Short Chain Fatty Acids Metabolism

Short chain fatty acids (SCFAs) have been the focus of intense study for years due to their ability to improve gut health.¹ SCFAs are produced in the colon by microbial fermentation of fiber—one of the main reasons increased consumption of fiber is recommended to increase gut health—and have been used to alleviate symptoms of several gut disorders.^2,3 The most abundant SCFAs in the colon are butyrate, propionate, and acetate,² each produced by a different set of bacteria,^3,4 and each with a different physiological contribution to gut function and health.

SCFAs and Gut Health

SCFAs have a range of reported health benefits, including increased gut barrier function, increased liver metabolism, reduction of inflammatory bowel disease (IBD)-associated symptoms, promotion of immune tolerance and anti-inflammatory immune responses, regulation of lipid, cholesterol, and glucose metabolism, and protection against some cancers including colorectal and liver.⁵ 

The most well-studied SCFA, butyrate, is a critical energy source for colonocytes, helps maintain gut barrier integrity, helps protect the gut barrier, and regulates mucus production (which further influences gut barrier function)³—all important for appropriate nutrient absorption and prevention of inappropriate immune responses. 

Butyrate and acetate also influence appetite by regulating gut hormones and, in the case of acetate, crossing the blood-brain barrier to impact appetite signals sent and received by the hypothalamus.^1,3,6 Acetate and propionate have also been implicated in insulin secretion and blood glucose control as well as the regulation of lipolysis and adipogenesis.^1,3 SCFAs, particularly butyrate, can also improve gut motility.⁶

SCFAs and the Microbiome

While the beneficial effects of SCFAs have historically been attributed to fiber, the past five to ten years of microbiome research have increasingly demonstrated the critical role played by the human microbiome in not only SCFA production, but also the regulation of hormones (particularly those playing a role in the gut-brain axis). 

The relationship between the gut microbiome and SCFAs appears to be bidirectional, with the presence of SCFAs regulating further production by changing the pH of the intestinal milieu and favoring the production of propionate and acetate over butyrate.² And diet—unsurprisingly, given the central role of fiber in SCFA production—directly and significantly impacts SCFA production through modulation of the gut microbiome.³ 

The human microbiome is now the not-so-missing link between fiber consumption and the many benefits associated with fiber. Because the production of SCFAs is the result of bacterial metabolism, an increasing number of studies are utilizing metabolomics approaches to deeply investigate SCFA production and the impact of SCFAs on human health. 

Metabolon’s suite of products, including the Global Discovery Panel and Complex Lipids, Bile Acids, and SCFA Targeted Panels have supported several of the seminal papers using metabolomics to deeply characterize the intricate relationship between the gut microbiome and human health.^8-12 Some of these studies, with their deeper, phenotypic resolution, suggest that SCFAs might not always be good.

When Are SCFAs Harmful?

A growing body of evidence, centered around microbiome metabolomics, demonstrates that SCFAs aren’t always beneficial. For example, research has provided a connection between the microbiome, SCFAs, and the link between IBD and liver conditions such as autoimmune hepatitis and primary sclerosing cholangitis.¹³ 

Using an ex vivo model of ulcerative colitis, the study authors replicated several positive impacts of SCFA but additionally revealed a proinflammatory impact of SCFAs during acute T cell-mediated inflammation.¹³ Metabolomics analysis using the Metabolon Discovery Panel and the SCFA Targeted Panel revealed that this paradoxical finding was due in part to metabolic reprogramming that further caused gut barrier dysfunction and injury to liver cells.¹³

Metabolon’s Microbiome Portfolio

Metabolon is proud to help advance our understanding of the human microbiome and how it impacts human health. Our SCFA and Bile Acids Targeted Panels, which detect microbially-derived metabolites of interest, are a powerful add-on to our Global Discovery and Complex Lipids Targeted Panels. Together, this suite of panels targets hundreds of microbially-derived metabolites across over a dozen pathways including bile acid metabolism, sulfur metabolism, nitrogen metabolism, vitamin B metabolism, and more, and can place them in the context of host metabolism (using the untargeted metabolomics Global Discovery Panel). Our decades of experience and unmatched metabolite databases can help you maximize the discovery potential of your microbiome research projects. Contact us today to learn more about how Metabolon can help you advance your microbiome studies.

Contact us today to learn more.

References

1. Martin-Gallausiaux C, Marinelli L, and Blottière M. SCFA: mechanisms and functional importance in the gut. Proc Nutr Soc. 2021;80(1):37—49. doi: 10.1017/S0029665120006916
2. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DK, and Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. 2013;54(9):2325—2340. doi: 10.1194/jlr.R036012
3. Nogal A, Valdes AM, and Menni C. The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health. Gut Microbes. 2021;13(1):1897212. doi: 10.1080/19490976.2021.1897212
4. Macfarlane S and Macfarlane GT. Regulation of short-chain fatty acid production. Proc Nutr Soc. 2003;62(1):67—72. doi: 10.1079/PNS2002207
5. Ohtani N and Hara E. Gut‐liver axis‐mediated mechanism of liver cancer: A special focus on the role of gut microbiota. Cancer Sci. 2021;112(11): 4433–4443. doi: 10.1111/cas.15142
6. Fernández-Bello I, Monzón Manzano E, García Río F, Justo Sanz R, Cubillos-Zapata C, Casitas R, et al. A.Procoagulant state of sleep apnea depends on systemic inflammation and endothelial damage. Arch Bronconeumol. 2022;58(2):117—124. doi: 10.1016/j.arbres.2020.11.017
7. Canani RB, Di Costanzo M, Leone L, Pedata M, Meli R, and Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol. 2011;17(2):1519—1528. doi: 10.3748/wjg.v17.i12.1519
8. Visconti A, Le Roy CI, Rosa F, Rossi N, Martin TC, Mohney RP et al. Interplay between the human gut microbiome and host metabolism. Nat Commun. 2019;10(1):4505. doi: 10.1038/s41467-019-12476-z.
9. Henriques SF, Dhakan DB, Serra L, Francisco AP, Carvalho-Santos Z, Baltazar C et at. Metabolic cross-feeding in imbalanced diets allows gut microbes to improve reproduction and alter host behaviour. Nat Commun. 2020;11(1):4236. doi: 10.1038/s41467-020-18049-9
10. Bao R, Hesser LA, He Z, Zhou X, Nadeau K, and Nagler C. Fecal microbiome and metabolome differ in healthy and food-allergic twins. J Clin Invest. 2021;131(2):e141935. doi: 10.1172/JCI141935
11. Wastyk HC, Fragiadakis GK, Perelman D, Dahan D, Merrill BD, Yu FB et al. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021;184(16):4137-4153.e14. doi: 10.1016/j.cell.2021.06.019
12. Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360(6391):eaan5931. doi: 10.1126/science.aan5931
13. Trapecar M, Communal C, Velazquez J, Maass CA, Huang YJ, Schneider K, et al. Gut-Liver Physiomimetics Reveal Paradoxical Modulation of IBD-Related Inflammation by Short-Chain Fatty Acids. Cell Systems. 2020;10(3):223—239. doi: 10.1016/j.cels.2020.02.008