Home Journals Articles Updates About
CN
image
收藏切换
Tryptophan metabolism and piglet diarrhea: Where we stand and the challenges ahead
收藏切换
PDF
Xuan Zhaoa, 1, Jiaman Panga, 1, Wanghong Zhangb, Xie Penga, Zhenguo Yanga, Guangdong Baia, *, Yaoyao Xiaa, *
Animal Nutrition | 2024, 17(1) : 123 - 133
Less
收藏切换
Animal Nutrition | 2024, 17(1): 123-133
• Original Research Article •
Tryptophan metabolism and piglet diarrhea: Where we stand and the challenges ahead
Full
Xuan Zhaoa, 1, Jiaman Panga, 1, Wanghong Zhangb, Xie Penga, Zhenguo Yanga, Guangdong Baia, *, Yaoyao Xiaa, *
Affiliations
  • aCollege of Animal Science and Technology, Southwest University, Chongqing 400715, China
  • bYunnan Vocational College of Agriculture, Kunming 650211, China
doi: 10.1016/j.aninu.2024.03.005
Outline
收藏切换

The intestinal architecture of piglets is vulnerable to disruption during weaning transition and leads to diarrhea, frequently accompanied by inflammation and metabolic disturbances (including amino acid metabolism). Tryptophan (Trp) plays an essential role in orchestrating intestinal immune tolerance through its metabolism via the kynurenine, 5-hydroxytryptamine, or indole pathways, which could be dictated by the gut microbiota either directly or indirectly. Emerging evidence suggests a strong association between piglet diarrhea and Trp metabolism. Here we aim to summarize the intricate balance of microbiota–host crosstalk by analyzing alterations in both the host and microbial pathways of Trp and discuss how Trp metabolism may affect piglet diarrhea. Overall, this review could provide valuable insights to explore effective strategies for managing piglet diarrhea and the related challenges.

Tryptophan metabolism  /  Piglet  /  Diarrhea  /  Intestinal microbiota  /  Inflammatory response
Xuan Zhao, Jiaman Pang, Wanghong Zhang, Xie Peng, Zhenguo Yang, Guangdong Bai, Yaoyao Xia. Tryptophan metabolism and piglet diarrhea: Where we stand and the challenges ahead[J]. Animal Nutrition, 2024 , 17 (1) : 123 -133 . DOI: 10.1016/j.aninu.2024.03.005
Full Text
Less
1.　Introduction
Less
Early weaning in swine production has garnered widespread adoption due to its potential to expedite the pig slaughter cycle and enhance sows' reproductive efficiency (Campbell et al., 2013). However, pigs confront an array of biological stressors spanning physiological, environmental, and social challenges upon separation from the sows. It is imperative to recognize that the stress induced by early weaning can give rise to unfavorable outcomes, particularly concerning piglets, as compromised intestinal health results in diarrhea and amplifies mortality rates (Zhao et al., 2020). Throughout the weaning process, the intestinal microbiota coexisting in the gut responds to environmental and lifestyle stimuli within short timescales, ranging from hours to days. The intestinal microbiota, composed of myriad microbes facilitating host health, provides colonization resistance against gastrointestinal disorders (Chen et al., 2020; Fassarella et al., 2020). Due to underdeveloped gastrointestinal systems and limited immunity, weaned piglets are more susceptible to the external environment and are more prone to pathogens (Meng et al., 2020). Consequently, their susceptibility to intestinal infection and frequent intestinal diseases is heightened, contributing to elevated morbidity, and mortality rates, primarily through diarrhea.
Disruptions in host–microbiota crosstalk reinforce disease development. Diet and nutrients profoundly impact intestinal microbiota composition, localization, and their interaction with host immunological pathways (Tilocca et al., 2017; Fan et al., 2023). Tryptophan (Trp) is an essential amino acid that serves as the precursor for synthesizing multiple pivotal bioactive compounds (Xue et al., 2023b). Trp and its metabolites play roles in pathophysiological processes, including metabolism, inflammatory responses, immune responses, and intestinal equilibrium. It should be noted that Trp is primarily metabolized through three pathways: the kynurenine (KYN) pathway, the 5-hydroxytryptamine (5-HT) pathway, and the indole pathway (Fan et al., 2023). The KYN pathway is the predominant metabolic route for Trp, with over 95% of Trp converted into an array of bioactive compounds (Vecsei et al., 2013), and the indoleamine 2,3-dioxygenase (IDO) subset of the KYN pathway has long been acknowledged to contribute substantially to the control of general inflammation (Mellor and Munn, 2003). The 5-HT pathway is involved in various physiological processes throughout the body. Notably, gut microbes can directly convert Trp into various molecules, such as indole and its derivatives, which maintain intestinal homeostasis by regulating inflammatory responses.
Growing evidence suggests the dysregulation of Trp metabolism plays a role in disease pathogenesis of swine production. In this article, we provide a contemporary overview of how Trp metabolism interfaces with microbiota–host crosstalk, specifically focusing on its implications for heightened diarrhea morbidity in weaning piglets. Beyond the direct conversion of Trp into bioactive molecules by the gut microbiota, we delve into how the gut microbiota regulates host Trp metabolism. Thus, gaining insight into these interactions could reveal novel targets for addressing gut-related disorders during the weaning transition.
2.　Trp metabolism: pathways and physiology
Less
Trp consists of a carbon bonded to an indole group in the third position. There are two Trp metabolic pathways: one for synthesizing tissue proteins, and the other for undergoing metabolic decomposition or conversion into other functional molecules. Trp is not autonomously synthesized in animals, which therefore need to rely on exogenous sources-primarily the diet (Agus et al., 2018). In addition to synthesizing tissue proteins, the metabolites of Trp play a crucial role in the regulation of physiological processes. For example, disease progression is influenced by the KYN pathway, 5-HT pathway, and indole pathway, which regulate inflammation, immune cell activity and the structure and functionality of epithelial cells (Zelante et al., 2013; Xue et al., 2023a).
2.1.　 Trp metabolism via the KYN pathway
The KYN pathway is governed by two rate-limiting enzymes, including Trp 2,3-dioxygenase (TDO) (mainly present in the liver) and (IDO1/2) (which participate in metabolizing Trp through the KYN pathway in the intestine). In comparison to IDO1, IDO2 exhibits significantly lower enzymatic efficiency. Therefore, it is believed that IDO2 may act as a negative regulator of IDO1 through a competitive mechanism. IDO can be regulated by pro-inflammatory cytokines (Bigelman et al., 2023) and bacterial lipopolysaccharides (Koopmans et al., 2006). Proinflammatory mediators like interferon-gamma (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) upregulate the expression of IDO in intestinal epithelial cells upon exposure to intense immunological activation and inflammatory damage (Haq et al., 2021). Through IDO and TDO, Trp is swiftly converted to KYN. The stimulation of various enzymes leads to the formation of relevant metabolic branches, resulting in the production of kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3-HAA), quinolinic acid (QA) and NAD+ (Fig. 1). In the KYN pathway, Trp plays a complex regulatory role in the immune system through the production of metabolites such as KYN and NAD+ which regulate immune cell metabolism (Minhas et al., 2019). Some metabolites, such as KYN, KYNA, and xanthurenic acid have been proven to act as aryl hydrocarbon receptor (AhR) ligands with the capacity to stimulate AhR-dependent gene expression (Romani et al., 2014).
2.2.　 Trp metabolism via the 5-HT pathway
Roughly 1% to 2% of the ingested Trp undergoes conversion to 5-HT and melatonin through the 5-HT pathway (Gao et al., 2018; Roager and Licht, 2018). The gastrointestinal tract is the primary site of 5-HT production (Daubert and Condron, 2010). Trp is enzymatically converted by Trp hydroxylase to produce 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to form 5-HT. Further conversion of 5-HT can yield melatonin, which plays a crucial role in immune regulation (Chen et al., 2011; Xia et al., 2019). 5-HT binds to receptors (5-HTR) in the intestine to regulate intestinal motility and endocrine activity (Fig. 1). The 5-HT pathway regulates the gut–brain axis and intestinal homeostasis by triggering numerous functions in the gastrointestinal tract (Watts et al., 2012). Specifically, metabolites such as 5-HT are an important gastrointestinal signaling molecule that conveys signals from the gut to neurons and influences intestinal peristalsis, secretion, and the absorption of nutrients (Chen et al., 2011; Muller et al., 2016).
2.3.　 Trp metabolism via indole pathway
Approximately 4% to 6% of Trp undergoes conversion by gut microbiota, yielding various indole derivatives, including indole, indole acetaldehyde (IAM), indole acrylic acid (IA), indole acetic acid (IAA), indole-3 aldehyde (IAld), tryptamine (TAM), indole pyruvate (IPYA), indole lactic acid (ILA), and indole-3 propionic acid (IPA) (Fig. 1). Clostridium and Lactobacillus have been demonstrated to convert Trp into IPYA; and under the action of Trp enzymes in Bacteroides, Escherichia coli, and Clostridium, they are catalyzed to produce indole (Roager and Licht, 2018). Clostridium and Ruminococcus can decarboxylate Trp to TAM, while Lactobacillus can metabolize Trp to indole-3-formaldehyde, and Bifidobacterium can convert Trp to IAA. Within the biological system, the activity of a pathway depends on both Trp content in the diet and whether the corresponding metabolic enzyme system is present in the gut microbiota. Different microbes have distinct enzymes, which necessitates collaborative interactions between multiple microbes to generate particular indole derivatives from Trp (Gao et al., 2018). Some indole derivatives can bind to AhR on the surface of intestinal cells, leading to cytokine release, including interleukin-6 (IL-6), interleukin-17 (IL-17), and interleukin-22 (IL-22), which further regulate intestinal mucosal immunity, intestinal barrier, and intestinal homeostasis (Wei et al., 2021).
2.4.　 Gut microbiota regulation of Trp metabolism
Intestinal microbiota plays a central role in maintaining metabolic homeostasis. Trp metabolites are crucial mediators facilitating communication between the host and the microbiota. The rate at which circulating Trp is utilized by the host is contingent upon the delicate balance between bacterial Trp metabolism and Trp production. As previously outlined, the microbiota significantly influences the indole pathway. Genus carrying the TAM gene can metabolize Trp into indole and its derivatives, and these metabolites can be used as ligands of AhR and retinoid-related orphan receptor γt (RORγt), thus regulating intestinal homeostasis (Wyatt and Greathouse, 2021). Furthermore, their regulatory roles in the 5-HT pathway have been substantiated in germ-free mice, presenting impaired 5-HT production, particularly in the colon, consequently leading to lower 5-HT concentrations in the blood (Yano et al., 2015). Moreover, compelling evidence supports the pivotal role of the intestinal microbiota in stimulating IDO1 activity. This stimulation results in the inhibition of the KYN pathway and a subsequent reduction in Trp levels, a phenomenon notably observed in germ-free mice. Trp metabolism through the KYN pathway is notably augmented following supplementation with intestinal microbiota. Several studies have illuminated the relationship between Toll-like receptors (TLR) and metabolic alterations in the KYN pathway (Clarke et al., 2012; Fila et al., 2021). Changes in the intestinal microbiota composition can trigger abnormal TLR activation, thus augmenting the KYN pathway. In addition, certain gut microbes possess enzymes homologous to those in the KYN pathway, enabling them to produce KYN and downstream metabolites (Agus et al., 2018). In turn, the modulation of host Trp levels in the microenvironment is believed to involve the arrest of microbial proliferation, which significantly benefits the host. Interestingly, Trp supplementation in piglets can improve gut microbiota diversity, decrease conditional pathogens, and increase Trp-metabolizing bacteria (such as Lactobacillus) (Liang et al., 2018, 2019).
3.　Piglet diarrhea
Less
Diarrhea is a significant and increasing cause of mortality among weaned piglets, inflicting substantial economic losses on swine farming. The occurrence of diarrhea in piglets is a complex interplay involving invasion by foreign pathogens, diet alterations, and separation stress (Vogt and Finlay, 2017; Gao et al., 2019). The intestine, which is the principal organ for digestion and absorption in pigs, is often the frontline in dealing with the challenges imposed by diarrhea. These challenges manifest as disturbances in intestinal barrier function, mucus secretion, the mucosal immune system, and the intestinal microbiota (Xie et al., 2019). Once the epithelial barrier is damaged, the vulnerability to pathogen invasion escalates, ultimately leading to intestinal inflammation and diarrhea.
3.1.　 Diarrhea induces intestinal injury
In terms of physiological structure, intestinal villi play a vital role as the initial line of defense since they have direct and prolonged contact with the luminal contents of the intestine, thereby increasing the susceptibility to pathogen invasion (Jayaraman et al., 2013; Bai et al., 2023). Studies have shown that diarrhea can lead to an increase in crypt depth (CD) and a decrease in villus height, along with alterations in the relative weight of the intestine. These changes in intestinal morphology indicate the impact of diarrhea on the structure and health of the pig intestine.
The intestinal barrier, crucial for gut health, is comprised of the epithelial layer and mucus. The epithelium consists of various cell types like enterocytes, goblet cells, paneth cells, and enteroendocrine cells, each with specific functions contributing to nutrient absorption, mucus secretion, antimicrobial peptide production, and hormone secretion respectively (Yu et al., 2018). These cells are tightly bound to each other with tight junctions, gap junctions, adherent junctions, and desmosomes, forming a selective and semipermeable barrier. Weaning, a pivotal event for piglets, can impair this physical barrier, disrupting tight junctions and increasing intestinal permeability (Wang et al., 2020). Decreased expression of critical tight junction proteins like claudin-1, occludin, and zona occludens-1 (ZO-1) is a hallmark of intestinal barrier injury. Elevated intestinal permeability allows pathogens, endotoxins, and other antigens to breach the intestinal mucosal barrier, ultimately causing intestinal ailments like diarrhea and enteritis (Deng et al., 2022). Mucins (MUC) and antimicrobial proteins form the mucus layer, secreted by goblet cells and epithelial cells, respectively. As the chemical barrier, the mucus layer can effectively impede the invasion of microbial pathogens, contributing to maintaining intestinal homeostasis (Tang et al., 2022). In contrast, MUC2 forms the bulk of the mucus needed to function properly. Piglet diarrhea causes the destruction of the mucus layer, impairs the intestinal microenvironment, and further destroys intestinal barrier integrity, leading to inflammation (Xia et al., 2022). Moreover, a decrease in the number of goblet cells results in decreased MUC secretion, and the mucus layer becomes thin, which contributes to pathogens passing by the mucus layer to disrupt the chemical barrier while accelerating the damage to the physical barrier, mucosal immune barrier, and microbial barrier (Tang et al., 2022). These alterations in physical and chemical barriers are critical features of intestinal barrier injury and contribute to piglet gastrointestinal disorders.
The mucosal immune system, a complex but orderly local immune system, can provide protection against over 90% of intestinal pathogens, mainly composed of immune organs, immune cells, and immune molecules (Yang et al., 2022b). Immune cells in the intestine may recognize either intestinal autoantigens or foreign antigens via pattern recognition receptors (PRR), including nucleotide-binding oligomerization domain (NOD) like receptors and TLR (Wang et al., 2019b). Pattern recognition receptors can directly regulate numerous inflammatory pathways, such as peroxisome proliferator-activated receptor-γ (PPAR-γ), mitogen-activated protein kinase (MAPK), and nuclear factor-kappa B (NF-κB), which enhance immunocompetence and alleviate damage. Weaning stress activates the intestinal immune system to contribute to the production of proinflammatory cytokines, which accelerate intestinal damage and dysfunction and lead to diarrhea (Tang et al., 2022). These immune factors include TNF-α, IFN-γ, interleukin-1β (IL-1β), IL-6, interleukin-8 (IL-8), and secretory immunoglobulin A (sIgA). Diarrhea can promote colonic inflammatory responses by activating recombinant myeloid differentiation factor 88 (MyD88)-dependent TLR4 signaling in pig macrophages (Zhou et al., 2022). Moreover, the increased T cell count and matrix metalloproteinase indicate the onset of intestinal inflammation and the decreased CD4+/CD8+ T lymphocyte ratio (Tang et al., 2022). These immune responses underscore the intricate interplay between the mucosal immune system and gut health, particularly in the context of diarrhea and its associated inflammation.
3.2.　 Changes of intestinal microbiota in diarrheal piglets
The intestinal microbiota of pigs presents obvious dynamic changes in composition and diversity over time after birth. Piglets are born with a sterile environment in the intestine, and the microbes start colonizing after birth (such as E. coli and Streptococcus spp.) (Luo et al., 2022). Within two days after birth, facultative anaerobes, obligate anaerobes, and aerobic bacteria gradually colonize the gastrointestinal tract, which is associated with the vaginal microbiota, breast milk and the living environment (Beaumont et al., 2020; Teng et al., 2020). Weaning is considered one of the most critical periods in pig production; it triggers remodeling in the intestinal microbiota and tends to be stable at the late stage (Beaumont et al., 2020; Luo et al., 2022). The feed of piglets is switched from liquid milk toward solid-based feed after weaning, while the immature gastrointestinal tract fails to adapt to dietary changes to utilize these nutrients. Undigested nutrients by the host enter the large intestine for microbial fermentation and facilitate the propagation of pathogens, eventually resulting in diarrhea and pathological intestinal damage in piglets (Gresse et al., 2017; Tang et al., 2022).
E. coli is the most common microbe in the intestinal microbiota and consists of diverse strains, some of which possess pathogenic features (Hermann-Bank et al., 2015). Enterotoxigenic E. coli (ETEC) is mainly responsible for postweaning diarrhea in piglets (Kim et al., 2022; Wang et al., 2022). ETEC strains colonize the intestinal mucosa by adhesins, and then induce diarrhea by releasing enterotoxins that cause fluid-electrolyte disturbance and acid-base imbalance of piglets (Bin et al., 2018). Of the enterotoxins, the excretive STa (heat-stable toxin A) is the main culprit in causing diarrhea (Wang et al., 2022; Wu et al., 2023). Moreover, more abundant Enterococcus in diarrheal piglets than healthy piglets mean Enterococcus increases the risk of piglet diarrhea (Hermann-Bank et al., 2015). Indeed, previous researchers have reported that Enterococcus (E. hirae and E. durans) and E. coli co-contributed to the development of diarrhea (Gryaznova et al., 2022), which might be due to the villous atrophy in the small intestine of piglets (Jonach et al., 2014; Larsson et al., 2014). Salmonella can also induce intestinal barrier injury via inflammatory reactions, eventually leading to diarrhea (Thiagarajah et al., 2015). Furthermore, a metagenomic analysis shows diarrheic piglets have increased Sutterella, Campylobacter, and Fusobacteriaceae (Yang et al., 2017). Moreover, Fusobacterium can inhibit T-cell responses and promote inflammation, which contributes to piglet diarrhea (Nosho et al., 2016). It has been reported that Veillonella, Campylobacterales, and Salmonella typhimurium as pathogens can also induce inflammatory bowel disease, leading to piglet diarrhea (Li et al., 2018; Huang et al., 2019).
Hermann-Bank found that the relative abundance of Actinobacteria (Bifidobacterium boum and Corynebacterium kutscheri) and Firmicutes (Lactobacillus acidophilus and Streptococcus gallolyticus subsp) is decreased in diarrhetic piglets (Hermann-Bank et al., 2015). Actinobacteria and Firmicutes can digest various carbohydrates to produce short-chain fatty acids (SCFA), which are beneficial for regulating the host's intestinal immunity by divining T cells, neutrophils, and macrophages (Wang et al., 2021; Xie et al., 2023). The decreased Actinobacteria and Firmicutes abundance reduces SCFA production and weakens immune regulatory function, ultimately causing diarrhea. Another study similarly found that the abundance of Firmicutes in the diarrhetic piglets is decreased, including Blautia, Ruminococcus, Enterococcus, Clostridium, Streptococcus, and Lactobacillus (Yang et al., 2017). In addition, the lower ratio between Bacteroidetes and Firmicutes is also a contributing factor in the etiology of piglet diarrhea (Bin et al., 2018). This variation is most likely due to the increased oxygen level in the intestine caused by ETEC infection or Vibrio cholera infection, which inhibits the growth of anaerobes and supports facultative anaerobes (e.g., Bacilli, member of Firmicutes) (Albenberg et al., 2014; David et al., 2015). It is also evident that Alloprevotella and Oscillospira are decreased in weaned piglets (Li et al., 2018), which are producers of succinate, acetate, and butyrate, which can improve gut barrier function and exhibit anti-inflammatory properties (Gophna et al., 2017; Wang et al., 2021). In conclusion, decreased richness and diversity in the intestinal microbiota is the leading cause of piglet diarrhea.
4.　Perturbations in Trp metabolism of diarrheal piglets
Less
Trp metabolism disorder is strongly associated with diarrhea in piglets. The development of diarrhea is usually accompanied by Trp metabolic disorder, which alters Trp-associating metabolite levels in host and microbial pathways, ultimately causing intestinal inflammation and diarrhea and leading to a decrease in the survival rate and growth retardation of piglets. In recent years, the roles and underlying mechanisms of Trp metabolism in diarrhetic piglets have gradually been unraveled (Fig. 2). When inflammation occurs, the metabolites of Trp in the intestine can exert anti-inflammatory and immunosuppressive effects by acting on AhR. Aryl hydrocarbon receptor is a ligand-activated transcription factor belonging to the family of the Per-Arnt-Sim proteins and is widely expressed in many leukocytes (such as macrophages and dendritic cells), T lymphocytes, innate lymphoid cells, and intestinal epithelial cells (IEC) (Hukkanen, 2012; Pernomian et al., 2020). Weaning-associated intestinal inflammation induces aberrant AhR signaling in weaned piglets. As AhR ligands, the metabolites of Trp associated with the KYN and indole pathways may regulate inflammation by mechanisms dependent on AhR activation to relieve diarrhea in piglets (Zhang et al., 2022; Han et al., 2023). Therefore, AhR has recently been postulated as a molecular target for controlling intestinal inflammation and diarrhea, although the underlying mechanisms have not yet been elucidated.
4.1.　 Host endogenous Trp metabolism and diarrhea
The KYN pathway is the major route for Trp metabolism in the host and has a multilevel association with inflammatory bowel disease (IBD), with diarrhea being a frequent consequence of IBD. Diarrhea and inflammation can activate the KYN pathway, leading to elevated serum KYN levels (Li et al., 2020). Indoleamine 2,3-dioxygenase-1 is the initial rate-limiting enzyme in Trp catabolism within the KYN pathway and plays an important role in regulating adaptive immunity (Nayak-Kapoor et al., 2018; Grifka-Walk et al., 2021). When inflammation occurs in the mucosa, activated IDO1 can exert anti-inflammatory and immunosuppressive through KYN production, immune reactivity, and gut microbial composition, suggesting the acceleration of Trp metabolism to KYN (Wolf et al., 2004; Gao et al., 2018). Kynurenine and its derivatives act as direct ligands of AhR and can contribute to the activation and transcription targeted genes, including IL-6, IL-22, vascular endothelial growth factor A (VEGFA), and cytochrome P450 1A1 (CYP1A1) (Hubbard et al., 2015), thereby inducing the generation of regulatory T cells to resist hyper-inflammatory responses (Bessede et al., 2014). Li et al. have also found that KYN can exert immunosuppressive effects via AhR to realize the regulation of immune responses by suppressing effector T cell proliferation and increasing regulatory T cell development (Li et al., 2019). Meanwhile, KYN, XA, and KYNA can facilitate the proliferation of IEC and improved barrier function through their interactions with AhR and an increased expression of IL-22. These derivatives such as KYNA can regulate intestinal inflammation via the glycolysis of T cells and mitochondrial respiration of IEC (Michaudel et al., 2023). In addition, activated AhR regulates the Treg/Th17 axis to resist inflammatory responses and differentiate innate immune cells like dendritic cells and macrophages (Lamas et al., 2018; Grifka-Walk et al., 2021). The KYN pathway may also control the balance between anti-inflammatory and proinflammatory responses in intestinal immune cells by regulating the secretion of IDO1 (Kaszaki et al., 2008). In colitis, IDO-deficient mice display more severe colitis and significantly increased proinflammatory cytokines (Takamatsu et al., 2013). More importantly, the lower IDO activity leads to both decreased KYN and increased 5-HT concentrations (Machado et al., 2017). The pathological injury induced by IDO deletion is probably due to increased 5-HT synthesis in the intestines and the activation of proinflammatory cytokines, as well as a decrease in the number of CD4+Foxp3+ regulatory T cells (Chen et al., 2021; Craig et al., 2022). In summary, IDO is activated during inflammation, thus increasing KYN levels by consuming more Trp, which goes on to serve as an AhR ligand activating AhR to exert anti-inflammatory and immunosuppressive effects.
5-hydroxytryptamine, as an essential signaling molecule in organisms, triggers multiple signals in the intestine and nervous system and is implicated in a wide range of physiological functions through activating specific 5-HT receptors (Mawe and Hoffman, 2013). Intestine-derived 5-HT can convey signals from the intestine to intrinsic or extrinsic neurons, modulating intestinal peristalsis and motility, secretion, and the absorption of nutrients through 5-HTR signaling, vasodilatation, and platelet function (Hu et al., 2023; Liu et al., 2023). Additionally, 5-HT participates in the regulation of diarrhea by affecting intestinal inflammation. The inhibition of serotonin transporter (SERT) expression in the intestine is a sign of inflammation induced by an enteric source of 5-HT, which leads to the secretion-enhancing effect promoted by 5-HT in the mucosa and promotes colon inflammation induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) or the deletion of the anti-inflammatory factor interleukin-10 (IL-10) (Gershon, 2013). This is due to the lack of SERT, which increases the release of 5-HT from enterochromaffin cells, promoting intestinal inflammation, therefore 5-HT is unmistakably proinflammatory (Liu et al., 2021). Notably, inflammation can raise the concentration of 5-HT in the serum and gastrointestinal tract wall of piglets, which is further accompanied by diarrhea (Bulc et al., 2022; Yang et al., 2022a; Wang et al., 2023). Trp hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of 5-HT, contains two isoforms, of which TPH1 is mainly expressed by specialized gut endocrine cells (Jones et al., 2020). Typically, an elevated 5-HT level is associated with the upregulation of TPH1 in the small intestinal mucosa, implying that TPH1 plays an important role in this physiological process. Thus, inhibiting TPH1 is an attractive strategy to curb inflammation and attenuate diarrhea (Chojnacki et al., 2021; Zhai et al., 2023). Previous studies have found that the increasing 5-HT content activates the innate immune system by binding to 5-HTR, eventually bringing adaptive immunity to bear and mediating the full force of inflammation in the bowel (Faba et al., 2022; Liu et al., 2023). These subtle changes in immune activation may contribute to the diarrhea caused by 5-HT. Unlike TPH1, TPH2 is primarily expressed in neurons of the raphe nuclei of the brain stem and a subset of neurons in the enteric nervous system (Jones et al., 2020). Interestingly, the deletion of TPH2 seems to increase the severity of inflammation, emphasizing the immune protective effect of neuronal 5-HT. Studies have found that the 5-HT produced by TPH2 can protect the enteric nervous system from the neurotoxic effects of inflammation (Gershon, 2012). This suggests that 5-HT plays both offence and defense in the intestine, depending on the site of 5-HT synthesis (Najjar et al., 2023). However, there is no direct evidence to show the mitigating effect of TPH2 on diarrhea, and this area of study should be investigated using more targeted techniques. Although the relationship between endogenous Trp metabolism and diarrhea has not yet been reported, the changes in endogenous Trp metabolites and the corresponding enzymes in the inflammatory responses function as indicators of diarrhea.
4.2.　 Microbial Trp metabolism and diarrhea
The gut microbiota can directly utilize Trp, which partially limits Trp availability for the host. Microbial metabolites of Trp, such as indole and indolic acid derivatives, play a dominant role in intestinal AhR and pregnane X receptor (PXR) activity, modulating mucosal immune responses or mucosal barrier integrity which ultimately impacts diarrhea (Lamas et al., 2016). Additionally, gut microbiota can stimulate IDO1 activity, which affects the decomposition of Trp. Namely, AhR and IDO1 participate in connecting microbial Trp catabolism and host endogenous Trp metabolites with regulatory T cells' functions. Interestingly, in the absence of IDO1, AhR/IL-22 activities are not reduced (Bessede et al., 2014). The upregulation of AhR/IL-22 activity in response to the absence of IDO1 suggests a compensatory or alternative mechanism. Therefore, AhR and IL-22 are associated with maintaining mucosal immunity and responding to signals from the gut microbiota. In addition, AhR stimulation may in turn affect IDO1. The positive feedback loop between IDO1 and AhR is required for the coevolution of the gut microbiota and the mammalian immune system, which is beneficial for the host under strong inflammatory conditions and prevents dysregulated immunity.
Microbial Trp metabolites can affect intestinal homeostasis by regulating the secretion of IL-22, promoting the production of antimicrobial peptides, and protecting the intestine against pathogenic infection via AhR (Levy et al., 2017). Indole derivatives such as ILA and IAld can activate AhR in CD4+ T cells and subsequently regulate intraepithelial lymphocytes via CD4+ CD8αα+ (Cervantes-Barragan et al., 2017). Furthermore, indole is considered to be a beneficial signaling molecule in IEC and ameliorates intestinal inflammation by modulating inflammation-mediated via alterations in the gut microbiota composition and innate immune responses (Whitfield-Cargile et al., 2016). Indole can reduce the expression of Salmonella pathogenicity island-1 (SPI-1) genes to weaken the invasion and colonization capabilities of enteric bacteria. Indole treatment can increase the expression of genes associated with strengthening the mucosal barrier and MUC production and the secretion of the anti-inflammatory cytokine IL-10, as well as decrease activation of NF-κB mediated by TNF-α, IL-8 expression (a proinflammatory), and the adherence of pathogenic E. coli to HCT-8 cells, rather than other indole-like molecule treatments, such as H-indole-2,3-dione, 7-hydroxyindole, 5-hydroxyindole, 2-hydroxyindole, and indole-3-acetic acid (Bansal et al., 2010). This suggests that variations in NF-κB activation and cellular resistance are highly associated with indole (Gao et al., 2018).
Indole can be further metabolized by the intestinal microbiota into indole derivatives, which are also important for maintaining intestinal immune homeostasis. Indole acrylic acid is considered an essential factor in resisting intestinal inflammation. Inflammation can promote Peptostreptococcus species to produce IA, improving both IL-10 and MUC gene expression to mitigate inflammatory responses (Wlodarska et al., 2017). Indole-3 propionic acid, which is metabolized by Clostridium sporogenes, can control inflammation by regulating the expression of immune factors, including interleukin-12 (IL-12), interferon-γ (INF-γ), TNF, IL-1β, and IL-10, as well as inducing the differentiation and augmented suppressive potential of Tr1 cells (Pernomian et al., 2020). Bacteroides thetaiotaomicron can metabolize Trp into IAA and IPA, which activate the AhR and enhance Treg cell function to inhibit intestinal inflammation (Li et al., 2021). Lactobacillus reuteri increases the levels of IAld and reduces intestinal inflammation via the activation of the AhR/IL-22 axis. Furthermore, IAld could stabilize and improve intestinal microbiota composition to alleviate inflammation (Xue et al., 2023b). However, diarrheal diseases are accompanied by disturbances in gut microbial diversity, which may perturb Trp metabolism in microbial pathways. Not surprisingly, low levels of indole, 5-hydroxyindole acetic acid (5-HIAA), IAA, and other derivatives were found in diarrheal piglets. They, therefore, can reduce AhR activation and further result in inflammation and diarrhea (Fu et al., 2021; Song et al., 2021; Han et al., 2023). Thus, a stable intestinal microbial community is crucial to reduce piglet diarrhea.
5.　Trp metabolism: from a disrupted equilibrium to therapeutic strategies
Less
Diarrhea can be classified into infectious and non-infectious types, which are caused by pathogen and stress of feeding management, respectively (Wang et al., 2019a), resulting in intestinal barrier disruption and gut microbiota dysbiosis, ultimately triggering inflammation and immune responses (Ghosh et al., 2021). Alterations in Trp levels and metabolites strongly correlate with clinical features in diarrhea, encompassing mucosal barrier dysfunction, microbiome dysbiosis, and inflammation severity. Given the impact of Trp metabolism in pathological conditions, utilizing Trp and its metabolites as biomarkers holds promise in supporting diagnosis, prognosis, and guiding therapeutic decisions. Previous studies have shown dietary Trp supplementation during the weaning period of piglets can effectively modulate diarrhea. Piglets supplemented with 0.35% Trp decreases the diarrhea rate (33.8%) compared with those of 0.14% dietary Trp (43.5%) (Rao et al., 2021). Moreover, Trp can relieve intestinal inflammation, improve barrier function, and modulate the microbiome in piglets challenged by diquat or lipopolysaccharide (Liu et al., 2019, 2022). This modulation primarily manifests through the interactions between the host immune system and the gut microbiome (Hu et al., 2023). Conversely, high concentrations of dietary Trp (0.75%) could have the opposite effect on small intestinal structure in weaned piglets (Tossou et al., 2016).
Diarrhea triggers the synthesis of numerous proinflammatory cytokines in the intestine, such as IL-1β, IL-6, and IL-8. Excessive secretion of these cytokines can cause inflammation and disrupt intestinal barrier integrity (Zhao et al., 2022). The biological effects of Trp metabolites and their disease alterations suggest their potential as therapeutic targets. This can be achieved directly by utilizing Trp metabolites, targeting their receptors, or indirectly manipulating the gut microbiota (Fig. 3). Trp exhibits anti-inflammatory effects in mammals and is vital in regulating inflammatory responses. Studies have revealed that Trp can reduce the release of proinflammatory cytokines and increase anti-inflammatory factors (Kim et al., 2010; Shizuma et al., 2013). Dietary supplementation with 0.2% to 0.4% Trp has been observed to decrease the abundance of Clostridium and Streptococcus while increasing the levels of Lactobacillus and Clostridium. Additionally, it raises the concentration of sIgA (Liang et al., 2018). Intriguingly, L-Trp is not catabolized by porcine intestinal epithelial cells, but it can regulate intracellular protein turnover and the expression of tight junction proteins (Wang et al., 2015). Trp metabolites can regulate the expression of intestinal cytokines and consequently modulate intestinal inflammation. Trp acts as a precursor for serotonin, a neurotransmitter, and undergoes enzyme catalysis through the 5-HT pathway and the KYN pathway. This process is implicated in the onset of visceral hypersensitivity observed in diarrhea (Li et al., 2017). Oral Trp supplementation has been shown to regulate the synthesis of 5-HT and melatonin, enhancing the innate immune response in animals. Melatonin is also confirmed to possess anti-inflammatory properties. Abnormalities in 5-HT metabolism can result in gastrointestinal dysfunction, although the precise mechanism remains poorly understood. It is speculated that other Trp metabolites, primarily those of the KYN pathway, play a crucial role in regulating intestinal function. Immune cells break down Trp into KYN, a pivotal regulator of immune responses during infection and inflammation. Kynurenine exhibits antimicrobial activities, directly affecting the proliferation of intestinal microbiota (Nino-Castro et al., 2014). The interplay between the intestinal microbiota and host Trp metabolism in the KYN pathway is intertwined with the immune system. In the KYN pathway, KYN modulates intestinal homeostasis by stimulating AhR and regulating IDO expression (Bessede et al., 2014). This is the case in settings of intestinal inflammation, where dietary Trp supplementation alleviates colitis severity through restoration of AhR ligand production. Several bacterial Trp metabolites, including indole, IAA, IPA, IA, IAld, indole-3-acetaldehyde (IAAld), and KYN, have been proven to be AhR ligands. Approaches involving the supplementation of Trp and its metabolites have shown promising effects in treating inflammatory conditions caused by weaning diarrhea. Through AhR, these metabolites may provide essential cues to the host for resisting colonization, defending against mucosal inflammation, and targeting a range of immune cells, including epithelial lymphocytes, Th17 cells, macrophages, and dendritic cells, thus regulating immune responses to ensure immune barrier integrity.
The pathological role of microbial Trp metabolism in diarrhea might be feasible to target, as shown by manipulation of the intestinal microbiota with diet and L. reuteri products inducing the AhR agonist IAA to reprogram intraepithelial CD4+ T cells into immunoregulatory CD4+CD8αα+ T cells (Cervantes-Barragan et al., 2017). Intestinal microbes play a crucial role in developing diarrhea through interactions with Trp metabolites. Using fecal transplantation, studies have revealed that IAAld alleviates intestinal inflammation by influencing intestinal microbiota composition. B. thetaiotaomicron can increase the levels of IAA and IPA, inhibiting intestinal inflammation via the activation of AhR and enhancing Treg cell function (Li et al., 2021). Indole-3 propionic acid is produced by intestinal symbiotic bacteria such as Peptostreptococcus (Platten et al., 2019) and Clostridium (Lavelle and Sokol, 2020), which promote immune regulation. Recent research has high-lighted the potential of IPA to promote nerve regeneration and repair when it enters the bloodstream (Serger et al., 2022). Additionally, IPA contributes to maintaining barrier function and inhibiting the production of tumor necrosis factors by activating AhR receptors and PXR. This activation induces the production of immune cells that promote tolerance, ultimately reducing the inflammatory response and enhancing immune tolerance in the intestine (Flannigan et al., 2023). Furthermore, the manipulation of the KYN and 5-HT pathways in the intestine through microbiota-based approaches is also attractive. Evidence of gut microbial influence on KYN concentrations and IDO activity reveals that targeting the gut microbiome to modulate KYN pathway prevents diseases. Studies of Bifidobacterium infantis have reported that KYN metabolites are increased after colonization (Desbonnet et al., 2008). Although studies have shown the addition of the Lactobacillus johnsonii probiotic has reduced IDO activity (Marcial et al., 2017), it can also promote the transformation of the indole pathway (Roager and Licht, 2018), possibly as part of an adaptive mechanism to maintain immune homeostasis in the presence of gut microbiota. However, a better understanding of microbial processes is needed, specifically how microbiota and Trp metabolites regulate Trp metabolism to cope with diarrhea.
6.　Conclusion and future perspective
Less
Weaned piglets are susceptible to the external environment due to immature gastrointestinal development and low immunity. This heightened sensitivity often results in diarrhea. Additionally, there is a decrease in the abundance of beneficial bacteria in the intestine, accompanied by abnormal Trp metabolism. Tryptophan significantly influences physiology and physiopathology through three main pathways: the KYN, 5-HT, and indole pathways. These pathways can be regulated either directly or indirectly through the gut microbiota. As a result, Trp metabolism in the intestine emerges as a critical player in a therapeutic context. This could involve using molecules targeting specific Trp metabolites or leveraging microbes that manipulate Trp metabolism. Targeting Trp metabolites, including IDO1, KYN, 5-HT, indole, and their derivatives via the AhR signaling pathway, represents a novel and promising strategy for treating diarrhea and associated conditions. Considering the complex and variable nature of the intestine microbiota, it is potential to identify universal principles regarding bacterial Trp metabolites. Manipulating the intestinal microbiota to influence Trp metabolism could be a practical approach in addressing diarrhea and related challenges in weaned piglets.
References
Less
Agus A, Planchais J, Sokol H. Gut Microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 2018;23(6):716-24. https://doi.org/10.1016/j.chom.2018.05.003.
Albenberg L, Esipova TV, Judge CP, Bittinger K, Chen J, Laughlin A, Grunberg S, Baldassano RN, Lewis JD, Li HZ, Thom SR, Bushman FD, Vinogradov SA, Wu GD. Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology 2014;147(5):1055-63. https://doi.org/10.1053/j.gastro.2014.07.020.
Bai GD, Zou YB, Zhang WT, Jiang X, Qin JW, Teng T, Sun HY, Shi BM. Perinatal exposure to high concentration glyphosate-based herbicides induces intestinal apoptosis by activating endoplasmic reticulum stress in offspring. Sci Total Environ 2023;865:161223. https://doi.org/10.1016/j.scitotenv.2022.161223.
Bansal T, Alaniz RC, Wood TK, Jayaraman A. The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc Natl Acad Sci U S A 2010;107(1):228-33. https://doi.org/10.1073/pnas.0906112107.
Beaumont M, Paës C, Mussard E, Knudsen C, Cauquil L, Aymard P, Barilly C, Gabinaud B, Zemb O, Fourre S, Gautier R, Lencina C, Eutamène H, Theodorou V, Canlet C, Combes S. Gut microbiota derived metabolites contribute to intestinal barrier maturation at the suckling-to-weaning transition. Gut Microbes 2020;11(5):1268-86. https://doi.org/10.1080/19490976.2020.1747335.
Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, Bicciato S, Mazza EM, Macchiarulo A, Vacca C, Iannitti R, Tissi L, Volpi C, Belladonna ML, Orabona C, Bianchi R, Lanz TV, Platten M, Della Fazia MA, Piobbico D, Zelante T, Funakoshi H, Nakamura T, Gilot D, Denison MS, Guillemin GJ, DuHadaway JB, Prendergast GC, Metz R, Geffard M, Boon L, Pirro M, Iorio A, Veyret B, Romani L, Grohmann U, Fallarino F, Puccetti P. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 2014;511(7508):184-90. https://doi.org/10.1038/nature13323.
Bigelman E, Pasmanik-Chor M, Dassa B, Itkin M, Malitsky S, Dorot O, Pichinuk E, Kleinberg Y, Keren G, Entin-Meer M. Kynurenic acid, a key L-tryptophan-derived metabolite, protects the heart from an ischemic damage. PLoS One 2023;18(8):e0275550. https://doi.org/10.1371/journal.pone.0275550.
Bin P, Tang ZY, Liu SJ, Chen S, Xia YY, Liu JQ, Wu HC, Zhu GQ. Intestinal microbiota mediates Enterotoxigenic Escherichia coli-induced diarrhea in piglets. BMC Vet Res 2018;14(1):385. https://doi.org/10.1186/s12917-018-1704-9.
Bulc M, Palus K, Całka J, Kosacka J, Nowicki M. Streptozotocin-induced diabetes causes changes in serotonin-positive neurons in the small intestine in pig model. Int J Mol Sci 2022;23(9):4564. https://doi.org/10.3390/ijms23094564.
Campbell JM, Crenshaw JD, Polo J. The biological stress of early weaned piglets. J Anim Sci Biotechnol 2013;4(1):19. https://doi.org/10.1186/2049-1891-4-19.
Cervantes-Barragan L, Chai JN, Tianero MD, Luccia BD, Ahern PP, Merriman J, Cortez VS, Caparon MG, Donia MS, Gilfillan S, Cella M, Gordon JI, Hsieh CS, Colonna M. Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells. Science 2017;357(6353):806-10. https://doi.org/10.1126/science.aah5825.
Chen CQ, Fichna J, Bashashati M, Li YY, Storr M. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol 2011;17(34):3888-98. https://doi.org/10.3748/wjg.v17.i34.3888.
Chen LM, Bao CH, Wu Y, Liang SH, Wang D, Wu LY, Huang Y, Liu HR, Wu HG. Tryptophan-kynurenine metabolism: a link between the gut and brain for depression in inflammatory bowel disease. J Neuroinflammation 2021;18(1):135. https://doi.org/10.1186/s12974-021-02175-2.
Chen LM, Collij V, Jaeger M, van den Munckhof ICL, Vila AV, Kurilshikov A, Gacesa R, Sinha T, Oosting M, Joosten LAB, Rutten JHW, Riksen NP, Xavier RJ, Kuipers F, Wijmenga C, Zhernakova A, Netea MG, Weersma RK, Fu JY. Gut microbial coabundance networks show specificity in inflammatory bowel disease and obesity. Nat Commun 2020;11(1):4018. https://doi.org/10.1038/s41467-020-17840-y.
Chojnacki C, Popławski T, Konrad P, Fila M, Chojnacki J, Błasiak J. Serotonin pathway of tryptophan metabolism in small intestinal bacterial overgrowth-A pilot study with patients diagnosed with lactulose hydrogen breath test and treated with rifaximin. J Clin Med 2021;10(10):2065. https://doi.org/10.3390/jcm10102065.
Clarke G, McKernan DP, Gaszner G, Quigley EM, Cryan JF, Dinan TG. A distinct profile of tryptophan metabolism along the kynurenine pathway downstream of Toll-like receptor activation in irritable bowel syndrome. Front Pharmacol 2012;3:90. https://doi.org/10.3389/fphar.2012.00090.
Craig CF, Filippone RT, Stavely R, Bornstein JC, Apostolopoulos V, Nurgali K. Neuroinflammation as an etiological trigger for depression comorbid with inflammatory bowel disease. J Neuroinflammation 2022;19(1):4. https://doi.org/10.1186/s12974-021-02354-1.
Daubert EA, Condron BG. Serotonin: a regulator of neuronal morphology and circuitry. Trends Neurosci 2010;33(9):424-34. https://doi.org/10.1016/j.tins.2010.05.005.
David LA, Weil A, Ryan ET, Calderwood SB, Harris JB, Chowdhury F, Begum Y, Qadri F, LaRocque RC, Turnbaugh PJ. Gut microbial succession follows acute secretory diarrhea in humans. mBio 2015;6(3):e00381-15. https://doi.org/10.1128/mBio.00381-15.
Deng YY, Zhang Z, Yang H, Wang J, Feng LJ, Su Y, Xu DJ. Mycophenolic acid induces the intestinal epithelial barrier damage through mitochondrial ROS. Oxid Med Cell Longev 2022;2022:4195699. https://doi.org/10.1155/2022/4195699.
Desbonnet L, Garrett L, Clarke G, Bienenstock J, Dinan TG. The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat. J Psychiatr Res 2008;43(2):164-74. https://doi.org/10.1016/j.jpsychires.2008.03.009.
Faba L, de Groot N, Ramis G, Cabrera-Gomez CG, Doelman J. Serotonin receptors and their association with the immune system in the gastrointestinal tract of weaning piglets. Porcine Health Manag 2022;8(1):8. https://doi.org/10.1186/s40813-022-00250-5.
Fan L, Xia YY, Wang YX, Han DD, Liu YL, Li JH, Fu J, Wang LL, Gan ZD, Liu BN, Fu J, Zhu CR, Wu ZH, Zhao JB, Han H, Wu H, He YW, Tang YL, Zhang QZ, Wang YB, Zhang F, Zong X, Yin J, Zhou XH, Yang XJ, Wang JJ, Yin YL, Ren WK. Gut microbiota bridges dietary nutrients and host immunity. Sci China Life Sci 2023;66(11):2466-514. https://doi.org/10.1007/s11427-023-2346-1.
Fassarella M, Blaak E, Penders J, Nauta A, Smidt H, Zoetendal E. Gut microbiome stability and resilience: elucidating the response to perturbations in order to modulate gut health. Gut 2020;66(11):2466-514. https://doi.org/10.1136/gutjnl-2020-321747.
Fila M, Chojnacki J, Pawlowska E, Szczepanska J, Chojnacki C, Blasiak J. Kynurenine pathway of tryptophan metabolism in migraine and functional gastrointestinal disorders. Int J Mol Sci 2021;22(18):10134. https://doi.org/10.3390/ijms221810134.
Flannigan KL, Nieves KM, Szczepanski HE, Serra A, Lee JW, Alston LA, Ramay H, Mani S, Hirota SA. The pregnane X receptor and indole-3-propionic acid shape the intestinal mesenchyme to restrain inflammation and fibrosis. Cell Mol Gastroenterol Hepatol 2023;15(3):765-95. https://doi.org/10.1016/j.jcmgh.2022.10.014.
Fu QY, Tan Z, Shi LG, Xun WJ. Resveratrol attenuates diquat-induced oxidative stress by regulating gut microbiota and metabolome characteristics in piglets. Front Microbiol 2021;12:695155. https://doi.org/10.3389/fmicb.2021.695155.
Gao J, Xu K, Liu HN, Liu G, Bai MM, Peng C, Li TJ, Yin YL. Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism. Front Cell Infect Microbiol 2018;8:13. https://doi.org/10.3389/fcimb.2018.00013.
Gao J, Yin J, Xu K, Li T, Yin YL. What is the impact of diet on nutritional diarrhea associated with gut microbiota in weaning piglets: a system review. Biomed Res Int 2019;2019:6916189. https://doi.org/10.1155/2019/6916189.
Gershon MD. Serotonin is a sword and a shield of the bowel: serotonin plays offense and defense. Trans Am Clin Climatol Assoc 2012;123:268-80.
Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes 2013;20(1):14-21. https://doi.org/10.1097/MED.0b013e32835bc703.
Ghosh S, Whitley CS, Haribabu B, Jala VR. Regulation of intestinal barrier function by microbial metabolites. Cell Mol Gastroenterol Hepatol 2021;11(5):1463-82. https://doi.org/10.1016/j.jcmgh.2021.02.007.
Gophna U, Konikoff T, Nielsen HB. Oscillospira and related bacteria-From metagenomic species to metabolic features. Environ Microbiol 2017;19(3):835-41. https://doi.org/10.1111/1462-2920.13658.
Gresse R, Chaucheyras-Durand F, Fleury MA, Van de Wiele T, Forano E, Blanquet-Diot S. Gut microbiota dysbiosis in postweaning piglets: understanding the keys to health. Trends Microbiol 2017;25(10):851-73. https://doi.org/10.1016/j.tim.2017.05.004.
Grifka-Walk HM, Jenkins BR, Kominsky DJ. Amino acid trp: the far out impacts of host and commensal tryptophan metabolism. Front Immunol 2021;12:653208. https://doi.org/10.3389/fimmu.2021.653208.
Gryaznova MV, Dvoretskaya YD, Syromyatnikov MY, Shabunin SV, Parshin PA, Mikhaylov EV, Strelnikov NA, Popov VN. Changes in the microbiome profile in different parts of the intestine in piglets with diarrhea. Animals 2022;12(3):320. https://doi.org/10.3390/ani12030320.
Han Q, Liu RZ, Wang HW, Zhang RX, Liu HG, Li JH, Bao J. Gut microbiota-derived 5-hydroxyindoleacetic acid alleviates diarrhea in piglets via the aryl hydrocarbon receptor pathway. J Agric Food Chem 2023;71(41):15132-44. https://doi.org/10.1021/acs.jafc.3c04658.
Haq S, Grondin JA, Khan WI. Tryptophan-derived serotonin-kynurenine balance in immune activation and intestinal inflammation. FASEB J 2021;35(10):e21888. https://doi.org/10.1096/fj.202100702R.
Hermann-Bank ML, Skovgaard K, Stockmarr A, Strube ML, Larsen N, Kongsted H, Ingerslev HC, Molbak L, Boye M. Characterization of the bacterial gut microbiota of piglets suffering from new neonatal porcine diarrhoea. BMC Vet Res 2015;11:139. https://doi.org/10.1186/s12917-015-0419-4.
Hu ZG, Feng LY, Jiang Q, Wang WL, Tan BE, Tang XG, Yin YL. Intestinal tryptophan metabolism in disease prevention and swine production. Anim Nutr 2023;15:364-74. https://doi.org/10.1016/j.aninu.2023.08.002.
Huang AN, Cai RJ, Wang Q, Shi L, Li CL, Yan H. Dynamic change of gut microbiota during porcine epidemic diarrhea virus infection in suckling piglets. Front Microbiol 2019;10:322. https://doi.org/10.3389/fmicb.2019.00322.
Hubbard TD, Murray IA, Perdew GH. Indole and tryptophan metabolism: endogenous and dietary routes to Ah receptor activation. Drug Metab Dispos 2015;43(10):1522-35. https://doi.org/10.1124/dmd.115.064246.
Hukkanen J. Induction of cytochrome P450 enzymes: a view on human in vivo findings. Expert Rev Clin Pharmacol 2012;5(5):569-85. https://doi.org/10.1586/ECP.12.39.
Jayaraman S, Thangavel G, Kurian H, Mani R, Mukkalil R, Chirakkal H. Bacillus subtilis PB6 improves intestinal health of broiler chickens challenged with Clostridium perfringens-induced necrotic enteritis. Poult Sci 2013;92(2):370-4. https://doi.org/10.3382/ps.2012-02528.
Jonach B, Boye M, Stockmarr A, Jensen TK. Fluorescence in situ hybridization investigation of potentially pathogenic bacteria involved in neonatal porcine diarrhea. BMC Vet Res 2014;10(1):68. https://doi.org/10.1186/1746-6148-10-68.
Jones LA, Sun EW, Martin AM, Keating DJ. The ever-changing roles of serotonin. Int J Biochem Cell Biol 2020;125:105776. https://doi.org/10.1016/j.biocel.2020.105776.
Kaszaki J, Palasthy Z, Erczes D, Racz A, Torday C, Varga G, Vecsei L, Boros M. Kynurenic acid inhibits intestinal hypermotility and xanthine oxidase activity during experimental colon obstruction in dogs. Neurogastroenterol Motil 2008;20(1):53-62. https://doi.org/10.1111/j.1365-2982.2007.00989.x.
Kim CJ, Kovacs-Nolan JA, Yang CB, Archbold T, Fan MZ, Mine Y. l-Tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis. J Nutr Biochem 2010;21(6):468-75. https://doi.org/10.1016/j.jnutbio.2009.01.019.
Kim N, Gu MJ, Kye YC, Ju YJ, Hong R, Ju DB, Pyung YJ, Han SH, Park BC, Yun CH. Bacteriophage EK99P-1 alleviates enterotoxigenic Escherichia coli K99-induced barrier dysfunction and inflammation. Sci Rep 2022;12(1):941. https://doi.org/10.1038/s41598-022-04861-4.
Koopmans SJ, Guzik AC, van der Meulen J, Dekker R, Kogut J, Kerr BJ, Southern LL. Effects of supplemental L-tryptophan on serotonin, cortisol, intestinal integrity, and behavior in weanling piglets. J Anim Sci 2006;84(4):963-71. https://doi.org/10.2527/2006.844963x.
Lamas B, Natividad JM, Sokol H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol 2018;11(4):1024-38. https://doi.org/10.1038/s41385-018-0019-2.
Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, Bridonneau C, Jegou S, Hoffmann TW, Natividad JM, Brot L, Taleb S, Couturier-Maillard A, Nion-Larmurier I, Merabtene F, Seksik P, Bourrier A, Cosnes J, Ryffel B, Beaugerie L, Launay JM, Langella P, Xavier RJ, Sokol H. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 2016;22(6):598-605. https://doi.org/10.1038/nm.4102.
Larsson J, Lindberg R, Aspán A, Grandon R, Westergren E, Jacobson M. Neonatal piglet diarrhoea associated with enteroadherent enterococcus hirae. J Comp Pathol 2014;151(2):137-47. https://doi.org/10.1016/j.jcpa.2014.04.003.
Lavelle A, Sokol H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020;17(4):223-37. https://doi.org/10.1038/s41575-019-0258-z.
Levy M, Blacher E, Elinav E. Microbiome, metabolites and host immunity. Curr Opin Microbiol 2017;35:8-15. https://doi.org/10.1016/j.mib.2016.10.003.
Li Y, Hu N, Yang D, Oxenkrug G, Yang Q. Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism. FEBS J 2017;284(6):948-66. https://doi.org/10.1111/febs.14026.
Li HX, Ning SY, Ghandi M, Kryukov GV, Gopal S, Deik A, Souza A, Pierce K, Keskula P, Hernandez D, Ann J, Shkoza D, Apfel V, Zou YL, Vazquez F, Barretina J, Pagliarini RA, Galli GG, Root DE, Hahn WC, Tsherniak A, Giannakis M, Schreiber SL, Clish CB, Garraway LA, Sellers WR. The landscape of cancer cell line metabolism. Nat Med 2019;5(5):850-60. https://doi.org/10.1038/s41591-019-0404-8.
Li KY, Hao ZH, Du JY, Gao YM, Yang SY, Zhou YL. Bacteroides thetaiotaomicron relieves colon inflammation by activating aryl hydrocarbon receptor and modulating CD4+T cell homeostasis. Int Immunopharmacol 2021;90:107183. https://doi.org/10.1016/j.intimp.2020.107183.
Li PP, Zheng JM, Bai Y, Wang DX, Cui ZJ, Li YQ, Zhang J, Wang YZ. Characterization of kynurenine pathway in patients with diarrhea-predominant irritable bowel syndrome. Eur J Histochem 2020;64(s2):3132. https://doi.org/10.4081/ejh.2020.3132.
Li Y, Guo Y, Wen ZS, Jiang XM, Ma X, Han XY. Weaning stress perturbs gut microbiome and its metabolic profile in piglets. Sci Rep 2018;8(1):18068. https://doi.org/10.1038/s41598-018-33649-8.
Liang HW, Dai ZL, Kou J, Sun KJ, Chen JQ, Yang Y, Wu GY, Wu ZL. Dietary l-tryptophan supplementation enhances the intestinal mucosal barrier function in weaned piglets: implication of tryptophan-metabolizing microbiota. Int J Mol Sci 2019;20(1):20. https://doi.org/10.3390/ijms20010020.
Liang HW, Dai ZL, Liu N, Ji Y, Chen JQ, Zhang YC, Yang Y, Li J, Wu ZL, Wu GY. Dietary l-tryptophan modulates the structural and functional composition of the intestinal microbiome in weaned piglets. Front Microbiol 2018;9:1736. https://doi.org/10.3389/fmicb.2018.01736.
Liu GM, Lu JJ, Sun WX, Jia G, Zhao H, Chen XL, Kim IH, Zhang RN, Wang J. Tryptophan supplementation enhances intestinal health by improving gut barrier function, alleviating inflammation, and modulating intestinal microbiome in lipopolysaccharide-challenged piglets. Front Microbiol 2022;13:919431. https://doi.org/10.3389/fmicb.2022.919431.
Liu JB, Zhang Y, Li Y, Yan HL, Zhang HF. L-tryptophan enhances intestinal integrity in diquat-challenged piglets associated with improvement of redox status and mitochondrial function. Animals 2019;9(5):266. https://doi.org/10.3390/ani9050266.
Liu N, Sun SQ, Wang PJ, Sun YN, Hu QJ, Wang XY. The mechanism of secretion and metabolism of gut-derived 5-hydroxytryptamine. Int J Mol Sci 2021;22(15):7931. https://doi.org/10.3390/ijms22157931.
Liu ZY, Ling YD, Peng Y, Han SB, Ren YT, Jing YJ, Fan WL, Su Y, Mu CL, Zhu WY. Regulation of serotonin production by specific microbes from piglet gut. J Anim Sci Biotechnol 2023;14(1):111. https://doi.org/10.1186/s40104-023-00903-7.
Luo YH, Ren W, Smidt H, André-Denis GW, Yu B, Schyns G, McCormack UM, Cowieson AJ, Yu J, He J, Yan H, Wu JL, Mackie RI, Chen DW. Dynamic distribution of gut microbiota in pigs at different growth stages: composition and contribution. Microbiol Spectr 2022;10(3):e0068821. https://doi.org/10.1128/spectrum.00688-21.
Machado MO, Oriolo G, Bortolato B, Kohler CA, Maes M, Solmi M, Grande I, Martin-Santos R, Vieta E, Carvalho AF. Biological mechanisms of depression following treatment with interferon for chronic hepatitis C: a critical systematic review. J Affect Disord 2017;209:235-45. https://doi.org/10.1016/j.jad.2016.11.039.
Marcial GE, Ford AL, Haller MJ, Gezan SA, Harrison NA, Cai D, Meyer JL, Perry DJ, Atkinson MA, Wasserfall CH, Garrett T, Gonzalez CF, Brusko TM, Dahl WJ, Lorca GL. Lactobacillus johnsonii N6.2 modulates the host immune responses: a double-blind, randomized trial in healthy adults. Front Immunol 2017;8:655. https://doi.org/10.3389/fimmu.2017.00655.
Mawe GM, Hoffman JM. Serotonin signalling in the gut-functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 2013;10(8):473-86. https://doi.org/10.1038/nrgastro.2013.105.
Mellor AL, Munn DH. Tryptophan catabolism and regulation of adaptive immunity. J Immunol 2003;170(12):5809-13. https://doi.org/10.4049/jimmunol.170.12.5809.
Meng QW, Luo Z, Cao CY, Sun SS, Ma QQ, Li ZY, Shi BM, Shan AS. Weaning alters intestinal gene expression involved in nutrient metabolism by shaping gut microbiota in pigs. Front Microbiol 2020;11:694. https://doi.org/10.3389/fmicb.2020.00694.
Michaudel C, Danne C, Agus A, Magniez A, Aucouturier A, Spatz M, Lefevre A, Kirchgesner J, Rolhion N, Wang YZ, Lavelle A, Galbert C, Da Costa G, Poirier M, Lapiere A, Planchais J, Nadvornik P, Illes P, Oeuvray C, Creusot L, Michel ML, Benech N, Bourrier A, Nion-Larmurier I, Landman C, Richard ML, Emond P, Seksik P, Beaugerie L, Arguello RR, Moulin D, Mani S, Dvorak Z, Bermudez-Humaran GL, Langella P, Sokol H. Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases. Gut 2023;72(7):1296-307. https://doi.org/10.1136/gutjnl-2022-327337.
Minhas PS, Liu L, Moon PK, Joshi AU, Dove C, Mhatre S, Contrepois K, Wang Q, Lee BA, Coronado M, Bernstein D, Snyder MP, Migaud M, Majeti R, Mochly-Rosen D, Rabinowitz JD, Andreasson KI. Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation. Nat Immunol 2019;20(1):50-63. https://doi.org/10.1038/s41590-018-0255-3.
Muller CL, Anacker AMJ, Veenstra-VanderWeele J. The serotonin system in autism spectrum disorder: from biomarker to animal models. Neuroscience 2016;321:24-41. https://doi.org/10.1016/j.neuroscience.2015.11.010.
Najjar SA, Hung LY, Margolis KG. Serotonergic control of gastrointestinal development, motility, and inflammation. Compr Physiol 2023;13(3):4851-68. https://doi.org/10.1002/cphy.c220024.
Nayak-Kapoor A, Hao ZL, Sadek R, Dobbins R, Marshall L, Vahanian NN, Jay Ramsey W, Kennedy E, Mautino MR, Link CJ, Lin RS, Royer-Joo S, Liang X, Salphati L, Morrissey KM, Mahrus S, McCall B, Pirzkall A, Munn DH, Janik JE, Khleif SN. Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J Immunother Cancer 2018;6(1):61. https://doi.org/10.1186/s40425-018-0351-9.
Nino-Castro A, Abdullah Z, Popov A, Thabet Y, Beyer M, Knolle P, Domann E, Chakraborty T, Schmidt SV, Schultze JL. The IDO1-induced kynurenines play a major role in the antimicrobial effect of human myeloid cells against Listeria monocytogenes. Innate Immun 2014;20(4):401-11. https://doi.org/10.1177/1753425913496442.
Nosho K, Sukawa Y, Adachi Y, Ito M, Mitsuhashi K, Kurihara H, Kanno S, Yamamoto I, Ishigami K, Igarashi H, Maruyama R, Imai K, Yamamoto H, Shinomura Y. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer. World J Gastroenterol 2016;22(2):557-66. https://doi.org/10.3748/wjg.v22.i2.557.
Pernomian L, Duarte-Silva M, de Barros Cardoso CR. The aryl hydrocarbon receptor (AHR) as a potential target for the control of intestinal inflammation: insights from an immune and bacteria sensor receptor. Clin Rev Allergy Immunol 2020;59(3):382-90. https://doi.org/10.1007/s12016-020-08789-3.
Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov 2019;18(5):379-401.
Rao ZB, Li JL, Sh i BS, Zeng Y, Liu YB, Sun ZH, Wu LT, Sun WZ, Tang ZR. Dietary tryptophan levels impact growth performance and intestinal microbial ecology in weaned piglets via tryptophan metabolites and intestinal antimicrobial peptides. Animals 2021;11(3):817. https://doi.org/10.3390/ani11030817.
Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nat Commun 2018;9(1):3294. https://doi.org/10.1038/s41467-018-05470-4.
Romani L, Zelante T, De Luca A, Iannitti RG, Moretti S, Bartoli A, Aversa F, Puccetti P. Microbiota control of a tryptophan-AhR pathway in disease tolerance to fungi. Eur J Immunol 2014;44(11):3192-200. https://doi.org/10.1002/eji.201344406.
Serger E, Luengo-Gutierrez L, Chadwick JS, Kong G, Zhou L, Crawford G, Danzi MC, Myridakis A, Brandis A, Bello AT, Muller F, Sanchez-Vassopoulos A, De Virgiliis F, Liddell P, Dumas ME, Strid J, Mani S, Dodd D, Giovanni SD. The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature 2022;607(7919):585-92. https://doi.org/10.1038/s41586-022-04884-x.
Shizuma T, Mori H, Fukuyama N. Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis. Turk J Gastroenterol 2013;24(1):30-5. https://doi.org/10.4318/tjg.2013.0558.
Song M, Zhang FL, Chen L, Yang Q, Su H, Yang XH, He HW, Ling MF, Zheng JS, Duan C, Lai XM, Pan MS, Zhu XT, Wang LN, Gao P, Shu G, Jiang QY, Wang S. Dietary chenodeoxycholic acid improves growth performance and intestinal health by altering serum metabolic profiles and gut bacteria in weaned piglets. Anim Nutr 2021;7(2):365-75. https://doi.org/10.1016/j.aninu.2020.07.011.
Takamatsu M, Hirata A, Ohtaki H, Hoshi M, Hatano Y, Tomita H, Kuno T, Saito K, Hara A. IDO1 plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfateinduced colitis in mice. J Immunol 2013;191(6):3057-64. https://doi.org/10.4049/jimmunol.1203306.
Tang XP, Xiong KN, Fang RJ, Li MJ. Weaning stress and intestinal health of piglets: a review. Front Immunol 2022;13:1042778. https://doi.org/10.3389/fimmu.2022.1042778.
Teng T, Gao F, He W, Fu HY, Guo J, Bai GD, Shi BM. An early fecal microbiota transfer improves the intestinal conditions on microflora and immunoglobulin and antimicrobial peptides in piglets. J Agric Food Chem 2020;68(17):4830-43. https://doi.org/10.1021/acs.jafc.0c00545.
Thiagarajah JR, Donowitz M, Verkman AS. Secretory diarrhoea: mechanisms and emerging therapies. Nat Rev Gastroenterol Hepatol 2015;12(8):446-57. https://doi.org/10.1038/nrgastro.2015.111.
Tilocca B, Burbach K, Heyer CME, Hoelzle LE, Mosenthin R, Stefanski V, Camarinha-Silva A, Seifert J. Dietary changes in nutritional studies shape the structural and functional composition of the pigs’ fecal microbiome-from days to weeks. Microbiome 2017;5(1):144. https://doi.org/10.1186/s40168-017-0362-7.
Tossou MC, Liu HN, Bai MM, Chen S, Cai YH, Duraipandiyan V, Liu HB, Adebowale TO, Al-Dhabi NA, Long LN, Tarique H, Oso AO, Liu G, Yin YL. Effect of high dietary tryptophan on intestinal morphology and tight junction protein of weaned pig. Biomed Res Int 2016;2016:2912418. https://doi.org/10.1155/2016/2912418.
Vecsei L, Szalardy L, Fulop F, Toldi J. Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov 2013;12(1):64-82. https://doi.org/10.1038/nrd3793.
Vogt SL, Finlay BB. Gut microbiota-mediated protection against diarrheal infections. J Travel Med 2017;24(suppl_1):S39-43. https://doi.org/10.1093/jtm/taw086.
Wang H, Ji Y, Wu GY, Sun KJ, Sun YL, Li W, Wang B, He BB, Zhang Q, Dai ZL, Wu ZL. l-tryptophan activates mammalian target of rapamycin and enhances expression of tight junction proteins in intestinal porcine epithelial cells. J Nutr 2015;145(6):1156-62. https://doi.org/10.3945/jn.114.209817.
Wang L, Li W, Xin SZ, Wu S, Peng CL, Ding HY, Feng SB, Zhao C, Wu JJ, Wang XC. Soybean glycinin and beta-conglycinin damage the intestinal barrier by triggering oxidative stress and inflammatory response in weaned piglets. Eur J Nutr 2023;62(7):2841-54. https://doi.org/10.1007/s00394-023-03188-8.
Wang LL, Wu YW, Xu J, Huang QY, Zhao Y, Dong S, Wang XX, Cao XN, Wang CN, Wu AQ, Zhou D, Chen C, Yang HS, Li JZ, Konstantinos P, Tu Q, Zhang GH, Yin J. Colicins of escherichia coli lead to resistance against the diarrhea-causing pathogen enterotoxigenic E. coli in pigs. Microbiol Spectr 2022;10(5):e0139622. https://doi.org/10.1128/spectrum.01396-22.
Wang TX, Yao WL, Li J, Shao YF, He QY, Xia J, Huang F. Dietary garcinol supplementation improves diarrhea and intestinal barrier function associated with its modulation of gut microbiota in weaned piglets. J Anim Sci Biotechnol 2020;11(1):12. https://doi.org/10.1186/s40104-020-0426-6.
Wang XF, Tsai TC, Deng FL, Wei XY, Chai JM, Knapp J, Apple J, Maxwell CV, Lee JA, Li Y, Zhao JC. Longitudinal investigation of the swine gut microbiome from birth to market reveals stage and growth performance associated bacteria. Microbiome 2019a;7(1):109. https://doi.org/10.1186/s40168-019-0721-7.
Wang YP, Fu YH, He YY, Kulyar MFEA, Iqbal M, Li K, Liu JG. Longitudinal characterization of the gut bacterial and fungal communities in yaks. J Fungi 2021;7(7):559. https://doi.org/10.3390/jof7070559.
Wang YY, Yan X, Zhang WW, Liu YY, Han DP, Teng KD, Ma YF. Lactobacillus casei zhang prevents jejunal epithelial damage to early-weaned piglets induced by Escherichia coli K88 via regulation of intestinal mucosal integrity, tight junction proteins and immune factor expression. J Microbiol Biotechnol 2019b;29(6):863-76. https://doi.org/10.4014/jmb.1903.03054.
Watts SW, Morrison SF, Davis RP, Barman SM. Serotonin and blood pressure regulation. Pharmacol Rev 2012;64(2):359-88. https://doi.org/10.1124/pr.111.004697.
Wei GZ, Martin KA, Xing PY, Agrawal R, Whiley L, Wood TK, Hejndorf S, Ng YZ, Low JZY, Rossant J, Nechanitzky R, Holmes E, Nicholson JK, Tan EK, Matthews PM, Pettersson S. Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 2021;118(27):e2021091118. https://doi.org/10.1073/pnas.2021091118.
Whitfield-Cargile CM, Cohen ND, Chapkin RS, Weeks BR, Davidson LA, Goldsby JS, Hunt CL, Steinmeyer SH, Menon R, Suchodolski JS, Jayaraman A, Alaniz RC. The microbiota-derived metabolite indole decreases mucosal inflammation and injury in a murine model of NSAID enteropathy. Gut Microbes 2016;7(3):246-61. https://doi.org/10.1080/19490976.2016.1156827.
Wlodarska M, Luo CW, Kolde R, d'Hennezel E, Annand JW, Heim CE, Krastel P, Schmitt EK, Omar AS, Creasey EA, Garner AL, Mohammadi S, O'Connell DJ, Abubucker S, Arthur TD, Franzosa EA, Huttenhower C, Murphy LO, Haiser HJ, Vlamakis H, Porter JA, Xavier RJ. Indoleacrylic acid produced by commensal peptostreptococcus species suppresses inflammation. Cell Host Microbe 2017;22(1):25-37.e6. https://doi.org/10.1016/j.chom.2017.06.007.
Wolf AM, Wolf D, Rumpold H, Moschen AR, Kaser A, Obrist P, Fuchs D, Brandacher G, Winkler C, Geboes K, Rutgeerts P, Tilg H. Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease. Clin Immunol 2004;113(1):47-55. https://doi.org/10.1016/j.clim.2004.05.004.
Wu T, Zhang Q, Xu HW, Li P, Zhao D, Wang L, Yi D, Hou YQ. Protective effects of α-terpineol and Bacillus coagulans on intestinal function in weaned piglets infected with a recombinant Escherichia coli expressing heat-stable enterotoxin STa. Front Vet Sci 2023;10:1118957. https://doi.org/10.3389/fvets.2023.1118957.
Wyatt M, Greathouse KL. Targeting dietary and microbial tryptophan-indole metabolism as therapeutic approaches to colon cancer. Nutrients 2021;13(4):1189. https://doi.org/10.3390/nu13041189.
Xia B, Zhong RQ, Wu WD, Luo CZ, Meng QS, Gao QT, Zhao Y, Chen L, Zhang S, Zhao X, Zhang HF. Mucin O-glycan-microbiota axis orchestrates gut homeostasis in a diarrheal pig model. Microbiome 2022;10(1):139. https://doi.org/10.1186/s40168-022-01326-8.
Xia YY, Chen SY, Zeng SJ, Zhao YY, Zhu CR, Deng BC, Zhu GQ, Yin YL, Wang WC, Hardeland R, Ren WK. Melatonin in macrophage biology: current understanding and future perspectives. J Pineal Res 2019;66(2):e12547. https://doi.org/10.1111/jpi.12547.
Xie J, Tian SM, Liu J, Huang SJ, Yang M, Yang XB, Xu RC, Lin JZ, Han L, Zhang DK. Combination therapy with indigo and indirubin for ulcerative colitis via reinforcing intestinal barrier function. Oxid Med Cell Longev 2023;2023. https://doi.org/10.1155/2023/2894695.2894695-2894695.
Xie YH, Wang LX, Sun H, Wang YX, Yang ZB, Zhang GG, Yang WR. Immunomodulatory, antioxidant and intestinal morphology-regulating activities of alfalfa polysaccharides in mice. Int J Biol Macromol 2019;133:1107-14. https://doi.org/10.1016/j.ijbiomac.2019.04.144.
Xue C, Gu XY, Zheng QX, Shi QM, Yuan X, Chu QF, Jia JJ, Su YS, Bao ZY, Lu J, Li LJ. Effects of 3-HAA on HCC by regulating the heterogeneous macrophages-A scRNA-Seq analysis. Adv Sci (Weinh) 2023a;10(16):e2207074. https://doi.org/10.1002/advs.202207074.
Xue C, Li GL, Zheng QX, Gu XY, Shi QM, Su YS, Chu QF, Yuan X, Bao ZY, Lu J, Li LJ. Tryptophan metabolism in health and disease. Cell Metab 2023b;35(8):1304-26. https://doi.org/10.1016/j.cmet.2023.06.004.
Yang N, Li MH, Huang YT, Liang XA, Quan ZZ, Liu HY, Li JT, Yue XQ. Comparative efficacy of fish meal replacement with enzymatically treated soybean meal on growth performance, immunity, oxidative capacity and fecal microbiota in weaned pigs. Front Vet Sci 2022a;9:889432. https://doi.org/10.3389/fvets.2022.889432.
Yang QL, Huang XY, Zhao SG, Sun WY, Yan ZQ, Wang PF, Li SG, Huang WZ, Zhang SW, Liu LX, Gun SB. Structure and function of the fecal microbiota in diarrheic neonatal piglets. Front Microbiol 2017;8:502. https://doi.org/10.3389/fmicb.2017.00502.
Yang SS, Yang N, Huang X, Yi L, Liu G, Jansen CA, Savelkoul HFJ, Liu GL. Pigs’ intestinal barrier function is more refined with aging. Dev Comp Immunol 2022b;136:104512. https://doi.org/10.1016/j.dci.2022.104512.
Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015;161(2):264-76. https://doi.org/10.1016/j.cell.2015.02.047.
Yu ZD, Song G, Liu J, Wang JY, Zhang PY, Chen KS. Beneficial effects of extracellular polysaccharide from Rhizopus nigricans on the intestinal immunity of colorectal cancer mice. Int J Biol Macromol 2018;115:718-26. https://doi.org/10.1016/j.ijbiomac.2018.04.128.
Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F, Carvalho A, Puccetti P, Romani L. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 2013;39(2):372-85. https://doi.org/10.1016/j.immuni.2013.08.003.
Zhai LX, Huang CH, Ning ZW, Zhang YJ, Zhuang M, Yang W, Wang XL, Wang JQ, Zhang L, Xiao HT, Zhao L, Asthana P, Lam YY, Chow CFW, Huang JD, Yuan SF, Chan KM, Yuan CS, Lau JYN, Wong HLX, Bian ZX. Ruminococcus gnavus plays a pathogenic role in diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis. Cell Host Microbe 2023;31(1):33-44.e35. https://doi.org/10.1016/j.chom.2022.11.006.
Zhang RF, Huang GW, Ren YT, Wang HF, Ye YX, Guo JQ, Wang MT, Zhu WY, Yu KF. Effects of dietary indole-3-carboxaldehyde supplementation on growth performance, intestinal epithelial function, and intestinal microbial composition in weaned piglets. Front Nutr 2022;9:896815. https://doi.org/10.3389/fnut.2022.896815.
Zhao X, Fu HY, Qiu SN, Teng T, Bai GD, Ju DX, Sun YC, Shi BM. Effects of early protein restriction on the growth performance and gut development of pigs fed diets with or without antibiotic. Animal 2020;14(7):1392-401. https://doi.org/10.1017/S1751731119002921.
Zhao X, Jiang L, Fang XY, Guo ZQ, Wang XX, Shi BM, Meng QW. Host-microbiota interaction-mediated resistance to inflammatory bowel disease in pigs. Microbiome 2022;10(1):115. https://doi.org/10.1186/s40168-022-01303-1.
Zhou XH, Liu YH, Xiong X, Chen JQ, Tang WJ, He LQ, Zhang ZG, Yin YL, Li FN. Intestinal accumulation of microbiota-produced succinate caused by loss of microRNAs leads to diarrhea in weanling piglets. Gut Microbes 2022;14(1):2091369. https://doi.org/10.1080/19490976.2022.2091369.
Appendix
Less
Year 2024 volume 17 Issue 1
PDF
51
29
Cite this Article
BibTeX
Article Info
doi: 10.1016/j.aninu.2024.03.005
  • Receive Date：2023-10-12
  • Online Date：2026-01-28
Article Data
Affiliations
History
  • Received：2023-10-12
  • Revised：2024-02-13
  • Accepted：2024-03-20
Affiliations
    aCollege of Animal Science and Technology, Southwest University, Chongqing 400715, China
    bYunnan Vocational College of Agriculture, Kunming 650211, China

Corresponding:

*

Corresponding authors. E-mail addresses: (G. Bai)
(Y. Xia).
References
Share
https://castjournals.cast.org.cn/joweb/aninu/EN/10.1016/j.aninu.2024.03.005
Share to
QR

Scan QR to access full text

Cite this article
BibTeX
Citations
表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
  • BibTeX
  • EndNote
  • RefWorks
  • TxT
Links
Articles
Latest Articles
Most Read
Collections
Updates
Events
News
Multimedia
About
About Us
Contact
No. 86 Xueyuan South Road, Haidian District, Beijing
100081
010-62199257
qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House