Collin Gow, C.N.C.

Scientific Evidence On Butyrate:

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• Regulates transepithelial transport

• Modulates motility

• Prevents and inhibits colon carcinoma

• Enhances absorptive and antisecretive capabilities of intestinal mucosa

• Increases expression of mucin genes and stimulates production of mucin

• Inhibits NF-κB and reduces expression of cytokine genes TNFα, IL1β, IL2, IL6, IL8, and IL12

• Reduces reactive oxygen species

• Increases amount of reduced glutathione

https://smw.ch/article/doi/smw.2012.13596

Butyric acid: what is the future for this old substance?

DOI: https://doi.org/10.4414/smw.2012.13596

• Reduces obesity and insulin resistance

• Promotes a change from lipid synthesis to lipid oxidation

• May activate AMP-k or MAPK

• Induces production of gut hormones reducing food intake

• Promotes colon motility

• Reduces inflammation

• Increases visceral irrigation

• Induces apoptosis

• Inhibits tumor cell progression

• Inhibits histone deacetylation

• Induces the differentiation of T-regulatory cells

• Assists in controlling intestinal inflammation

• May reduce the risk of inflammatory bowel disease

• Gut barrier maintanence

Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, de Los Reyes-Gavilán CG, Salazar N. Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health. Front Microbiol. 2016;7:185. Published 2016 Feb 17. doi:10.3389/fmicb.2016.00185

• Preferred energy source for colon epithelial cells

• Supports normal intestinal PH

• Increases bile salt solubility, increases mineral absorption, decreases ammonia absorption, inhibits growth of pathogens

• Stimulates proliferation of normal colon epithelial cells

• Prevents proliferation and induces apoptosis of colorectal cancer cells

• Affects gene expression of colon epithelial cells

• Plays a protective role against colitis

• Improves gut barrier function by stimulating the formation of mucin, antimicrobial peptides, and tight-junction proteins

• Stimulates the absorption of water and sodium

• Reduces oxidative stress in the colon

• Promotes satiety

Rivière A, Selak M, Lantin D, Leroy F, De Vuyst L. Bifidobacteria and Butyrate-Producing Colon Bacteria: Importance and Strategies for Their Stimulation in the Human Gut. Front Microbiol. 2016;7:979. Published 2016 Jun 28. doi:10.3389/fmicb.2016.00979

• Reduces appetite

• Stimulates the metabolic activity of brown adipose tissue

Li Z, Yi C, Katiraei S, et al

Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit

Gut 2018;67:1269-1279.

• Enhances mitochondrial respiration of colonocytes

• Prevents colonocyte autophagy (catabolic self-eating)

Donohoe DR, Garge N, Zhang X, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011;13(5):517-26.

• Prevents adhesion of antigen-presenting cells

• Inhibits the proliferation and activation of T cells

Meijer K, de Vos P, Priebe MG. Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Curr Opin Clin Nutr Metab Care. 2010 Nov;13(6):715-21. doi: 10.1097/MCO.0b013e32833eebe5.

• Improves neuroinflammation in aging mice (attenuates pro-inflammatory cytokine expression in microglia)

Matt SM, Allen JM, Lawson MA, Mailing LJ, Woods JA, Johnson RW. Butyrate and Dietary Soluble Fiber Improve Neuroinflammation Associated With Aging in Mice. Front Immunol. 2018;9:1832. Published 2018 Aug 14. doi:10.3389/fimmu.2018.01832

• Limits intestinal inflammation by promoting the formation of regulatory T cells

• Modulates the function of innate immune cells

• Inhibits histone deacetylases

• Activates a receptor for niacin in the colon

• Promotes expression of the pro-homeostatic cytokine IL-18

• Increases colonic epithelial cell oxygen consumption (a good thing)

• Supports normal intestinal barrier function

• Plays a role in maintaining healthy colon barrier function

• Promotes and maintains mucosal homeostasis

Cushing K, Alvarado DM, Ciorba MA. Butyrate and Mucosal Inflammation: New Scientific Evidence Supports Clinical Observation. Clin Transl Gastroenterol. 2015;6(8):e108. Published 2015 Aug 27. doi:10.1038/ctg.2015.34

• Regulates transepithelial fluid transport

• Ameliorates mucosal inflammation and oxidative status

• Reinforces epithelial defense barrier

• Modulates visceral sensitivity and intestinal motility

• Prevents and inhibits colorectal cancer

• Potentially useful effects on hemoglobinopathies, genetic metabolic diseases, hypercholesterolemia, insulin resistance, and ischemic stroke

• Major energy source for colonocytes

• Stimulates sodium chloride absorption at the intestinal level

• Increases WAF1 gene expression

• Downregulates NRP-1

• Inhibits NF-κB in human colonic epithelial cells which regulates genes involved in inflammatory responses such as IL-1b, TNF-α, IL-2, IL-6, IL-8, IL-12, iNOS, COX-2, ICAM-1, VCAM-1, TCR-α, and MHC class II molecules

• NF-κB is frequently disregulated in colon cancer, inflammatory bowel disease, ulcerative colitis, Chron's disease

• Upregulates PPARγ and inhibits IFNγ signaling reducing inflammation

• Modulates oxidative stress in colonic mucosa

• Increases the expression of the MUC2 gene stimulating mucin production and enhancing protection against luminal agents

• Decreases intestinal cell permeability by assembling tight-junction via AMPK

• Regulates colonic mucosa homeostasis

• Modulates neuronal excitability

• Significantly increases the proportion of choline acetyltransferase and increases the cholinergic-mediated colonic circular muscle contractile response which may help with gastric motility

• Increases compliance, reduces pain, reduces urge, and reduces discomfort during rectal barostat procedure suggesting potential beneficial effect in IBS

• Reduced insulin resistance by 50% in mouse study

• Postbiotic

Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol. 2011;17(12):1519-28.

• Anti-inflammatory effect by activating G-protein-coupled receptors and inhibiting histone deacetylases

• One of the major metabolites of gut microbiota

• Maintains homeostasis in the gut

• Inhibits osteoclastogenesis which may reduce bone destruction which is directly related to RA prognosis

• Antiinflammatory effect by downregulating IL-12 and upregulating IL-10

• Ameliorates autoimmune diseases such as experimental allergic encephalomyelitis, GvHD, and ulcerative colitis

• Ameliorates rheumatoid inflammation

Kim DS, Kwon JE, Lee SH, et al. Attenuation of Rheumatoid Inflammation by Sodium Butyrate Through Reciprocal Targeting of HDAC2 in Osteoclasts and HDAC8 in T Cells. Front Immunol. 2018;9:1525. Published 2018 Jul 6. doi:10.3389/fimmu.2018.01525

• Attenuates high fat diet induced non alcoholic fatty liver disease in mice

• Corrects high fat diet induced gut microbiota imbalance

• Elevates abundances of beneficial bacteria

• Restores high fat diet induced intestinal mucosa damage

• Increases expression of ZO-1 in small intestine

• Decreases the levels of gut endotoxin in serum and liver compared with high fat group

• Downregulates endotoxin associated genes TLR4 and Myd88 and pro-inflammation genes such as MCP-1, TNF-α, IL-1, IL-2, IL-6 and IFN-γ in liver or epididymal fat

• Ameliorates liver inflammation and fat accumulation

• Reduces triglyceride and cholesterol levels in liver

• Decreases NAS score

• Improves FBG and HOMA-IR and ALT and AST

Zhou D, Pan Q, Xin FZ, et al. Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier. World J Gastroenterol. 2017;23(1):60-75.

• Stimulates appetite suppressing hormones

• Increases capacity for cold induced thermogenesis

• Completely blocked high fat diet induced weight gain in mice

• Reduced fasting insulin and leptin levels

• Protects against diet-induced obesity in mice

Lin HV, Frassetto A, Kowalik EJ, et al. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 2012;7(4):e35240.

• At low concentration promotes intestinal barrier function as measured by transepithelial electrical resistance

• At high concentration reduces TER and increases gut permeability

Peng L, He Z, Chen W, Holzman IR, Lin J. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatr Res. 2007 Jan;61(1):37-41.

• Increases colonic blood flow

• May enhance colonic anastomosis healing

• May reduce the symptoms of ulcerative colitis and may prevent the progression of colitis in general

Velázquez OC, Lederer HM, Rombeau JL. Butyrate and the colonocyte. Production, absorption, metabolism, and therapeutic implications. Adv Exp Med Biol. 1997;427:123-34.

• Regulates GPR41-mediated sympathetic nervous system activity controlling body energy expenditure and maintaining metabolic homeostasis

• Increases expression of trefoil factors (TFFs), which are mucin-associated peptides that help maintain and repair the intestinal mucosa

• Stimulates the production of antimicrobial peptides such as IL-37

Liu H, Wang J, He T, et al. Butyrate: A Double-Edged Sword for Health?. Adv Nutr. 2018;9(1):21-29.

• Decreases IBS symptoms

• Increases the effectiveness of peristalsis

• Counteracts acute dehydration from diarrhoea

• Decreases symptoms of diverticulosis

Borycka-Kiciak K, Banasiewicz T, Rydzewska G. Butyric acid - a well-known molecule revisited. Prz Gastroenterol. 2017;12(2):83-89.

• Upregulates the expression of tight junction proteins

Yan H, Ajuwon KM. Butyrate modifies intestinal barrier function in IPEC-J2 cells through a selective upregulation of tight junction proteins and activation of the Akt signaling pathway. PLoS One. 2017;12(6):e0179586. Published 2017 Jun 27. doi:10.1371/journal.pone.0179586

• Enhances intestinal barrier by regulating the assembly of tight junctions

Peng L, Li ZR, Green RS, Holzman IR, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr. 2009;139(9):1619-25.

• Promotes reassembly of tight-junctions

Miao W, Wu X, Wang K, et al. Sodium Butyrate Promotes Reassembly of Tight Junctions in Caco-2 Monolayers Involving Inhibition of MLCK/MLC2 Pathway and Phosphorylation of PKCβ2. Int J Mol Sci. 2016;17(10):1696. Published 2016 Oct 10. doi:10.3390/ijms17101696

• Represses permeability-promoting claudin-2 tight-junction protein expression

Zheng L, Kelly CJ, Battista KD, et al. Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor-Dependent Repression of Claudin-2. J Immunol. 2017;199(8):2976-2984.

• Enhances mRNA expression of the intestinal mucosal tight junction proteins occludin and zonula occluden protein-1

Ma X, Fan PX, Li LS, Qiao SY, Zhang GL, Li DF. Butyrate promotes the recovering of intestinal wound healing through its positive effect on the tight junctions. J Anim Sci. 2012 Dec;90 Suppl 4:266-8. doi: 10.2527/jas.50965.