Homeostasis of short-chain fatty acids in the intestine: a key role for bacterial metabolism

Highlights

The levels of short-chain fatty acids are affected by exogenous and endogenous factors
The short-chain fatty acids produced in the intestine are classified into 74 strains
The short-chain fatty acid synthesis pathways are divided into 4 categories
This review analyzes the catalytic mechanisms of 4 rate-limiting enzymes
Dietary intervention may be a viable option for regulating the balance of short-chain fatty acids in the intestine

Introduction

The most important pathway for SCFA synthesis is endogenous fermentation by intestinal bacteria. The fermentation of indigestible carbohydrates (dietary fiber) produces the energy required for bacterial growth and forms SCFA-dominant end products. The many species found in the intestine have greatly expanded the diversity of intestinal bacteria. Studies have shown that many intestinal bacteria can synthesize SCFA using dietary fiber as a substrate. The first step is to convert dietary fiber into monosaccharides by glycoside hydrolases, and then generate the main end product SCFA through carbon metabolism pathways during anaerobic fermentation. In addition to consuming dietary fiber, intestinal bacteria can also convert other substrates for SCFA synthesis, such as amino acids from dietary or endogenous proteins, or organic acids such as lactic acid.

Many factors affect SCFA production by bacteria, one of which is the interference with intestinal microorganisms, which in turn affects the abundance and diversity of intestinal SCFA-producing bacteria, thereby affecting SCFA production. Some external measures may interfere with the intestinal flora, such as oral flora, oral probiotics, fecal flora transplantation, and interactions between intestinal flora. Another factor is host physiology, including the intestinal environment, microbial-host interactions, and even social stress, which can affect the intestinal microbiome and microbial metabolites SCFA. Food composition is also a key factor affecting the intestinal flora. Short-term macronutrient changes may affect the intestinal microbiome, and the impact of antibiotics on the intestinal flora cannot be ignored. These factors will affect the abundance and diversity of the intestinal flora, and ultimately affect the metabolic characteristics of the SCFA-producing species population, leading to fluctuations in endogenous SCFA levels.

SCFA plays an important role in health, so the balance of endogenous SCFA is of great significance for maintaining human health. Studies have shown that bacteria play a vital role in the production of SCFA, and various bacteria synthesize SCFA with different efficiencies. The same species may produce different SCFAs under different conditions, which is essentially the substrate preference of the enzymes produced by a given bacterium. There are various metabolic pathways in SCFA-producing bacteria, and the catalytic efficiency of key enzymes in these pathways is different. It is important and urgent to clarify the metabolic characteristics and rationally regulate the levels of SCFAs by understanding the key SCFA-producing bacteria, the main metabolic pathways of SCFA synthesis, the rate-limiting steps, and the related key enzymes based on microbial diversity in detail. Therefore, Xiuting Li, Baoguo Sun, etc. from Beijing Food Nutrition and Human Health High-tech Innovation Center of Beijing Technology and Business University discussed the diversity, metabolic pathways and key enzymes of intestinal bacteria producing SCFAs, and also pointed out the technical feasibility and prospects of regulating intestinal SCFA balance.

Importance and regulation of SCFAs balance for health

The positive effects of SCFA on health have been widely studied. Recent studies have also shown that SCFA plays a key role in promoting the resolution of neutrophil inflammation, reducing plasma total cholesterol, inducing T cell-mediated ureteritis and hydronephrosis, reprogramming of hepatic fat accumulation, improving insulin response, and stimulating insulin secretion.

Abnormal levels of SCFA may have a negative impact on human health, and both low or excessive levels may have adverse effects on health. Studies have found that increased production or reduced absorption of propionate is associated with an increased risk of type 2 diabetes and obesity, and excessive production of SCFA may also lead to obesity. Other studies have speculated that there is a causal relationship between visceral hypersensitivity and intestinal SCFA content in patients with irritable bowel syndrome. Other studies have confirmed that butyrate can upregulate the mRNA level of lumbar spinal acid-sensitive ion channel 1A and contribute to spinal sensitization, which is considered to be one of the molecular effects of central sensitization that causes visceral pain. Therefore, the balance of endogenous SCFA is important for health. And according to current research, the impact of SCFA on health is complex and dynamic, not just a single cause and effect relationship.

Multiple pathways directly or indirectly affect endogenous SCFA levels. The most effective direct measure is SCFA infusion therapy, and oral intake is another direct measure. The positive effects of direct intake of SCFA into the body, such as oral intake of acetate, butyrate or mixed SCFA, can greatly affect the metabolism of glucose and fatty acids, and can also regulate the homeostasis of colonic Treg cells. Indirect SCFA regulation measures are based on the regulation of the intestinal microbiota, such as changing the dietary composition, oral probiotics or prebiotics, and fecal microbiota transplantation, thereby affecting the fitness, abundance and metabolism of SCFA-producing bacteria, and ultimately regulating the level of endogenous SCFA.

Diet can effectively change the abundance of intestinal bacteria and SCFA synthesis

SCFAs synthetic pathways in gut bacteria

SCFA synthesis using sugar as substrate

Dietary fiber (such as xylanase, glucanase and arabinase) is the main substrate for the production of SCFA by intestinal bacteria. Glycoside hydrolases degrade dietary fiber into monosaccharides (pentoses or hexoses), which then produce SCFAs through glycolysis or pentose phosphate pathway. Acetate is mainly produced by two-step enzyme catalysis (pyruvate formate lyase (EC 2.3.1.54) and acetate-CoA ligase (EC 6.2.1.13)) from acetone and metabolic intermediate acetyl-CoA. Acetogenic bacteria, such as some species of Clostridium, can convert one molecule of glucose into three molecules of acetate, while most non-acetogenic anaerobic bacteria in the intestine produce other products, including succinate, lactate and ethanol, during the synthesis of acetate to rebalance the carbon metabolism in the body.

SCFA synthesis through carbon chain elongation pathway using acetate and ethanol as substrates

Extending the carbon chain using the CoA-dependent pathway is the classic pathway for the synthesis of butyrate. Two molecules of acetyl-CoA can be condensed to form one molecule of butyryl-CoA, which is then converted into butyrate through the butyryl-CoA: acetate-CoA transferase pathway. Butyryl-CoA can also be converted into butyrate by a combination of phosphotransbutyrylase and butyrate kinase. Butyrate is mainly synthesized by Firmicutes via butyryl-CoA:acetate-CoA transferase, while phosphotransbutyrylase and butyrate kinase are less common in human colonic bacteria. Several dominant species in the intestinal bacteria produce butyrate via the butyryl-CoA:acetate-CoA transferase pathway, such as Anaerobic Bacillus, Clostridium, Eubacterium, Eubacterium rectum, Clostridium tenuissima, and Roseburia.

Synthesis of branched-chain SCFAs using amino acids as substrates

Amino acids such as valine, leucine, and isoleucine are substrates that can synthesize isobutyric acid, isooctanoic acid, isovaleric acid, and 2-methylbutyric acid. The first step is to generate branched-chain α-keto acids catalyzed by aminotransferase (EC 2.6.1.42), after which branched-chain α-keto acid dehydrogenase (EC 1.2.4.4) and dihydroacyltransferase (EC 2.3.1.168) work together to convert α-keto acids into acylated branched-chain SCFAs, and the last step is to release free branched-chain SCFAs using thioesterase (EC 3.2.1.14). The degradation of amino acids may also affect the synthesis of acetate and propionate. For example, the metabolism of glutamate, alanine, and aspartate can affect the metabolism of the tricarboxylic acid cycle and the precursor of propionate, succinate.