Bioactivities, Mechanisms, Production, and Potential Application of Bile Acids in Preventing and Treating Infectious Diseases

Engineering ›› 2024, Vol. 38 ›› Issue (7) : 18 -33. DOI: 10.1016/j.eng.2023.11.017

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Review

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Received	Accepted	Published
2023-05-09	2023-11-09	2024-07-01
Issue Date	Revised Date
2024-06-14	2023-10-12

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Abstract

Infectious diseases are a global public health problem, with emerging and re-emerging infectious diseases on the rise worldwide. Therefore, their prevention and treatment are still major challenges. Bile acids are common metabolites in both hosts and microorganisms that play a significant role in controlling the metabolism of lipids, glucose, and energy. Bile acids have historically been utilized as first-line, valuable therapeutic agents for related metabolic and hepatobiliary diseases. Notably, bile acids are the major active ingredients of cow bezoar and bear bile, which are commonly used traditional Chinese medicines (TCMs) with the therapeutic effects of clearing heat, detoxification, and relieving wind and spasm. In recent years, the promising performance of bile acids against infectious diseases has attracted attention from the scientific community. This paper reviews for the first time the biological activities, possible mechanisms, production routes, and potential applications of bile acids in the treatment and prevention of infectious diseases. Compared with previous reviews, we comprehensively summarize existing studies on the use of bile acids against infectious diseases caused by pathogenic microorganisms that are leading causes of global morbidity and mortality. In addition, to ensure a stable supply of bile acids at affordable prices, it is necessary to clarify the biosynthesis of bile acids in vivo, which will assist scientists in elucidating the accumulation of bile acids and discovering how to engineer various bile acids by means of chemosynthesis, biosynthesis, and chemoenzymatic synthesis. Finally, we explore the current challenges in the field and recommend a development strategy for bile-acid-based drugs and the sustainable production of bile acids. The presented studies suggest that bile acids are potential novel therapeutic agents for managing infectious diseases and can be artificially synthesized in a sustainable way.

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Keywords

Bile acids / Infectious diseases / Bioactivities / Mechanisms / Anti-infective agents

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Shuang Liu, Shuo Yang, Biljana Blazekovic, Lu Li, Jidan Zhang, Yi Wang. Bioactivities, Mechanisms, Production, and Potential Application of Bile Acids in Preventing and Treating Infectious Diseases. Engineering, 2024, 38(7): 18-33 DOI:10.1016/j.eng.2023.11.017

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1. Introduction

Infectious diseases include both communicable and noncommunicable diseases and occur primarily in the nervous system, skin, lungs, liver, and intestines. A variety of infectious diseases caused by bacteria, viruses, fungi, and other pathogens are among the leading causes of morbidity and mortality worldwide [1]. The deadliest communicable infectious diseases in human history include malaria, smallpox, Spanish influenza, tuberculosis, plague, acquired immune deficiency syndrome (AIDS), and cholera. Malaria, which is caused by Plasmodium parasites, infected billions of people over the past century and remains a serious public health threat in the tropics today [2]. Tuberculosis, which results from infection with Mycobacterium tuberculosis, is a leading infectious cause of death worldwide that kills more than one million people each year [3]. Smallpox, caused by the variola virus, is one of the oldest and deadliest infectious diseases and is highly contagious, with a mortality rate of about 30% [4]. Cholera is a severe intestinal disease caused by Vibrio cholerae, and there have been many cholera outbreaks in the world [5]. Plague, also known as the Black Death, is caused by Yersinia pestis and remains a hot topic of international public health concern [6]. In recent years, severe acute respiratory infection coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, and H1N1 flu (swine flu), caused by the influenza A virus, have joined the list of the world’s deadliest diseases [7]. In addition, non-communicable diseases such as bacteremia, septicemia, sepsis, and septic shock caused by pathogen invasion are serious complications in critically ill patients, and are the leading causes of death in childbirth, surgery, inflammation, trauma, burns, and chronic diseases. Taken together, infectious diseases are a global public health threat, and their prevention and treatment still remains a major challenge.

Traditional Chinese medicine (TCM) has been used in the treatment of infectious diseases for thousands of years, and its efficacy has been recognized by people around the world. In China, TCM played an especially important role during the COVID-19 pandemic, during which the government repeatedly recommended TCM as the primary therapy [8]. Fu-Zheng-Qu-Xie ("reinforce healthy qi and eliminate pathogenic qi," meaning to support health and dispel pathogens) is the basic principle of TCM in treating diseases, and TCM has unique advantages in preventing pathogen invasion, alleviating toxin damage, inhibiting drug resistance, improving clinical manifestations, blocking cytokine storm, and strengthening the immune system [9]. Jun-Chen-Zuo-Shi (sovereign, minister, assistant, guide) is the compatibility principle of Chinese medicine formulas [10], where Jun refers to the botanical drug playing the primary role in addressing disease, which is supported by the minister drug; Chen, while the assistant drug; Zuo, helps to counter toxicity and the guide drug; Shi, coordinates or enhances the efficacy of the other drugs. Many classical prescriptions have been widely used to treat various infectious diseases. For example, Babao Yushu Wan, Pian Zai Huang (Pien Tze Huang), and Shiyi Qingwen Wan are used to treat infectious diseases and epidemics [11,12]. Niuhuang Jiedu Wan, Niuhuang Shangqing Wan, Meihua Dianshe Wan, Liushen Wan, and Xiongdan Wan have been commonly used to treat sore throat, swollen gums, keratitis, and conjunctivitis [13 ⇓⇓⇓-17]. Angong Niuhuang Wan, Xiongdan Niu-huang Capsule, and Tanreqing Injection (TRQ) have been used to treat upper respiratory tract infection, acute pneumonia, bronchitis, high fever, and severe influenza [18 ⇓-20]. Among these prescriptions, cow bezoar and bear bile are the main components and have been commonly used for thousands of years, due to their therapeutic potential of clearing heat, detoxification, and relieving wind and spasm. Cow bezoar is widely used in more than 650 famous prescriptions in China, and bear bile is considered to be the first of the "four precious Chinese medicines." Bile acids are the major active ingredients of cow bezoar and bear bile, and there is increasing evidence that bile acids hold the potential to contribute significantly to the prevention and treatment of infectious diseases.

Our research group has been engaged in the antibacterial field of TCM for over ten years, with a special focus on TRQ. TRQ is composed of Huangqin (Scutellariae Radix), Xiongdanfen (Ursi Fellis Pulvis), Shanyangjiao (Capra Hircus Cornu), Jinyinhua (Lonicerae Japonicae Flos), and Lianqiao (Forsythiae Fructus), and it is mainly used for upper respiratory tract infections, bronchitis, and pneumonia [21,22]. TRQ has been in use since 2003 and has been listed in the National Health and Family Planning Commission (NHFPC) and the State Administration of Traditional Chinese Medicine (SATCM) clinical guidelines for the treatment of human avian influenza, influenza A H1N1, influenza A H7N9, pediatric hand-foot-mouth disease, dengue fever, and Ebola. In addition, it has been continuously listed as the recommended drug in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (trial versions 6, 7, and 8). Although the clinical effects of TRQ have been recognized by a large number of patients in China, its pharmacodynamic material basis and pharmacological mechanism require further scientific investigation. We have found that bile acids-the major bioactive components of bear bile and TRQ-display promising potential against diseases caused by a variety of pathogenic bacteria [23,24]. Therefore, taking these findings in combination with existing studies, we speculate that bile acids are promising agents that could be developed as anti-infective drugs for infectious diseases.

Bile acids, which are widely distributed in animals, humans, and microorganisms, are crucial for controlling the metabolism of lipids, glucose, and energy. They play important roles in the regulation of nutrient absorption, host immunity, and microbial pathogenesis, and are valuable first-line treatments for related metabolic diseases, such as type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver disease (NAFLD) [25,26]. There are several bile acid drugs on the market for hepatobiliary diseases, such as Ursofalk (ursodeoxycholic acid (UDCA) capsules), Taurolite (tauroursodeoxycholic acid (TUDCA) capsules), sodium cholate tablets, chenodeoxycholic acid (CDCA) capsules, cholic acid (CA) capsules, and Ocaliva (obeticholic acid (OCA)), which have been shown to dissolve cholesterol gallstones and facilitate biliary secretion by inhibiting the cytotoxicity of hydrophobic bile acids and inducing apoptosis to protect cholangiocytes and hepatocytes [27 ⇓⇓⇓⇓-32]. In recent years, the promising performance of bile acids against infectious diseases has attracted attention from the scientific community. This paper reviews the bioactivity, possible mechanisms of action, production routes, and potential applications of bile acids in the treatment and prevention of infectious diseases in more detail than previous reviews, and evaluates their therapeutic potential as novel anti-infective agents.

2. Structures and distribution of bile acids

Bile acids are 24-carbon steroid derivatives consisting of three six-membered rings (A, B, and C) and one five-membered ring (D) with hydroxy substituents and aliphatic side chains [33]. Thus far, more than 100 bile acids have been found in nature; the structures of common bile acids are displayed in Fig. 1 [34 ⇓-36]. Typical bile acids (highlighted in blue) include CA, CDCA, UDCA, deoxy-cholic acid (DCA), ursocholic acid (UCA), hyocholic acid (HCA), hyo-deoxycholic acid (HDCA), and lithocholic acid (LCA). CA and CDCA are two of the major primary bile acids generated in the liver from cholesterol [37]. UDCA is produced naturally in the liver and is the only approved drug for primary biliary cirrhosis (PBC); it is conjugated with glycine and taurine to form TUDCA and glycour-sodeoxycholic acid (GUDCA), respectively [38]. DCA and LCA are the major secondary bile acids dehydroxylated by bacteria from CA and CDCA, respectively [39]. HCA and its derivatives account for about

76 %

of the total bile acids in pigs and are also present in human blood [40]. HDCA is a bioactive compound extracted from calculus bovis, which is commonly used in TCM for the treatment of stroke [41]. UCA-that is

3 α, 7 β, 12 α

-trihydroxy-5-cholan- 24-oic acid-may be a suitable drug for cholesterol lithiasis, hyperlipidemia, biliary dysplasia, PBC, chronic hepatitis, and biliary reflux gastritis [35].

The conjugated bile acids include taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), gly-cochenodeoxycholic acid (GCDCA), TUDCA, GUDCA, taurodeoxycholic acid (TDCA), glycodeoxycholic acid (GDCA), tau-roursocholic acid (TUCA), and glycoursocholic acid (GUCA). The conjugated bile acids have enhanced solubility in water; they are generally present as sodium salts in vivo and are more stable than free bile acids [42].

The common oxo-bile acids, highlighted in orange in Fig. 1, include 3-oxocholic acid (3-oxo-CA), 3-oxolithocholic acid (3-oxo-LCA), 7-oxodeoxycholic acid (7-oxo-DCA), 7-oxolithocholic acid (7-oxo-LCA), 12-oxochenodeoxycholic acid (12-oxo-CDCA), 12-oxoursodeoxycholic acid (12-oxo-UDCA), 12-oxolithocholic acid (12-oxo-LCA), and 7,12-dioxolithocholic acid (7,12-dioxo-LCA). They are oxidation products catalyzed by multiple hydroxys-teroid dehydrogenases (HSDHs) [35,36]. Specific bile acids (e.g.,

α

-muricholic acid,

β

-muricholic acid,

ω

-muricholic acid, and

λ

-muricholic acid) are present in rabbits, mice, and other rodents; their taurocholates are also shown in Fig. 1 against a green background [36].

The bile acid family generally consists of three classes: ①

C 24

bile acids,②

C 27

bile acids, and ③

C 27

bile alcohols [43]; their distribution in nature is presented in Fig. 2 [44 ⇓⇓⇓-48].

C 24

bile acids are mainly isolated from the bile of humans and animals such as bears, cows, pigs, dogs, sheep, ducks, geese, rabbits, chickens, pigeons, swans, snakes, and fish [44]. CA, CDCA, UDCA, HDCA, DCA, and LCA are typical

C 24

bile acids.

C 27

bile acids are much more abundant in lower primitive vertebrates, and a wide variety of

C 27

bile acids have been isolated from the bile of the capuchinbird, bare-throated bellbird, hornbill, and alligator [45 ⇓-47]. For example,

3 α, 7 α, 24 α

-dihydroxy-

5 β

-cholestan-27-oic acid and

3 α, 7 α, 12 α, 24 α -

tetrahydroxy-5

β

-cholestan-27-oic acid conjugated with taurine are two major bile acids isolated from the great hornbill and the Visayan tarictic hornbill [46]. Some typical

C 27

bile alcohols are shown in Fig. 2.

C 27

sulfate bile salts are always present in the west Indian manatee, elephant, arapaima, and sunfish [47,48]. In addition, bile acids can be divided into two groups based on their structures-namely, free and conjugated bile acids, where the former are conjugated with taurine or glycine to form the latter.

3. Bioactivities of bile acids

Bile acids are essential for the regulation of carbohydrate and lipid metabolism [49]. Since the 1970s, UDCA and CDCA have been demonstrated to be effective for cholesterol gallstones. They can reduce cholesterol saturation, restore the micro-colloidal state of lipids, and dissolve and break down the cholesterol in gallstones; they are also used for the treatment of PBC, cholangitis, cholecystitis, and acute suppurative cholangitis [29,50]. TUDCA is approved for the treatment of PBC [51]; in addition, several studies have shown that TUDCA possesses anti-apoptotic and neuroprotective activity, which has been demonstrated in several disease models, as well as clinically

25, 52, 53

. Moreover, since type 2 diabetes is related to the metabolic disorders of bile acids, HCA and its derivatives could improve glucose homeostasis and may be novel treatments for type 2 diabetes

39, 54, 55

. Taking into account the diverse pharmacological activities of bile acids, an increasing number of derivatives are being synthesized as drug candidates. OCA is a semisynthetic bile acid that is analogous to the natural acid CDCA and was approved in 2016 as a novel drug for clinical use in PBC. Acting as a potent farnesoid X receptor (FXR) agonist, able to regulate bile acid synthesis and secretion as well as lipid and glucose metabolism in the liver and intestine, OCA was also found to be promising drug for NAFLD [56,57].

Interestingly, in addition to the aforementioned pharmacological activities, bile acids exhibit a broad bioactivity spectrum, including antiviral, antibacterial, anti-inflammatory, and immunomodulatory activities, which are being increasingly revealed and unraveled (Fig. 3).

3.1. The antiviral effects of bile acids

Angiotensin-converting enzyme 2 (ACE2) has been identified as the receptor and entry point for SARS-CoV-2 into cells. G protein-coupled bile acid receptor 1 (GPBAR1) and FXR are two main bile acid receptors, and targeting the GPBAR1/FXR ligands are promising novel approaches for COVID-19 [58]. It has been reported that the natural GPBAR1 ligands, such as GUDCA, inhibit the receptor binding domain (RBD) of the spike protein from binding to ACE2 by approximately 20%. UDCA, TUDCA, BAR501, and BAR502 also slightly reduce the binding of RBD to ACE2 [58]. The bile acid receptor GPBAR1 promotes the release of glucagon-like peptide (GLP)-1 and functions as a positive modulator of ACE2 [59].

FXR is a direct regulator of ACE2 expression in the respiratory system, and FXR agonists such as UDCA can reduce FXR signaling and ACE2 expression in human nasal epithelium, thereby reducing susceptibility to SARS-CoV-2 infection [60 ⇓-62]. UDCA can also inhibit abnormal airway epithelial cell migration, prevent damage caused by SARS-CoV-2, and enhance the repair mechanism of the epithelial basal layer [63]. Recently, bear bile-which contains up to

40 % - 50 %

UDCA of total bile acids-was promoted as a coronavirus treatment [64]. CDCA and GCDCA have also been shown to reduce the SARS-CoV-2/ACE2 interaction by 45%-50%, while other semi-synthetic derivatives that are FXR receptor agonists-namely, BAR704 and OCA-reduced the RBD/ACE2 binding by 40% and 20%, respectively [58]. In addition, OCA was shown to possess marked antiviral and anti-inflammatory properties, controlling the expression of ACE2 and attenuating the symptoms of COVID-19 [61].

Influenza is an acute respiratory infection with high mortality, directly invading the respiratory tract and causing viral pneumonia, acute respiratory distress syndrome, shock, and other serious life-threatening complications [65]. The 1918 flu pandemic caused an estimated 21 million deaths, and the combined death toll from influenza since 1920 may already exceed that of the 1918 pandemic. Influenza caused by the influenza A virus remains a serious health threat to populations worldwide and carries the risk of the development of viral resistance [60]. CDCA and TUDCA could be developed as potential anti-influenza A drugs, although their mechanisms are different. CDCA has been shown to inhibit influenza A virus replication in vitro by blocking the nuclear export of viral ribonucleoprotein (vRNP) [66]. TUDCA was approved for sale in China under a trade name in 2007; as a matrix protein 2 (M2) proton channel inhibitor, it can disrupt the oligomeric states of M2 proton channels and abolish or induce inefficient viral infection [67]. Another finding suggested that TUDCA inhibits herpes simplex virus type 1 (HSV-1) replication through the endoplasmic reticulum (ER) stress pathway [68].

CDCA, HDCA, and UDCA attenuated the replication of three subtypes of influenza A virus in A549 and MDCK cell cultures, with a half maximal inhibitory concentration

I C 50

ranging from 5.5-

11.5, 31.0 - 73.7

, and

34.2 - 58.7 μ m o l ⋅ L - 1

, respectively. Unfortunately, no standard anti-viral drug was used as a positive control in this research [66]. However, another study reported that the

I C 50

values of oseltamivir, zanamivir, and peramivir for influenza A virus range from 0.04-748.14, 0.15-50.97, and 0.05-178.23

n m o l ⋅ L - 1

, respectively [69]. Viral gastroenteritis in pigs is commonly caused by porcine deltacoronavirus (PDCoV), for which no vaccine or antiviral drug is currently available. Both CDCA and LCA can inhibit PDCoV replication through the GPCR-IFN-λ3- ISG15 signaling axis in an intestinal epithelial cell line (IPEC-J2) [70]. The antiviral effects of bile acids are shown in Table 1 [58,60 ⇓-62,66 ⇓-68,70].

3.2. The antibacterial effects of bile acids

Cholangitis and cholecystitis often occur simultaneously, most commonly with secondary bacterial infection due to cholestasis [71]. Bacterial culture of bile from patients with acute obstructive suppurative cholangitis revealed the presence of Escherichia coli (E. coli), Clostridium perfringens, Klebsiella pneumoniae (K. pneumo-niae), Pseudomonas aeruginosa, and Enterococcus faecalis. There is some evidence that UDCA may have therapeutic effects on alimentary tract infections. Clostridium difficile (C. difficile), a leading pathogen in diarrhea and colitis, is a life-threatening nosocomial pathogen, and C. difficile infections occur when the normal colonic microbiota is metabolically dysregulated. In vitro, UDCA treatment significantly reduced

C

. difficile spore germination, vegetative growth, and toxin activity, and the patients were free of infection for more than ten months after intaking UDCA [71,72]. UDCA blocked the growth and invasion of extended-spectrum

β

-lactamase (ESBL)-enteroaggregative E. coli (EAEC) both in vitro and in vivo, and attenuated the colitis symptoms [73].

Our recent studies showed that CDCA and UDCA significantly suppressed the viability of methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) value of CDCA was

320 μ g ⋅ m L - 1

. CDCA has a synergistic effect with amino-glycosides and may enhance their germicidal ability against MSSA and MRSA. The combination of CDCA and amikacin (AMK) significantly reduced biofilm formation and had a protective effect on a mouse model infected with Staphylococcus aureus (S. aureus) [23]. The synergistic mechanism is based on the ability of CDCA to dissipate the chemical potential

Δ p H

of the proton motive force (PMF) and enhance reactive oxygen species (ROS) generation by inhibiting superoxide dismutase (SOD) activity in both MSSA and MRSA. In addition, CDCA can act synergistically with carbapenems against MRSA, which was subsequently validated on 25 clinical strains. Moreover, we found that UDCA exhibited remarkable activity against both MSSA and MRSA strains (MIC

= 1280 μ g ⋅ m L - 1

)[24].

CDCA has been shown to have inhibitory effects against other pathogenic bacteria as well. CDCA effectively inhibits the invasion of Salmonella typhimurium, a zoonotic infectious pathogen, in epithelial cells. Notably, we found that CDCA directly inhibits the transcriptional regulator HilD, which is closely related to the virulence and pathogenesis [74]. DCA and CDCA exert extremely rapid bactericidal effects against Neisseria gonorrhoeae, the causative agent of gonorrhea [75,76]. Although the

β

-lactam antibiotics are the most important antibacterial agents, they exhibit greatly reduced efficacy against the emergence of

β

- lactamases. CA was found to be an inhibitor against the

β

- lactamase produced by multidrug-resistant strains, and a combination of CA and ampicillin showed remarkable antibacterial activity and synergistic effect (fractional inhibitory concentration (FIC)

≤ 0.5

) against seven

β

-lactamase-producing strains [77]. Isoallolithocholic acid (IsoalloLCA), which is produced by enteric Odoribacteraceae strains, exhibits potent antimicrobial effects against multidrug-resistant

C

. difficile and Enterococcus faecium (E. faecium), and may potentially maintain intestinal homeostasis [78]. In addition, IsoalloLCA strongly inhibits the growth and spread of other Gram-positive pathogens, including vancomycin-resistant E. faecium (VRE), MRSA, Streptococcus dysgalactiae subsp. equisimilis (SDSE), Clostridium perfringens, Streptococcus pyogenes, Streptococcus sanguinis, Bacillus cereus, and Listeria monocytogenes. IsoalloLCA exerts potent antimicrobial activity in morphological changes, including collapse, swelling, and the formation of multiple cross walls of

C

. difficile and VRE, which has been observed via scanning and transmission electron microscopy [78 ⇓-80]. DCA and LCA also inhibit the growth of C. difficile [79 ⇓⇓-82]. Theriot and Petri [83] reported that enteric infections such as cholera, amebic dysentery, and

C

. difficile colitis are profoundly influenced by bile acid metabolism. The antibacterial effects of bile acids are listed in Table 2 [23,71 ⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓-82].

3.3. The anti-inflammatory effects of bile acids

Infectious diseases are clinical conditions with a wide variety of pathogens, multiple routes of infection, and individual differences in symptoms and signs, and the associated common inflammatory factors involved in the inflammatory response are caused by a variety of infections. Since the inflammatory response triggered by certain infections is frequently the cause of tissue damage and death, strategies that aim to reduce inflammation may be beneficial in the evaluation of new anti-infective agents [84].

It is well known that bile acids regulate lipid, glucose, and energy metabolism by activating the signaling pathways mediated by the GPBAR1 and FXR receptors, which are the two main receptors of bile acids in the treatment of metabolic diseases. Interestingly, there is mounting evidence that bile acids can alleviate and inhibit the inflammatory response through the GPBAR1 and FXR receptors both directly and indirectly, which indicates that the anti-inflammatory mechanism of bile acids is closely related to the treatment of certain metabolic diseases, such as gallstone, cholecystitis, type 2 diabetes, and NAFLD.

UDCA, an existing drug in reducing inflammation and preventing cell death, holds potential for the treatment of COVID-19 patients in cases characterized by cytokine storm syndrome [64]. During C. difficile infection, it was reported that UDCA decreased the inflammatory mediator NO release and the expression levels of tumor necrosis factor-

α T N F - α

, interleukin-1

α I L - 1 α

, interleukin-1β (IL-1β), and interleukin-6 (IL-6). In addition, UDCA increased the expression level of interleukin-10 (IL-10) and attenuated the host inflammatory response [72,85]. Moreover, UDCA and LCA have been reported to improve gut-barrier integrity and reduce inflammation in murine colitis by activating Takeda G protein-coupled receptor 5 (TGR5), also known as GPBAR1 [86,87]. UDCA has a protective effect on the development of colonic inflammation in vivo, while LCA-the primary metabolite of UDCA-may be a potent inhibitor of intestinal inflammation [88].

Ocular alkali burn (OAB) is often accompanied by inflammation; TUDCA was reported to inhibit the inflammation response and protect the cornea and retina from injury, suggesting that TUDCA may be a potential therapeutic intervention for OAB [89]. Several studies have revealed the anti-inflammatory effects of 3-oxo-LCA and IsoalloLCA. More specifically, 3-oxo-LCA and IsoalloLCA suppress T helper 17 cell (TH17) differentiation, isolithocholic acid enhances regulatory T cell (Treg) differentiation, which may be relevant to inflammatory diseases [90,91]. LCA, DCA, IsoalloLCA, and 3-oxo-LCA exhibited both similar and synergistic effects with Parabac-teroides distasonis in the treatment of rheumatoid arthritis [92].

In vivo and in vitro studies have revealed that UCA has favorable anti-inflammatory effects, making it promising anti-inflammatory therapeutic agent. The anti-inflammatory mechanism of UCA has been extensively investigated, including its inhibitory effect on histamine release, lipoxygenase, cyclooxygenase, phospholipase, and elastase activity [93]. CDCA has been found to suppress several pro-inflammatory adipokines and critical inflammatory regulators [94]. OCA is a potent FXR agonist with marked anti-inflammatory effects that suppresses the expression of nuclear factor kappa B (NF-кВ) [62]. Sinha et al. [95] found that supplementation with secondary bile acids reduced intestinal inflammation in three murine models of colitis.

Some bile acids have been shown to be effective against Gram-positive bacteria in animal experiments [96 ⇓-98]. DCA was found to inhibit

S

. aureus-induced endometritis by regulating the TGR5/protein kinase A (PKA)/NF-KB signaling pathway [96]. The secondary bile acids, mediated by the gut microbiota, alleviated

S

. aureus-induced mastitis through the TGR5-cyclic adenosine monophos-phate (cAMP)-protein kinase A (PKA)-NF-κB/NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) pathways in mice [97]. Moreover, DCA and LCA alleviated liver injury and inflammation in mice caused by K. pneumoniae infection [98]. In conclusion, the antiinflammatory activity of bile acids is attracting a great deal of attention due to their ability to protect the liver, promote bile secretion, and control intestinal inflammation. The anti-inflammatory effects of bile acids are shown in Table 3 [62,72,85 ⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓-98].

3.4. Maintaining immune homeostasis

Immune homeostasis is a physiological function of the immune system that maintains the stability of the internal environment by recognizing and eliminating senescent and damaged cells under normal circumstances. The disturbance of immune homeostasis leads to the occurrence of immune diseases. Bile acids play an important role in maintaining immunity and homeostasis, facilitating the differentiation of CD4+ T cells into various T cell subsets. It was reported that IsoalloLCA may play a critical role in maintaining immune homeostasis, and levels of IsoalloLCA may be a bio-marker in humans with inflammatory bowel disease [99].

Bile acids play critical roles in regulating intestinal immune responses; they regulate immune responses to intestinal microbial antigens through chemical communication with the receptors. FXR and GPBAR1, which are highly expressed in intestinal epithelial cells, inhibit inflammasome assembly and reduce the levels of pro-inflammatory cytokines [100 ⇓-102]. FXR is activated by primary bile acids, such as CA and CDCA, while GPBAR1 is mainly activated by secondary bile acids. The FXR and GPBAR1 receptors are signaling molecules placed at the interface of the host immune system with the intestinal microbiota and activated by bile acids [103 ⇓-105]. In addition, common bile acid receptors include the pregnane X receptor (PXR) and vitamin D receptor (VDR). LCA, 3- keto-LCA, CDCA, DCA, and CA can regulate several inflammatory factors of intestine epithelial cells and accelerate wound repair through PXR [106 ⇓⇓⇓-110]. VDR can be activated by 3-oxo-LCA, Isoal-loLCA, and LCA to inhibit TH17 differentiation and increase Treg differentiation [111,112]. Bile acids maintain intestinal immune homeostasis, and the related mechanisms partially overlap with the anti-inflammatory effects. Therefore, the bile acid receptors could be promising targets for intestinal disease intervention.

3.5. Enhancement of the solubilization of an antifungal drug

Amphotericin B, a broad-spectrum antifungal agent, is a first-line clinical drug and has become the gold standard for the treatment of fungal infections. It is used for patients with deep fungal infections caused by fungi, such as septicemia, endocarditis, meningitis, abdominal infection, lung infection, urinary tract infection, and endophthalmitis. Due to the limited solubility of amphotericin

B

, it is clinically solubilized with sodium deoxycholate (SDCA), which enhances the dissolution of amphotericin B [113].

4. Strategies for bile acids production

4.1. Extraction of bile acids from raw materials

The formation of primary bile acids from cholesterol takes place in the liver, and several key enzymes are involved in the formation of CDCA and CA. In mammals, bile acids are modified with glycine or taurine to form conjugated bile acid salts. These bile acids are then metabolized by intestinal bacteria to produce DCA, LCA, HDCA, and UDCA (Fig. 4) [114]. CDCA, CA, DCA, and HDCA are the primary bile acids of chicken, pig, cow, sheep, and poultry bile; they can be obtained via the resin method, supercritical extraction, organic solvent extraction, and the precipitation method [115 ⇓⇓⇓- 119]. However, these processes are complicated, their preparation cycles are long, and the sources are limited, so they cannot meet the needs of industrial production. UDCA is a safe first-line drug for the treatment of PBC [37]; however, it is an expensive bioactive ingredient that is mainly extracted from black bear bile using a tubeless drainage technique. Bears are a national second-class protected animal in China; therefore, due to the limited resources and animal protection laws, the existing tubeless drainage technique has been replaced by artificial synthesis for UDCA production [120,121].

4.2. The artificial synthesis of bile acids

Bile acids are the main component of bear bile and cow bezoar, which are rare medicinal animal materials in China. Due to the limited resources, chemocatalysis, biocatalysis, and chemoenzymatic synthesis are being considered as alternative ways to produce bile acids. Chemical synthesis has been widely used to synthesize UDCA since the 1950s; this process mainly consists of oxidation (Jones oxidation) and reduction (Wolff-Kishner) reactions [35]. Since CA is abundant in the bovine bile of cow and sheep, it used to be used as the precursor in UDCA chemocatalysis. However, the process of synthesizing UDCA from CDCA is simpler and the production cost is lower than synthesizing from CA; thus, with the maturation of its extraction process and large-scale production, CDCA has gradually replaced CA in the synthesis of UDCA. At present, CA, UCA, DCA, and HDCA are used as raw materials for the chemical synthesis of CDCA and UDCA. Many challenges still remain in the chemosynthesis of bile acids, as the complex reaction processes, low selectivity, harsh reaction conditions, high energy consumption, and high pollution limit the development of these processes’ industrialization.

Biocatalysis is playing an increasingly significant role in efficient and eco-friendly synthesis, and both whole-cell transformations and enzyme catalysis have been used in biocatalysis for bile acid production. Several microorganisms, such as Clostridium abso-num, Collinsella aerofaciens, E. coli, and Bacteroides fragilis, have been used in whole-cell transformations yielding UDCA, UCA, and 12-oxo-UDCA [35]. Fungal strains including Bipolaris, Gibberella, Cunninghamella and Curvularia, Pseudonocardia, Saccharothrix, Amycolatopsis, Lentzea, Saccharopolyspora, and Nocardia genera produce UDCA, and some strains can also produce CDCA, DCA, CA, 7-keto-DCA, and 3-keto-DCA [122]. It should be noted that whole-cell conversion has some disadvantages, such as demanding growth conditions, pathogenicity of microorganisms, and complex catalytic products.

Subsequently, whole-cell conversion is gradually being replaced by enzyme-catalyzed systems.

3 α - H S D H, 7 α - H S D H, 7 β - H S D H

, and

12 α - H S D H

are key enzymes involved in the biosynthesis of bile acids.

3 α - H S D H

catalyzes the oxidation of the C3-hydroxyl group and has been used for the clinical quantification of total bile acids in serum [123].

7 α - H S D H

and

7 β - H S D H -

two key biocatalysts for the synthesis of UDCA from CDCA-have attracted increasing attention; they catalyze the oxidation or reduction of a hydroxyl group at the C-7 position in steroid substrates [124]. The 12-OH group of CA, UCA, and DCA can be oxidized by

12 α -

HSDH to yield 12-oxo-CDCA, 12-oxo-UDCA, and 12-oxo-UDCA, respectively. These enzymes are able to perform hydroxylation and dehydroxylation reactions with high regioselectivity and stereoselectivity. P450 monooxygenase,

6 α

-hydroxylase,

7 α

-dehydroxylase, and lipase have also been characterized. CYP107D1 (OleP), a highly regio-and stereo-selective P450 monooxygenase, can hydroxylate LCA to form murideoxycholic acid (MDCA) as the only product [125]. Subsequently, Grobe et al. [126] engineered CYP107D1 (OleP), the S240A variant, and the triple mutant (F84Q/S240A/V291G) as biocatalysts for the regio- and stereo-selective

7 β

-hydroxylation of LCA to yield UDCA. The 6α-hydroxylase (CYP4A21) catalyzes the

6 α

-hydroxylation of CDCA to produce HCA, the primary bile acid in pigs; it is also used to produce HDCA from DCA [127].

7 α -

Dehydroxylase is responsible for the

7 α

-dehydroxylation of CA and UDCA to form DCA and LCA, respectively [128]. HDCA can be catalyzed by lipases to yield various HDCA derivatives [129]. Most of these sequences have been uploaded to the National Center for Biotechnology Information (NCBI) GenBank database, and many studies have conducted rational design to increase enzyme activity based on sequence-structure-function analysis.

However, the UDCA and CDCA produced by biocatalysis have a relatively high cost and are not competitive in the market. Che-moenzymatic synthesis combines the advantages of chemosynthesis and biosynthesis, with high stereoselectivity, high yield, and low toxicity, which makes it a potential option with broad industrial prospects. Overall, several cheap and accessible bile acids, including CA, DCA, HDCA, UCA, dehydrocholic acid (DHCA), and phocacholic acid (PCA), have been developed as raw materials for the chemoenzymatic synthesis of bile acids (Fig. 5).

5. Conclusions and future prospects

Based on the causative pathogen, infectious diseases can be classified as viral, bacterial, fungal, and parasitic infection. Drug efficacy is an age-old and escalating arms race between drugs and pathogens. At present, the emergence of drug resistance has become an alarming global problem. Hence, it is urgent to control its development and deterioration. Especially in infectious diseases caused by bacteria, the aggravation of bacterial drug-resistance presents a grim reality of the post-antibiotic era. Antibiotics have long been used to fight pathogenic bacteria, and bacteria are gradually developing long-term resistance to an increasing number of antibiotics. Although fungal resistance is not as widespread as bacterial resistance, echinocandin resistance in Candida glabrata and azole-resistant Aspergillus fumigatus have been documented to be increasing [130 ⇓⇓-133]. Due to the limited number of antifungal drugs and the emergence of drug resistance, available agents are limited. Similar situations exist for viruses and parasites, with the drug resistance of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) to lamivudine becoming a bottleneck in clinical treatment [134,135]. In recent years, the malaria parasite has been found to be resistant to quinine and chloroquine, both of which are first-line antimalarial drugs [136]. To address this issue, scientists around the world have been looking for new alternatives for eliminating pathogens without developing drug-resistance. Over hundreds of years, researchers have obtained a large number of anti-infective agents, most of which target pathogens. In comparison with the bacterial response to these drugs, bacteria are not prone to developing drug resistance to bile acids, making bile acids attractive candidates for drug development.

With the depletion of natural products and increasing drug resistance, the development of new antimicrobial agents has become increasingly difficult. In recent years, drug repurposing on the pathophysiological mechanisms of marketed drugs has been a hot topic for new drug research and development. For example, remdesivir is a broad-spectrum antiviral drug developed by Gilead Company; originally studied to treat Ebola virus infection, remde-sivir was the first drug used to treat COVID-19 patients in 2020 [137]. As a sedative and analgesic, thalidomide was initially used to treat morning sickness during pregnancy, although it was found to cause severe birth defects. Later, thalidomide was found to have anti-angiogenic and immunomodulatory activities with a unique anti-myeloma effect; thus, it is currently one of the common drugs used for multiple myeloma [138,139]. Promisingly, bile acid drugs for hepatobiliary diseases could be repurposed as novel anti-infective agents in the future, providing a new and effective way to prevent and treat infectious diseases, minimize drug resistance, shorten the drug development cycle, and reduce costs and safety risks.

At the present stage, the efficacy of antimicrobial agents is evaluated according to Clinical and Laboratory Institute (CLSI) standards and guidelines, which are applicable only to the evaluation of planktonic bacteria. This ignores the fact that bacteria usually exist in biofilm in the human body; about

80 %

of infections are highly correlated with bacterial biofilm, which is 10-1000 times more resistant than planktonic bacteria [140 ⇓-142]. Our previous studies showed that CDCA and other active natural products can enhance bactericidal capacity by inhibiting and disrupting the bio-film formation of pathogens [23]. In addition, we found that bile acids have synergistic effects with aminoglycosides and carbapen-ems against MRSA [23,24]. Considering the synergistic inhibitory effects and mechanisms, the combination of bile acids with existing antibiotics is a potential research direction for treating infections caused by multi-drug-resistant strains. Bile acids and derivatives could thus be developed as potential antibiotic adjuvants in the future.

It is also worth highlighting that the host, pathogens, and drugs interact with each other in anti-infective therapy. The discovery and development of host-acting drugs is a new trend and hotspot in the anti-infective field, with the three main strategies of weakening the interaction between pathogen and host, directly promoting antimicrobial efficacy, and supporting antimicrobial efficacy. Most studies in the literature focus on the effects on pathogens while ignoring host immunity. However, it was recently reported that UDCA does not target the SARS-CoV-2 virus, but instead regulates ACE2 expression through FXR in human cells, which may be effective for the prevention of SARS-CoV-2 and its variants in the future [62]. Moreover,

6 α

-ethyl-24-nor-

5 β

-cholane-

3 α, 7 α

, 23-triol-23 sulfate sodium salt (INT-767), a dual agonist of the FXR and GPBAR1 receptors, can inhibit HBV infection in vitro and in vivo. It has been suggested that bile acid derivatives could be developed as anti-HBV agent candidates [143]. In conclusion, this review summarizes the experimental evidence, potential mechanisms, and possible applications of bile acids in preventing and treating infectious diseases.

The safety and efficacy of bile acids for metabolic diseases have been validated by clinical data, including usage, dosage, formulation, and specification. Given their antiviral, antibacterial, and anti-inflammatory effects, bile acids may be promising anti-infective drugs in the future via drug repurposing. However, researchers have an insufficient understanding of pathological mechanisms and the processes of infectious diseases, which is a significant limitation to progress in this area; thus, further comprehensive studies are needed on both fundamental research and the clinical efficacy of bile acids in the prevention and treatment of infectious diseases. We hold the opinion that bile acids can be tailored to address related diseases by targeting specific receptors or pathways, thereby providing a more precise therapeutic schedule. With their effects on immune response, bile acids may be used in the treatment of other diseases characterized by immune abnormalities. Bile acids also hold promise for the maintenance of gut microbiota balance and intestinal health.

Thus far, the development of anti-infective drugs has not kept pace with the evolution of microorganisms. In contrast, TCM has been extensively used for thousands of years without the emergence of drug resistance, and its safety and efficacy have been proven. The basic principle of TCM is to "reinforce healthy qi and eliminate pathogenic qi," rather than killing pathogens directly. Hence, we speculate that TCM does not stimulate pathogens to mutate, making them less likely to develop resistance. The definitions of TCM terms are listed in Appendix A Table S1. TCM can be considered a treasure trove of bioactive compounds for drug discovery. The novel therapeutic strategy of combining TCM with antibiotics has demonstrated unique advantages against various infections.

Acknowledgments

This work was funded by the China Academy of Chinese Medical Sciences (CACMS) Innovation Fund (CI2021A00601), the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ16-YQ-037 and JJPY2022022), and the Scientific and Technological Innovation Project of the China Academy of Chinese Medical Sciences (CI2021B017-09).

Compliance with ethics guidelines

Shuang Liu, Shuo Yang, Biljana Blazekovic, Lu Li, Jidan Zhang, and Yi Wang declare that they have no conflict of interest or financial conflicts to disclose.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.eng.2023.11.017.

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