 | This article may be too technical for most readers to understand.(July 2023) |
Bile salt hydrolases (BSH) are microbial enzymes that deconjugate primary bile acids. [1] They catalyze the first step of bile acid metabolism and maintain the bile acid pool for further modification by the microbiota. [1] [2] BSH enzymes play a role in a range of host and microbe functions including host physiology, immunity, and protection from pathogens. [3] [4]
Bile salt hydrolases are members of the N-terminal nucleophilic hydrolase family, characterized by autocatalytic activation by an N-terminal nucleophile and subsequent amide bond cleavage. [2] [5] The majority of BSH enzymes are composed of homotetramers, although they have been known to assume other forms including homodimers and heterotrimers. [2] All BSHs contain a catalytic Cys2 nucleophile residue, which is located at the N-terminus of the enzyme. [2] While BSH structure may vary, other amino acids have been shown to be conserved across BSH-carrying bacteria. These include Arg18, Asp21, Asn82, and Arg228. [6]
In humans, primary bile acids are synthesized from cholesterol in the liver to form either cholic acid (CA), chenodeoxycholic acid or chenodeoxycholic acid [ clarification needed ] (CDCA). [7] These primary bile acids are then conjugated to the amino acids glycine or taurine and stored in the gallbladder. [7] During digestion, they are released and their detergent properties aid in the breakdown of dietary lipids. [8] While the majority of primary bile acids are recirculated back to the liver via enterohepatic circulation, a small portion remain in the gastrointestinal tract, where they are modified by bacteria carrying BSH enzymes. [7]
BSH specificity is thought to be determined by enzymatic structural differences and slight variations in amino acid composition. [6] In general, more BSHs are thought to have a preference for glycine-conjugated bile acids, although the extent of their specificity may not yet be understood. [9]
Deconjugation begins with the recognition of the substrate, which consists of a steroid core and a glyco- or tauro- amino acid. [2] While the precise mechanism of recognition is unknown, it has been hypothesized that BSHs recognize the substrate by their conjugated amino acid. [2] Upon recognition by the BSH, deconjugation begins with a nucleophilic attack by Cys2 on the amide bond of the target bile acid. [6] Subsequently, a tetrahedral intermediate is formed and stabilized by Asn82 and Asn173 while Arg18 stabilizes a negatively-charged sulfhydryl on the N-terminus of Cys2. [2] The negative charge on Cys2 is resolved by deacylation with water to finally produce a deconjugated primary bile acid. [6]
BSHs have also been found to perform a novel[ as of? ] function: reconjugation. [10] Unlike deconjugation, bile acid reconjugation involves the addition of amino acids to an unconjugated bile acid. [7] Additionally, microbial bile acid conjugation is not limited to glycine or taurine. Instead, most amino acids can be conjugated to an unconjugated backbone. [7] Microbial conjugation of bile acids has been hypothesized to either increase or decrease the antimicrobial properties of certain bile acids and their abundance may be altered in certain gastrointestinal diseases, although their exact roles in the gut have not been fully elucidated. [11]
One consequence of bile acid metabolism is the variety of effects on the host. In the case of BSHs, deconjugated bile acids can interact with host cellular receptors, thus altering aspects of host physiology. [1] [12] A key human cellular receptor is the farnesoid X receptor (FXR), a bile acid-activated transcription factor, which regulates bile acid synthesis and transport. [13] [14] Upon activation, FXR can repress bile acid synthesis and alter the bile acid pool. [14] Bacteria that possess a BSH are associated with lower human cholesterol levels because the secondary bile acids they produce act as FXR agonists and promote cholesterol excretion. [15] [16] BSHs also have an effect on host glucose metabolism, energy, and lipid absorption. [17] Through TGR-5, BSHs can regulate host glucose metabolism and have been shown to beneficially regulate insulin levels in diabetics. [12]
Bile acid metabolism, and by association BSHs, influences the immune system by shaping the gut microbiota and bile acid pool. [18] BSHs shape the microbiota by altering the bile acid pool and creating substrates for further modification by other gut bacteria. Because they act as gatekeepers for further bile acid modification, BSHs play an important role in the production of deconjugated bile acids that can be modified into secondary bile acids. [1] Secondary bile acids can influence innate immunity through their interactions with the bile acid receptors mentioned above, FXR and TGR-5. [19] FXR and TGR-5 are expressed by intestinal immune cells such as macrophages, as well as NKT cells and dendritic cells. [19] FXR has been shown to play a role with TLR-9 in inhibiting inflammation. [19] TGR-5 interactions with the secondary bile acids DCA and LCA can prevent inflammation, and loss of this bile acid receptor is associated with an inflamed state in the gut. [19]
In autoimmune disorders such as type 1 diabetes, the microbiome is perturbed. Due to this imbalance, a diseased state of the gut is associated with changes to the bile acid pool and different BSH phylotypes. Specifically, BSHs with high activity are associated with diseases while intermediate activity BSHs are associated with healthy individuals. [17]
BSHs are critical for secondary bile acid transformations, which are performed by different members of the gut microbiota. The composition of the gut microbiome is shaped in part by the deconjugated primary bile acids made available by BSHs. [1] The modification of the primary bile acid end-product of BSHs to secondary bile acids produces several potent antimicrobials, which can protect the gut microbiota from pathogens. [7] Secondary bile acids act as detergents and disrupt the microbial membrane, with some bile acids targeting specific types of bacteria such as Gram positives. [20] [21] Indirectly, bile acids shape the gut microbiota by regulating the innate immune system or activating cellular signaling machinery that excludes certain bacteria from the gut. [19] [21]
BSHs are commonly found in a variety of genera such as Lactobacillus , Enterococcus , and Bacteroides . [17] Recent[ when? ] advances relating to the Human Microbiome Project have allowed for the identification of variants in BSHs found in the human gut. [17] There are currently eight known phylotypes of BSH, with certain phylotypes being found in a single bacterial genus. [17] The BSHs found in different genera of bacteria may have different substrate specificity, which can be an important influence on the bile acid pool and gut microbiota. [9]
As both probiotics and live biotherapeutics become more advanced, strain selection is becoming more essential for good product design. BSHs are often found in candidate probiotic organisms due to their myriad effects on both human health and the gut microbiota. Bifidobacteria and Lactobacilli are two popular probiotic organisms, both of which carry a BSH. [17] BSHs play roles in reducing cholesterol levels and detoxifying bile acids that may damage the gut in high concentrations. [3] Current[ when? ] issues with use of BSH-containing bacteria in probiotics include bioavailability and further modification of deconjugated bile acids to potentially toxic secondary bile acids. [3]
The human microbiome is the aggregate of all microbiota that reside on or within human tissues and biofluids along with the corresponding anatomical sites in which they reside, including the skin, mammary glands, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, biliary tract, and gastrointestinal tract. Types of human microbiota include bacteria, archaea, fungi, protists, and viruses. Though micro-animals can also live on the human body, they are typically excluded from this definition. In the context of genomics, the term human microbiome is sometimes used to refer to the collective genomes of resident microorganisms; however, the term human metagenome has the same meaning.
Butyric acid, also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula CH3CH2CH2CO2H. It is an oily, colorless liquid with an unpleasant odor. Isobutyric acid is an isomer. Salts and esters of butyric acid are known as butyrates or butanoates. The acid does not occur widely in nature, but its esters are widespread. It is a common industrial chemical and an important component in the mammalian gut.
Lactobacillus acidophilus is a rod-shaped, Gram-positive, homofermentative, anaerobic microbe first isolated from infant feces in the year 1900. The species is most commonly found in humans, specifically the gastrointestinal tract, oral cavity, and vagina, as well as various fermented foods such as fermented milk or yogurt. The species most readily grows at low pH levels, and has an optimum growth temperature of 37 °C. Certain strains of L. acidophilus show strong probiotic effects, and are commercially used in dairy production. The genome of L. acidophilus has been sequenced.
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Gut microbiota, gut microbiome, or gut flora are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota. The gut is the main location of the human microbiome. The gut microbiota has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut–brain axis.
Bacteroides fragilis is an anaerobic, Gram-negative, pleomorphic to rod-shaped bacterium. It is part of the normal microbiota of the human colon and is generally commensal, but can cause infection if displaced into the bloodstream or surrounding tissue following surgery, disease, or trauma.
The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4, is a nuclear receptor that is encoded by the NR1H4 gene in humans.
Dysbiosis is characterized by a disruption to the microbiome resulting in an imbalance in the microbiota, changes in their functional composition and metabolic activities, or a shift in their local distribution. For example, a part of the human microbiota such as the skin flora, gut flora, or vaginal flora, can become deranged, with normally dominating species underrepresented and normally outcompeted or contained species increasing to fill the void. Similar to the human gut microbiome, diverse microbes colonize the plant rhizosphere, and dysbiosis in the rhizosphere, can negatively impact plant health. Dysbiosis is most commonly reported as a condition in the gastrointestinal tract or plant rhizosphere.
The term "infectobesity" refers to the hypothesis that obesity in humans can be caused by pathogenic organisms, and the emerging field of medical research that studies the relationship between pathogens and weight gain. The term was coined in 2001 by Dr. Nikhil V. Dhurandhar, at the Pennington Biomedical Research Center.
Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.
Limosilactobacillus fermentum is a Gram-positive species in the heterofermentative genus Limosilactobacillus. It is associated with active dental caries lesions. It is also commonly found in fermenting animal and plant material including sourdough and cocoa fermentation. A few strains are considered probiotic or "friendly" bacteria in animals and at least one strain has been applied to treat urogenital infections in women. Some strains of lactobacilli formerly mistakenly classified as L. fermentum have since been reclassified as Limosilactobacillus reuteri. Commercialized strains of L. fermentum used as probiotics include PCC, ME-3 and CECT5716
Long-term close-knit interactions between symbiotic microbes and their host can alter host immune system responses to other microorganisms, including pathogens, and are required to maintain proper homeostasis. The immune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect the host against harmful microorganisms while limiting host responses to harmless symbionts. Humans are home to 1013 to 1014 bacteria, roughly equivalent to the number of human cells, and while these bacteria can be pathogenic to their host most of them are mutually beneficial to both the host and bacteria.
Microbiota are the range of microorganisms that may be commensal, mutualistic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found to be crucial for immunologic, hormonal, and metabolic homeostasis of their host.
Bifidobacterium longum is a Gram-positive, catalase-negative, rod-shaped bacterium present in the human gastrointestinal tract and one of the 32 species that belong to the genus Bifidobacterium. It is a microaerotolerant anaerobe and considered to be one of the earliest colonizers of the gastrointestinal tract of infants. When grown on general anaerobic medium, B. longum forms white, glossy colonies with a convex shape. B. longum is one of the most common bifidobacteria present in the gastrointestinal tracts of both children and adults. B. longum is non-pathogenic, is often added to food products, and its production of lactic acid is believed to prevent growth of pathogenic organisms.
Muricholic acids are a group of bile acids found as one of the main forms in mice, which gives them their name, and at low concentrations in other species. Muricholic acids differ from the primary bile acids found in humans, cholic acid and chenodeoxycholic acid, by having a hydroxyl group in the β- configuration at the 6-position. The orientation of the hydroxyl group at the 7 position defines α- or β-muricholic acid. Muricholic acids are detectable at low concentrations in human urine.
The gut–brain axis is the two-way biochemical signaling that takes place between the gastrointestinal tract and the central nervous system (CNS). The "microbiota–gut–brain axis" includes the role of gut microbiota in the biochemical signaling events that take place between the GI tract and the CNS. Broadly defined, the gut–brain axis includes the central nervous system, neuroendocrine system, neuroimmune systems, the hypothalamic–pituitary–adrenal axis, sympathetic and parasympathetic arms of the autonomic nervous system, the enteric nervous system, vagus nerve, and the gut microbiota.
Microbiota-accessible carbohydrates (MACs) are carbohydrates that are resistant to digestion by a host's metabolism, and are made available for gut microbes, as prebiotics, to ferment or metabolize into beneficial compounds, such as short chain fatty acids. The term, ‘‘microbiota-accessible carbohydrate’’ contributes to a conceptual framework for investigating and discussing the amount of metabolic activity that a specific food or carbohydrate can contribute to a host's microbiota.
The microbiota are the sum of all symbiotic microorganisms living on or in an organism. The fruit fly Drosophila melanogaster is a model organism and known as one of the most investigated organisms worldwide. The microbiota in flies is less complex than that found in humans. It still has an influence on the fitness of the fly, and it affects different life-history characteristics such as lifespan, resistance against pathogens (immunity) and metabolic processes (digestion). Considering the comprehensive toolkit available for research in Drosophila, analysis of its microbiome could enhance our understanding of similar processes in other types of host-microbiota interactions, including those involving humans. Microbiota plays key roles in the intestinal immune and metabolic responses via their fermentation product, acetate.
The human milk microbiota, also known as human milk probiotics (HMP), encompasses the microbiota–the community of microorganisms–present within the human mammary glands and breast milk. Contrary to the traditional belief that human breast milk is sterile, advancements in both microbial culture and culture-independent methods have confirmed that human milk harbors diverse communities of bacteria. These communities are distinct in composition from other microbial populations found within the human body which constitute the human microbiome.
Bacteroides thetaiotaomicron is a gram-negative, rod shaped obligate anaerobic bacterium that is a prominent member of the normal gut microbiome in the distal intestines. Its proteome, consisting of 4,779 members, includes a system for obtaining and breaking down dietary polysaccharides that would otherwise be difficult to digest. B. thetaiotaomicron is also an opportunistic pathogen, meaning it may become virulent in immunocompromised individuals. It is often used in research as a model organism for functional studies of the human microbiota.
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