New Insights into Health Effects of Alcohol

Alcohol: an important prevention tool?

Epidemiological studies and controlled trials on alcohol consumption invariably show a U shaped mortality curve where abstinence is associated with higher mortality and increasing alcohol consumption improves health until mortality begins to rise again with high alcohol consumption.  As well as all-cause mortality there is a greater reduction of cardiovascular mortality (1) that apparently exceeds the protection afforded by taking statins. While the toxic effects of excess alcohol on brain and liver cells have been known for some time the biological mechanisms behind the protective effect of moderate alcohol consumption are less clear (2) but documented effects include increased high-density lipoprotein cholesterol and fibrinolysis, decreased platelet aggregation and coagulation factors, and beneficial effects on endothelial function and inflammation (3).

It has been just 10 years since the publication of the discovery of receptors for short chain fatty acids in 2003 (4) and there has been a huge interest generated in their important signaling functions and understanding of the relationship of gut microbiota and health, particularly inflammation (5).  The main source of short chain fatty acids is bacterial fermentation of fiber but alcohol is another important source of acetate which in some circumstances can be greater than the amount generated from fiber fermentation (6).  After consumption alcohol is quickly absorbed and metabolized to acetate increasing blood levels 10-20 fold.  Acetate is an energy source for most organs including brain cells and it is also a signaling molecule by at least two mechanisms; as an inhibitor of Histone Deacetylases and an agonist of free fatty acid receptors (FFAR2).  Because alcohol is converted to acetate after absorption mainly by liver cells the FFAR2 receptors primarily targeted would be on cells of the immune system and fat cells rather than intestinal epithelial cells.

Acetate is the most abundant SCFA, followed by propionate and butyrate, produced by bacterial fermentation of fiber which takes place mainly in the terminal ileum and large intestine (7).  The SCFA’s, particularly butyrate, are important energy substrates for intestinal epithelial cells and excess SCFA passes through to the liver and systemic circulation performing dual roles as an energy substrate and cell signaling.  Two G-protein coupled receptors for SCFA have been identified FFAR2 and FFAR3 which preferentially bind acetate/propionate and butyrate respectively (8).  There is a direct link between fiber consumption producing SCFA and increased GLP1 secretion from intestinal L cells which is triggered via the SCFA receptors FFAR2 and 3.  In addition SCFA’s can have direct effects on gene expression by inhibition of Histone Deacetylases HDAC(9) which has anti-proliferative and anti-inflammatory effects in vitro, and in in vivo models of intestinal inflammation (10) and either of these mechanisms are thought to be responsible for widespread beneficial effects of SCFA as listed below:

  • FFAR2 agonists reduce inflammation and regulate adipokine secretion in adipose tissue (11) increasing leptin and decreasing the pro-inflammatory resistin.
  • FFAR2 agonists have anti-inflammatory effects in colitis, arthritis and asthma (12)
  • FFAR2 agonists, SCFA induce T regulatory cells important in controlling intestinal barrier functions and immunity (9)
  • Acetate via acetylation effects protein function and gene expression and inhibits histone deacetylases.  Increased acetate levels stimulates mitochondrial function and has been linked to delaying the aging process (13).
  • FFAR2 agonist SCFA’s control Glucagon Like Peptide release from intestinal L cells (14). GLP1 slows gastric emptying, lowers glucose levels, and reduces food consumption.  GLP1 is an important regulator of glucose metabolism and also suppresses appetite (14).
  • GLP1 has been recently shown to stimulate apolipoprotein A-I gene expression in hepatocytes in culture (15) with important implications for increasing plasma HDL and protection against cardiovascular disease.
  • GLP1 prevents the accumulation of monocytes and macrophages in arterial wall and suppresses proinflammatory cytokine expression in macrophages (16).
  • FFAR2 agonists SCFA stimulate secretion of anorexic hormone PYY from intestinal L cells (14).
  • FFAR2 agonists SCFA also inhibit the secretion of the orexigenic hormone ghrelin (17).
  • FFAR2 agonists reduce endothelial cell expression of leukocyte adhesion molecules VCAM and ICAM which are important in the development of cardio-vascular diseases (18)

Summary

Acetate and other short chain fatty acids activate specific receptors that are widely expressed throughout body tissue importantly on immune cells and adipose tissue and suppress inflammation while the FFAR2 receptors in intestinal cells produce additional signaling molecules GLP1 and PYY which suppress appetite, stimulate hepatic HDL production and contribute to further anti-inflammatory and metabolic regulatory functions.  Pharmaceutical companies see a multibillion dollar business in producing drugs which mimic SCFA’s and Glucagon Like Peptides. GLP1 agonists exenatide and liraglutide are approved and widely prescribed for weight loss treatment programs but are already subject of claims of complications and class action law suits.  Although not profitable to “big pharma”, we suggest much better results are achievable with lifestyle measures involving increased fiber consumption and appropriate use of alcohol.

Works Cited

1. Streppel MT, Ocké MC, Boshuizen HC, Kok FJ, Kromhout D. Long-term wine consumption is related to cardiovascular mortality and life expectancy independently of moderate alcohol intake: the Zutphen Study. . s.l. : J Epidemiol Community Health. 2009 Jul;63(7):534-40.

2. Augusto Di Castelnuovo, Simona Costanzo, Vincenzo Bagnardi, Maria Benedetta Donati, Licia Iacoviello, Giovanni de Gaetano. Alcohol Dosing and Total Mortality in Men and WomenAn Updated Meta-analysis of 34 Prospective Studies. . s.l. : Arch Intern Med. 2006;166(22):2437-2445.

3. Michel M. Joosten, Marjan J. van Erk, Linette Pellis, Renger F. Witkamp, Henk F. J. Hendriks. Moderate alcohol consumption alters both leucocyte gene expression profiles and circulating proteins related to immune response and lipid metabolism in men. s.l. : British Journal of Nutrition (2012), 108, 620–627 doi:10.1017/S0007114511005988.

4. Andrew J. Brown, Susan M. Goldsworthy, Ashley A. Barnes, et al. The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids. s.l. : THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278, No. 13, Issue of March 28, pp. 11312–11319, 2003.

5. Gijs den Besten, Karen van Eunen, Albert K. Groen, Koen Venema, Dirk-Jan Reijngoud, Barbara M. Bakker. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. . s.l. : J. Lipid Res. 2013 54:(9) 2325-2340. .

6. al., Lihong Jiang et. Increased brain uptake and oxidation of acetate in heavy drinkers. . s.l. : J Clin Invest. 2013;123(4):1605–1614. doi:10.1172/JCI65153.

7. al., Brian T. Layden et. Short chain fatty acids and their receptors: new metabolic targets. . s.l. : Translational Research2013;161:131–140.

8. Brian T. Layden, Anthony R. Angueira, Michael Brodsky, Vivek Durai, William L. Lowe Jr.. Short chain fatty acids and their receptors: new metabolic targets. . s.l. : Translational Research2013;161:131–140.

9. Patrick M. Smith, Michael R. Howitt, Nicolai Panikov, Monia Michaud, Carey Ann Gallini, Mohammad Bohlooly-Y, Jonathan N. Glickman, Wendy S. Garrett. The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis. . s.l. : Science 341, 569 (2013). DOI: 10.1126/science.1241165.

10. Schilderink R, Verseijden C, de Jonge WJ. Dietary inhibitors of histone deacetylases in intestinal immunity and homeostasis. . s.l. : Front Immunol. 2013 Aug 1;4:226. doi: 10.3389/fimmu.2013.00226. eCollection 2013.

11. Sa’ad H. Al-Lahham, Han Roelofsen†, Marion Priebe†, Desiree Weening†, Martijn Dijkstra, Annemieke Hoek, Farhad Rezaee, Koen Venema, Roel J. Vonk. Regulation of adipokine production in human adipose tissue by propionic acid. . s.l. : Eur J Clin Invest 2010; 40 (5): 401–407.

12. Maslowski, Vieira, Aylwin, Kranich, Sierro, Di Yu, Schilter, Rolph, Mackay, Artis, Xavier, Teixeira, Mackay. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. . s.l. : Nature. 2009 October 29; 461(7268): 1282–1286. .

13. Tadahiro Shimazu, Matthew D. Hirschey, Jing-Yi Huang, Linh T.Y. Ho, Eric Verdin. Acetate metabolism and aging: An emerging connection. . s.l. : Mechanisms of Ageing and Development 131 (2010) 511–516.

14. Gwen Tolhurst, Helen Heffron, Yu Shan Lam, Helen E. Parker, Abdella M. Habib, Eleftheria Diakogiannaki, Jennifer Cameron, Johannes Grosse,2 Frank Reimann, Fiona M. Gribble. Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein–Coupled Receptor FFAR2. s.l. : Diabetes 61:364–371, 2012.

15. Chehade JM, Alcalde R, Naem E, Mooradian AD, Wong NC, Haas MJ. Induction of apolipoprotein A-I gene expression by glucagon-like peptide-1 and exendin-4 in hepatocytes but not intestinal cells. s.l. : Metabolism. 2013 Feb;62(2):265-74. doi: 10.1016/j.metabol.2012.07.005. Epub 2012 Aug 16.

16. Masayuki Arakawa, Tomoya Mita, Kosuke Azuma, Chie Ebato, Hiromasa Goto, Takashi Nomiyama, Yoshio Fujitani, Takahisa Hirose, Ryuzo Kawamori, Hirotaka W. Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-like Peptide-1 Receptor Agonist, Exendin-4. s.l. : Diabetes 59:1030–1037, 2010.

17. Julie-Anne Nazare, PhD, Vale´rie Sauvinet, BS, Sylvie Normand, PhD, Laetitia Gue´rin-Deremaux, PhD, Laure Gabert, BS, Michel De´sage, PhD, Daniel Wils, PhD, and Martine Laville, MD, PhD. Impact of a Resistant Dextrin with a Prolonged Oxidation Pattern on Day-Long Ghrelin Profile. s.l. : Journal of the American College of Nutrition, Vol. 30, No. 1, 63–72, 2011.

18. D. Zapolska-Downar, M. Naruszewicz. Propionate Reduces The Cytokine-Induced Vcam-1 And Icam-1 Expression By Inhibiting Nuclear Factor-K B (Nf-Kb) Activation . s.l. : Journal Of Physiology And Pharmacology 2009, 60, 2, 123-131. http://www.jpp.krakow.pl.

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