzheimers Dis. Sci. Short-chain fatty acids induce colonic mucosal injury in rats with various postnatal ages. Mitochondrial and redox abnormalities in autism lymphoblastoid cells: a sibling control study. ATP-linked respiration (a), maximal respiratory capacity (c), reserve capacity (d), glycolytic rate (e), and glycolytic Reserve (f) were reduced at 1.0mM BT relative to no BT exposure. Sodium butyrate exerts neuroprotective effects by restoring the blood-brain barrier in traumatic brain injury mice. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Mol. Med. Although we believe that this is an adaptation to protect the cell and might make AD-A LCLs more resistant to toxicants84, in our previous studies, we found that the AD-A LCLs are more sensitive to acute increases in ROS. BT has been shown to have positive health effects by stimulating mitochondrial function. Biophys. Neurosci. Ferrante, R. J. et al. Alterations in the enteric microbiome, dynamically throughout the lifecycle, but particularly in early life, have been implicated in health and disease, including psychiatric disorders such as depression and anxiety10, gastrointestinal (GI) disorders11, inflammatory airway disease12, diabetes13,14,15, obesity16,17, atopic disease5, neurodegenerative conditions18, and early brain development and behavior19,20,21. 13, 517526 (2011). Oncotarget 7, 5607156082 (2016). Rodrigues, M. F., Carvalho, E., Pezzuto, P., Rumjanek, F. D. & Amoedo, N. D. Reciprocal modulation of histone deacetylase inhibitors sodium butyrate and trichostatin A on the energy metabolism of breast cancer cells. Rossignol, D. A. Brain Res. Gut Bites | Chris Damman, MD, MA 26, 27458 (2015). Sun, J. et al. J. Google Scholar. Although BT regulates maximal respiratory capacity to a set-point, this occurs at higher BT concentrations (0.8mM) with the set-point being overall higher. Since there was few difference in these relationships across BT exposure times, the average of the two exposure times is presented. The models fit well to the data [ATP-linked respiration: F(8405)=137.8, p<0.0001, r2=0.63, r=0.79; proton leak respiration: F(8405)=36.3, p<0.0001, r2=0.40, r=0.63; maximum respiratory capacity: F(13,400)=76.7, p<0.0001, r2=0.60, r=0.77; reserve capacity: F(13,400)=52.01, p<0.0001, r2=0.41, r=0.64]. Total RNA was isolated from 5 million LCLs using the RNeasy mini kit (Qiagen, Hilden, Germany) following manufacturers protocol. Govindarajan, N., Agis-Balboa, R. C., Walter, J., Sananbenesi, F. & Fischer, A. Butchbach, M. E. et al. Standard error bars are provided in graphs. Google Scholar. Dispos. PLoS. Eur. Stilling, R. M. et al. 141, 3239 (2014). PubMed J. Med. This is consistent with our recent study where we demonstrated that treatment with DMNQ after prolonged exposure to a toxicant enhanced the respiratory parameters related to ATP production in AD-A but not AD-N LCLs84. In this study, we demonstrated, for the first time, that BT has a modulatory effect on mitochondrial function in LCLs from both healthy children and children with ASD. Furthermore, various low refined carbohydrate diets proposed to help in ASD may do so by reducing these substrates leading to reduced SCFA production by ASD-associated bacteria, while supplementation of foods higher in complex fibers (i.e., inulins) may exert a therapeutic response by preferentially increasing BT production over PPA18. 4e). Cummings, J. H., Pomare, E. W., Branch, W. J., Naylor, C. P. & Macfarlane, G. T. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Google Scholar. BT is an SCFA derived from the enteric microbiome which is a mitochondrial fuel and modulator of mitochondrial function and gene expression.