The microbial regulation of short-chain fatty acids by postbiotics on human physiological health.

Reflecting on the indigestible fibers in our ancestors' diets, they were much more abundant than in our current diets. Therefore, from an evolutionary perspective, the human genome and its physiological and nutritional needs do not align well with modern dietary habits. The fibers that reach the colon are fermented by gut anaerobic bacteria, producing short-chain fatty acids (SCFA) as metabolic byproducts. SCFA play a role in the dynamic balance of the gut. Recent studies have shown that SCFA can also affect tissues and organs outside the gut through their circulation in the blood. SCFA signal not only by binding to homologous G protein-coupled receptors on endocrine and immune cells in the body but also induce epigenetic changes in the genome by affecting the activity of histone acetyltransferases and histone deacetylases.

SCFA are key players in the interaction between diet, microbiota, and health.

SCFA have fewer than 6 carbon atoms in their aliphatic tails, with acetate (C2), propionate (C3), and butyrate (C4) being the most abundant in the gut. SCFA are metabolic byproducts of the microbial fermentation of undigested or partially digested complex polysaccharides in the human small intestine. These indigestible polysaccharides (NDP) are found in plant cell walls and are further divided into soluble and insoluble dietary fibers. Soluble NDP have high fermentability and typically produce more SCFA in the colon than soluble fibers.

Currently, there are three well-characterized human SCFA-sensing G protein-coupled receptors (GPCR) that are differentially expressed in various immune cell populations as well as in epithelial and endocrine cells critical for metabolic regulation. Studies on GPCR gene-deficient mice have identified the importance of SCFA signaling through these metabolite receptors in controlling inflammation and gut homeostasis.

Compared to populations consuming traditional high-fiber diets, human fiber intake has significantly decreased over the past century. Over the last 60 years, the prevalence of allergies, type 1 diabetes, inflammatory bowel disease (IBD), and autoimmune diseases has steadily increased. Recent systematic reviews and meta-analyses of prospective studies and randomized controlled trials have emphasized the importance of indigestible fibers for health.

SCFA are now becoming key participants in interactions with the host that influence health and disease, especially given recent evidence suggesting they have the ability to modify the epigenome and affect tissues and organs outside the gut.

SCFA - What are they

Early studies on cases of sudden death in humans indicated that gut microbiota produce large amounts of SCFA, with concentrations at the terminal ileum being approximately 13±6 mmol/kg and in the descending colon about 80±11 mmol/kg. In all parts of the colon, the concentration of acetate is at least twice that of propionate or butyrate. In the ascending colon, where most glycolytic fermentation occurs, the measurements of acetate, propionate, and butyrate vary by the geographic origin of the population, but acetate typically accounts for about 60–75% of the total fecal SCFA.

Regulation of diseases by short-chain fatty acids

Type 1 diabetes

Genetic susceptibility plays a role in type 1 diabetes (T1D), but, as with other autoimmune and allergic diseases, there is compelling evidence that environmental factors contribute to the etiology of this disease. Feeding special diets in the form of acetylated or butyrylated resistant starch, which release large amounts of acetate or butyrate in the colon after bacterial fermentation, can prevent diabetes in non-obese diabetic (NOD) mice. These results suggest that high-fiber diets and microbiota can have a synergistic effect in reducing the risk of T1D in susceptible populations. Interestingly, a diet combining acetate and butyrate can provide complete protection, indicating that these SCFA contribute to protection through different mechanisms. A diet using acetate alone alters the composition of B cell subpopulations in the spleen, while both diets reduce the frequency of autoreactive T cells in lymphoid tissues and decrease CD86 expression in mature marginal zone B cells that produce IL-12, which is related to the pathology of autoimmune diseases. Consistent with previous studies (previously targeting the periphery), a butyrate-rich diet increases the number and function of Tregs. The protective effects of SCFA against diabetes may also involve GPCRs sensitive to metabolic products (e.g., GPCR43) that participate in the production of enteroendocrine cells and pancreatic β-cells, which play important roles in glucose tolerance.

Effects of SCFA on the blood-brain barrier and neuroimmune endocrine function

Recently, mice orally supplemented with acetate, propionate, and butyrate in drinking water were protected from the effects of chronic psychosocial stress after one week of oral administration.

SCFA entering the bloodstream can also be transported across the blood-brain barrier (BBB) to the brain and cerebrospinal fluid (CSF). This may directly affect the levels of neurotrophic factors that regulate the growth and differentiation of neurons and synapses in the brain. Although the mechanisms are not clear, SCFA have been shown to modulate learning and memory in various brain diseases and regulate neuropeptides that favor appetite suppression. Additionally, SCFA play an important role in the permeability of the blood-brain barrier. Compared to conventional mice, GF mice have higher permeability of the BBB to small molecules, and recolonization with complex microbiota or SCFA-producing bacteria can restore the integrity of the BBB.

Metabolic diseases, obesity, and type 2 diabetes

As mentioned earlier, the metabolism of SCFA by the host can increase energy harvesting from the diet, which may lead to obesity. In contrast, multiple studies in rodents have shown that SCFA can prevent obesity by increasing energy expenditure and appetite control. As previously mentioned, propionate can influence weight control through sympathetic nervous system activity. Furthermore, SCFA reduce the expression of PPARγ, leading to increased oxidative metabolism in the liver and adipose tissue, reduced fat accumulation, liver steatosis, and increased insulin sensitivity. Recent results from a randomized clinical trial in patients with type 2 diabetes suggest that SCFA may be a promising strategy for treating pancreatic dysfunction in early type 1 and type 2 diabetes.

Based on studies in rodents, SCFA are considered to have beneficial rather than harmful effects on host metabolism. However, there are conflicting results regarding the beneficial effects of SCFAs on human glucose homeostasis, and further well-controlled long-term intervention studies are needed to confirm the beneficial effects of SCFAs in metabolic diseases.

Conclusion and future perspectives

An increasing amount of evidence supports the notion that microbial fermentation in the colon reduces the intake of NDP and the production of SCFA, which is a reason for the rising incidence of diseases that have been steadily increasing in high-income countries over the past 50 years. However, to fully leverage the opportunities for using SCFA in disease prevention and treatment, it is crucial to better understand the mechanisms by which SCFA function in the gut and other tissues and organs of the body. In the future, SCFA receptor-selective pharmacological agents may open new possibilities for therapeutic approaches by enhancing BBB integrity, regulating neurotransmission, and influencing the levels of neurotrophic factors, including applications in neurodegenerative diseases and behavior.

Cited from: Hee B, Wells J M. Microbial Regulation of Host Physiology by Short-chain Fatty Acids[J]. Trends in Microbiology, 2021.

Note: This article is for informational purposes only and does not serve as medical guidance.