Butyrate producers, "The Sentinel of Gut": Their intestinal significance with and beyond butyrate, and prospective use as microbial therapeutics

Abstract

Gut-microbial butyrate is a short-chain fatty acid (SCFA) of significant physiological importance than the other major SCFAs (acetate and propionate). Most butyrate producers belong to the Clostridium cluster of the phylum Firmicutes, such as Faecalibacterium, Roseburia, Eubacterium, Anaerostipes, Coprococcus, Subdoligranulum, and Anaerobutyricum. They metabolize carbohydrates via the butyryl-CoA: acetate CoA-transferase pathway and butyrate kinase terminal enzymes to produce most of butyrate. Although, in minor fractions, amino acids can also be utilized to generate butyrate via glutamate and lysine pathways. Butyrogenic microbes play a vital role in various gut-associated metabolisms. Butyrate is used by colonocytes to generate energy, stabilizes hypoxia-inducible factor to maintain the anaerobic environment in the gut, maintains gut barrier integrity by regulating Claudin-1 and synaptopodin expression, limits pro-inflammatory cytokines (IL-6, IL-12), and inhibits oncogenic pathways (Akt/ERK, Wnt, and TGF-β signaling). Colonic butyrate producers shape the gut microbial community by secreting various anti-microbial substances, such as cathelicidins, reuterin, and β-defensin-1, and maintain gut homeostasis by releasing anti-inflammatory molecules, such as IgA, vitamin B, and microbial anti-inflammatory molecules. Additionally, butyrate producers, such as Roseburia, produce anti-carcinogenic metabolites, such as shikimic acid and a precursor of conjugated linoleic acid. In this review, we summarized the significance of butyrate, critically examined the role and relevance of butyrate producers, and contextualized their importance as microbial therapeutics.

Keywords: butyrate producers; colorectal cancer; gut epithelial barrier; gut inflammation; gut-organ axis; immunomodulation; microbial homeostasis.

Figure 1

Microbial pathway to generate butyrate in gut: Majority of butyrate in the colon is generated by the metabolization of dietary fibers, primarily of carbohydrate origin (BHBD, β-hydroxybutyryl-CoA dehydrogenase; Bcd, butyryl-CoA dehydrogenase; But, butyryl-CoA: acetate CoA-transferase; Buk, butyrate kinase).

Figure 2

Dynamic role of butyrate producing microbial communities in gut: Along with butyrate, butyrate-producing communities also produce various bioactive molecules that are anti-microbial, anti-inflammatory, and anti-carcinogenic in nature. These molecules are of therapeutic importance in alleviating gut-associated disorders and maintaining gut-homeostasis (CLA, Conjugated Linoleic Acid; IL, Interleukin; MAM, Microbial Anti-inflammatory Molecule).

Figure 3

Warburg Effect: Inefficient butyrate metabolization by mitochondria of cancerous colonocytes leads to accumulation of butyrate, which in turn acts as an HDAC inhibitor and induces cancer. Additionally, majority of glucose is converted into lactate in cancerous colonocytes owing to their higher glycolysis rates, which is less energy efficient compared to phosphorylation of pyruvate in mitochondria via the TCA cycle. Therefore, cancerous colonocytes need higher glucose inflow and a higher rate of glycolysis to survive (MCT, Monocarboxylate Transporter; GLUT, Glucose Transporter; HDAC, Histone deacetylase, HAT; Histone acetyltransferase).