#FEMSmicroBlog: New roles for microbial butyrate in human health


The human gut contains a wide range of bacterial and eukaryotic species. Microbial genes outnumber human genes by up to 150-fold, hinting at a variety of functions. For example, the gut microbiota generates short-chain fatty acids, which are key metabolites in human body functions. The short review “Epigenetic effects of short-chain fatty acids from the large intestine on host cells” in microLife presents the local and systemic impacts of microbial metabolites like butyrate on the host, as Richard Stein and Leise Riber explain in this #FEMSmicroBlog entry. #FascinatingMicrobes


Short-chain fatty acids and gut microbes

The human colon (the large intestine) is among the most densely populated microbial habitats on Earth. Several gut bacterial species ferment non-digestible fibers from food and produce short-chain fatty acids. One key short-chain fatty acid is butyric acid, or butyrate.

Within the large intestine, butyrate establishes two concentration gradients. One gradient ranges from the proximal towards the distal colon. Due to peristaltic movements, unabsorbed butyrate moves from the proximal colon, where bacterial fermentation occurs, to the distal colon, thus establishing a gradient.

The second gradient arises due to the organization of the gut epithelium layer, which contains repetitive invaginations known as colonic crypts. Toward the luminal side of the crypts reside colonocytes. These epithelial cells absorb butyrate, thus leaving barely any molecules to reach the deep end of the crypts.

The lumen-to-crypt butyrate concentration gradient in the large intestine.
The lumen-to-crypt butyrate concentration gradient in the large intestine. From Stein and Riber (2023).

This is important since at the bottom of the colonic crypts reside stem and progenitor cells. In these undifferentiated cells, butyrate acts as an inhibitor of histone deacetylases, stopping their cell cycles. Due to the lumen-to-crypt gradient, no butyrate reaches the stem cells, which are thus protected. This is why healthy colonocytes are referred to as “metabolic sinkholes”.

Colon cancer cells are also undifferentiated but, unlike stem cells, they are not protected from butyrate. As a result, butyrate accumulates in cancer cells, inhibiting their cell cycle progression and promoting apoptosis. Thus, butyrate has the important role of simultaneously stimulating the growth of healthy colonocytes and inhibiting the growth of malignant cells.

Several organs are impacted by butyrate in the body.
Several organs are impacted by butyrate. From Stein and Riber (2023).


Butyrate and the developing gut microbiota

Butyrate seems to also impact the anatomical and physiological development of the human intestine. Studies in zebrafish revealed that their intestines contain randomly shaped folds and that cell division occurs at the base of these folds.

Unlike mammals, zebrafish lack both colonic crypts and bacteria that synthesize butyrate. Hence, intestinal stem cells and progenitor cells in zebrafish are exposed to the intestinal lumen. Studies showed that exposing the intestinal tract of zebrafish to butyrate results in the inhibition of the cell cycle of intestinal epithelial cells.

These studies can be related to humans; human infants contain colonic crypts that are not fully developed and thus shallow. Butyrate-producing bacteria start growing in the human gut microbiota only about six months after birth, with butyrate levels increasing about fourfold. This coincides with the development of the colonic crypts.

Hence, it is hypothesized that during early life, the development of intestinal crypts is coordinated with the rise of butyrate-producing bacteria. This would protect the intestinal stem cells in the undeveloped colon, as they are otherwise prone to butyrate damage.


Butyrate, a key microbial metabolite

Furthermore, short-chain fatty acids produced in the gastrointestinal tract were shown to impact cells and organs on a systemic level. For example, several gut metabolites penetrate the blood-brain barrier, impacting the central nervous system and mental health in the so-called gut-brain axis.

Only in recent years, butyrate emerged as one microbial metabolite with key functions in this axis. Studies found that butyrate shapes several biological processes in the brain, protects against neurodegenerative disorders, and even benefits memory.

The beneficial effects of butyrate on local and systemic levels are outlined in the short review Epigenetic effects of short-chain fatty acids from the large intestine on host cells” in microLife. Bacteria generate butyrate by fermenting non-digestible fiber in the large intestine. As such, this review highlights, once again, that both diet and the gut microbiota are critical factors in health and disease.


About the authors of this blog

Leise Riber holds a PhD in molecular microbiology and bacterial genetics from Roskilde University (Denmark) and currently serves as Assistant Professor at University of Copenhagen (Denmark). Her primary research interest lies in exploring the biology and dynamics of genetic parasites, such as plasmids and bacteriophages, as well as deciphering their molecular interactions with microbial communities. A particular focus lies in understanding the adaptive genetic features that shape the coevolution of bacteriophages, plasmids, and their bacterial hosts.

Richard A. Stein is an Industry Associate Professor at NYU Tandon School of Engineering. He holds an MD from the “Iuliu Haţieganu” University of Medicine and Pharmacy (Romania) and a PhD in Biochemistry from the University of Alabama in Birmingham (USA). Richard is interested in understanding the spread of infectious diseases in populations and the way commensal and pathogenic microorganisms shape gene expression in the host. Additionally, Richard’s work has explored the impact that misinformation and disinformation, especially in the realm of science and health, may exert on public health.

About this blog section

The section #FascinatingMicrobes for the #FEMSmicroBlog explains the science behind a paper and highlights the significance and broader context of a recent finding. One of the main goals is to share the fascinating spectrum of microbes across all fields of microbiology.

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