PART 1: The Microbiome: Short-Chain Fatty Acids and the LPS Connection

Human cells make up only 43% of the body’s total cell count, while microorganisms comprise the remaining 57% (1). Considering that over half of the body is made up of microscopic organisms, it is important to maintain the delicate balance between harmful, beneficial, and probiotic species in the microbiome. Alterations in the intestinal microbial composition have long been associated with chronic inflammation (2). By first defining the microbiome and how a healthy gut benefits its host, the major phyla of the microbiome can be examined, along with the role they play in human health. Of particular importance for this discussion is the production of short-chain fatty acids (SCFAs), which help prevent lipopolysaccharides from damaging the epithelial barrier, jeopardizing its integrity, causing systemic inflammation, and ultimately resulting in autoimmunity.

The human microbiome represents the entirety of microorganisms, including their genes, functional gene products, and metabolites, found in and on the human body at a given point in time. A healthy gut microbiome provides absorption of NaCl and water, nutrient synthesis, control of epithelial cell proliferation, and protection against pathogens by a barrier effect. In addition, fermentation of undigested dietary residue and endogenous mucous in the gut produce SCFAs, which are “the key mediators for communication between the host and gut microbes and are metabolites produced by microbes that have the ability to influence host immunity and metabolism” (3).

The intestinal microbiome is dominated by phyla Bacteroidetes and Firmicutes and together they produce three of the most abundant SCFAs. Bacteroidetes is a gram-negative bacteria and the main producer of the SCFAs acetate and propionate (4). These two SCFAs can travel across the epithelium to the liver, where they are involved in lipid biosynthesis (4). Firmicutes is a gram-positive bacteria and the primary contributor of butyrate, a SCFA that is metabolized in the epithelial mucosa and responsible for gluconeogenesis (4). In addition to lipid biosynthesis and gluconeogenesis, SCFAs affect gut integrity by decreasing the luminal pH and enhancing absorption of some nutrients, all while directly impacting gut microbiota composition (4). As noted in 2019 research by Holota et al. published in PLOS One, “SCFAs have long been known to exert beneficial effects against intestinal inflammation and protect intestinal epithelial integrity. However, the molecular targets for these bacterial metabolites have been identified only recently” (2). SCFAs can decrease inflammation and oxidative stress by two mechanisms. In the first mechanism, SCFAs activate G-protein receptors (GPCRs). In the Holota et al. study, loss of Gprotein coupled receptors FFA2 and FFA3 were associated with inflammatory responses, suggesting they are critical regulators of intestinal inflammation and epithelial barrier function (2). In the second mechanism, SCFAs inhibit nuclear class I histone deacetylases (HDACs), decreasing pro-inflammatory cytokines (IL-3, IL-6, tumor necrosis factor-α), and thereby reducing NF-κβ (4).

The intestinal microbiome is dominated by phyla Bacteroidetes and Firmicutes and together they produce three of the most abundant SCFAs. Bacteroidetes is a gram-negative bacteria and the main producer of the SCFAs acetate and propionate (4). These two SCFAs can travel across the epithelium to the liver, where they are involved in lipid biosynthesis (4). Firmicutes is a gram-positive bacteria and the primary contributor of butyrate, a SCFA that is metabolized in the epithelial mucosa and responsible for gluconeogenesis (4). In addition to lipid biosynthesis and gluconeogenesis, SCFAs affect gut integrity by decreasing the luminal pH and enhancing absorption of some nutrients, all while directly impacting gut microbiota composition (4). As noted in 2019 research by Holota et al. published in PLOS One, “SCFAs have long been known to exert beneficial effects against intestinal inflammation and protect intestinal epithelial integrity. However, the molecular targets for these bacterial metabolites have been identified only recently” (2). SCFAs can decrease inflammation and oxidative stress by two mechanisms. In the first mechanism, SCFAs activate G-protein receptors (GPCRs). In the Holota et al. study, loss of Gprotein coupled receptors FFA2 and FFA3 were associated with inflammatory responses, suggesting they are critical regulators of intestinal inflammation and epithelial barrier function (2). In the second mechanism, SCFAs inhibit nuclear class I histone deacetylases (HDACs), decreasing pro-inflammatory cytokines (IL-3, IL-6, tumor necrosis factor-α), and thereby reducing NF-κβ (4).

The balance of the microbiome is important in maintaining the health of an individual because the ratio of SCFAs in the colon is influenced by strain and quantity of gut micr obiota (4). SCFAs have many roles, but in the interest of this article, they decrease pro-inflammatory cytokines and help to offset the damage that LPS causes. A study done by Wang et al. set out to investigate the effects of SCFAs on septic shock and found butyrate significantly decreased the mortality of septic mice. Pretreatment with butyrate led to significant attenuation of the LPS-induced elevation of inflammatory TNF-α, IL-6, and IL- 1β levels while significantly increasing upregulation of anti-inflammatory cytokine IL-10 (6).

Although many gut microbial populations have been characterized as either “good” or “bad,” they only play a part in a larger and more complex biological system (3). In a population study done in Denmark, “Individuals whose guts contained a low diversity of bacteria were found to have higher levels of body fat and inflammation than those with high gut-microbial richness” (7). Human health is impacted by the diversity of our microbiome, and resulting metabolites like SCFAs decrease inflammation and repair LPS damage. We have only begun to understand the importance of microbiome diversity and how it impacts overall inflammation levels and ultimately, human health.

In our next installment in this series, we will look at inflammatory diseases associated with LPS, followed by how botanicals have shown promise in balancing the microbiome and favorably impacting inflammatory conditions commonly seen in clinical practice.

REFERENCES

1. Gallagher, James. “More Than Half of Your Body is not Human.” BBC News, 10 Apr. 2018, https://www.bbc.com/news/health-43674270

2. Holota Y, Dovbynchuk T, Kaji I, Vareniuk I, Dzyubenko N, Chervinska T, et al. (2019) The long-term consequences of antibiotic therapy: Role of colonic short-chain fatty acids (SCFA) system and intestinal barrier integrity. PLoS ONE 14(8): e0220642. https://doi.org/10.1371/ journal.pone.0220642

3. Kagele, Dominique. “The ‘Skinny’ on Gut Microbes and Your Health.” The Jackson Laboratory, 26 May 2015, https://www.jax.org/news-and-insights/jax-blog/2015/may/theskinny-on-gut-microbes-and-your-health#. Accessed 23 Dec. 2020.

4. Feng W, Ao H and Peng C (2018) Gut Microbiota, Short-Chain Fatty Acids, and Herbal Medicines. Front. Pharmacol. 9:1354. doi: 10.3389/fphar.2018.01354

5. “TLR4 (Toll like receptor 4) - Receptor of LPS of Bacteria”. Cloud-Clone Corp., 17 Feb 2015, http://www.cloud-clone.com/topic/201502170821230035.html. Accessed 15 Dec 2020.

6. Wang F, Liu J, Weng T, Shen K, Chen Z, Yu Y, Huang Q, Wang G, Liu Z, Jin S. The Inflammation Induced by Lipopolysaccharide can be Mitigated by Short-chain Fatty Acid, Butyrate, through Upregulation of IL-10 in Septic Shock. Scand J Immunol. 2017 Apr;85(4):258-263. doi: 10.1111/sji.12515. PMID: 27943364.

7. Le Chatelier, E., Nielsen, T., Qin, J. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013). https://doi.org/10.1038/nature12506