Dietary compounds in modulation of gut microbiota-derived metabolites

Gut microbiota, a group of microorganisms that live in the gastrointestinal tract, plays important roles in health and disease. One mechanism that gut microbiota in modulation of the functions of hosts is achieved through synthesizing and releasing a series of metabolites such as short-chain fatty acids. In recent years, increasing evidence has indicated that dietary compounds can interact with gut microbiota. On one hand, dietary compounds can modulate the composition and function of gut microbiota; on the other hand, gut microbiota can metabolize the dietary compounds. Although there are several reviews on gut microbiota and diets, there is no focused review on the effects of dietary compounds on gut microbiota-derived metabolites. In this review, we first briefly discussed the types of gut microbiota metabolites, their origins, and the reasons that dietary compounds can interact with gut microbiota. Then, focusing on gut microbiota-derived compounds, we discussed the effects of dietary compounds on gut microbiota-derived compounds and the following effects on health. Furthermore, we give our perspectives on the research direction of the related research fields. Understanding the roles of dietary compounds on gut microbiota-derived metabolites will expand our knowledge of how diets affect the host health and disease, thus eventually enable the personalized diets and nutrients.


Introduction
Gut microbiota is a group of microorganisms including bacteria, archaea, eukarya, etc., that dwell in the human gastrointestinal tract (1). The number of microorganisms in human gut microbiota is estimated to be as many as 10 14 bacterial cells, which is 10 times larger than the number of human cells (2). In recent decades, numerous studies have demonstrated that gut microbiota plays important role in maintenance of health by acting as a barrier to defend against pathogens, maintaining the integrity of the epithelial barrier, modulating the metabolism and immune functions of hosts, communicating with central nervous system (3). On the contrary, gut microbiota dysbiosis can lead to a large number of diseases, such as non-alcoholic fatty liver disease, obesity, inflammatory bowel disease, cancer, allergy, and depression (2,4). Because the importance of gut microbiota in health and disease, gut microbiota has become an important research frontier in health-related research fields. Normally, the gut microbiota is confined within the gastrointestinal lumen by gut barrier and translocation of gut bacteria can lead to local and systematic inflammation (5). To overcome the spatial limitation, gut microbiota develops a tactic of releasing a large number of gut microbiota metabolites from different chemical classes to exert extensive effects on host organs that are near or far away from gastrointestinal lumen (6). Gut microbiota contains 5 × 10 6 unique microbial genes collectively, which outnumber the genes of humans (7). With these genes, gut microbiota is capable of synthesizing a large group of metabolites. These gut microbiota-derived metabolites include, but not limited to, short chain fatty acids (SCFAs), bile acids, vitamins, tryptophan and indole derivatives (8). These metabolites can exert the functions of regulating of gut microbiota composition, host metabolism, nutrition absorption, gut motility, local and systemic immune response, circadian rhythm, etc., to maintain the health or promote the development of diseases (6).
Diet is one of the most important regulators of gut microbiota. Many dietary compounds exhibit low bioavailability or cannot not be absorbed directly, such as polysaccharides and polyphenol (9). When orally taken, these compounds can pass the small intestine and enter the colon, a comfortable place that most gut bacteria live. In the colon, dietary compounds can interact with gut microbiota. On one side, gut microbiota can transform the food compounds and produce new compounds derived from dietary compounds. For example, rutin can be transformed to quercetin and further into protocatechuic acid, 3,4-dihydroxyphenyl-acetic acid, etc., by gut microbiota (10). On the other side, food compounds can induce the functional and compositional change of gut microbiota. For example, coffee and its major components caffeine and chlorogenic acid can alter gut microbial community and SCFAs levels (11). The gut microbiota transformation of dietary compounds and dietary compounds modulation of gut microbiota composition have been extensively reviewed (12-14), however, there is no focused review on the effects of dietary compounds on gut microbiota metabolites. In this review, we focus on the effects of dietary compounds on gut microbiota-derived compounds and the following effects on health.

Gut microbiota metabolites in a nutshell
Gut microbiota not only contain a large number of bacteria that belong to more than 1,000 species, it also contain millions of microbial genes that is 150-fold larger than the number of human gene complements (7). With the aid of these genes, gut microbiota is capable of producing a large number of enzymes. These enzymes can ferment diverse food compounds that are not digested by human enzymes such as fiber or compounds that are released by human body such as primary bile acids. Consequently, gut microbiota can synthesis and release a large number of metabolites with great diverse of chemical structures. These gut microbiota-derived metabolites can be broadly grouped into 3 categories: (I) metabolites that are produced directly from dietary compounds by gut microbiota, such as SCFAs, tryptophan, and indole derivatives of tryptophan; (II) metabolites that are originally synthesized by hosts and chemically transformed by gut microbiota, such as secondary bile acids; (III) metabolites that are produced by gut microbiota de novo (15). A lot of metabolites show similar structure and bioactivities, and they are therefore grouped together. Currently, the extensively studied gut microbiota-derived metabolites include SCFAs, bile acids, branched chain amino acids (BCAAs), tryptophan and indole derivatives, etc. In Table 1, we have listed the typical groups of gut microbiota metabolites and their functions.
After the production and releasing, gut microbiota metabolites can be absorbed and transferred into circulating system. It is estimated that gut microbiota metabolites can account for 10% of the total metabolites in blood of mammalian (37). When absorbed, gut microbiota metabolites can be transported to target organs and tissues that are remote from gastrointestinal tract, and therefore exert a wide range of activities on hosts. These activities include, but not limited to, regulating the composition and function of gut microbiota, acting as nutrition, influencing nutrition absorption, modulating host metabolism, influencing intestinal barrier and gut motility, impacting the local and systemic immune response, modulating circadian rhythm and nervous system (6). With these bioactivities, gut microbiota metabolites play important roles in the development and progress of a variety of diseases such as cancer, non-alcoholic fatty liver disease, hypertension, Parkinson's disease, and ulcerative diseases (30, [38][39][40].

Dietary compounds can interact with gut microbiota and modulate gut microbiota metabolites
In gastrointestinal tract, most of the dietary compounds can be digested and absorbed by human body. Even so, significant amounts of digestible dietary compounds can reach the colon. For instance, the majority of proteins can be digested and absorbed in the small intestine, a relatively . /fnut. .   (42,44,45). Whatever the indirection, the final reactions of indirect reactions can be only attributed to the types of direct reactions we discussed. The bioavailability of many dietary compounds and herbal compounds is very low, yet they possess strong bioactivities. This discrepancy has perplexed researchers for a long time (46). Studies in recent decade have revealed that the interaction between gut microbiota and these compounds is one of the keys to decipher this conundrum. Gut microbiota can transform the chemical structure of dietary compounds and thus improve the bioavailability or potency. For example, curcumin, a polyphenolic compound with high hydrophobicity and poor solubility, exhibits wide spectrum of pharmacologic effects on diseases such as inflammatory diseases, cancers, cardiovascular diseases, and metabolic diseases (47). Animal studies and clinical trials indicated that the bioavailability of curcumin is very poor (about 1%) (48). Recent studies showed that gut microbiota can transform the curcumin into ferulic acid, dihydrocurcumin, tetrahydrocurcumin, curcumin-L-cysteine, bisdemethylcurcumin, etc., via gut bacteria such as Blautia sp. MRG-PMF1, Bacillus megaterium DCMB002 (49,50). Some of these products, such as dimethoxycurcumin, have superior bioactivities compared with their parent compound curcumin (51). Thus, the biotransformation of curcumin by gut microbiota can explain the contradiction between low bioavailability and strong bioactivities of curcumin. In addition to biotransformation, the gut microbiota metabolites may also explain this contradiction as well. Hydroxysafflor yellow A (HSYA) is a water-soluble compound isolated from Carthamus tinctorius L. with only 1.2% oral bioavailability (52). Yet it shows a group of bioactivities such as anti-tumor, neuroprotective, hepatoprotective, and pulmonary protective effects (53). In a high-fat diet-induced obese mice, oral administration of HSYA increased the abundances of Akkermansia and Romboutsia, as well as SCFAs-producing bacteria Butyricimonas and Alloprevotella (54). In addition, HSYA significantly increased acetic acid, propionic acid, and butyric acid, a group of SCFAs that is directly associated with obesity and intestinal integrity when their levels are decreased (54). The study suggested that increase of SCFAs may contribute to the pharmacological effects of HSYA. Taken together, transformation of dietary compounds by gut microbiota and modulation of gut microbiota metabolites by dietary compounds can explain the contradiction between low bioavailability and strong bioactivities of some dietary compounds.

Gut microbiota metabolites modulated by dietary compounds
In general, dietary compounds in modulation of gut microbiota metabolites can be achieved by the following ways: (1) dietary compounds directly be metabolized into gut microbiota metabolites by gut microbiota; (2) dietary compounds modulate the gut microbiota composition and thus influence the metabolites-producing activity; (3) dietary compounds directly inhibiting enzymes responsible for production of gut microbiota metabolites; (4) regulating the expression or activity of hepatic enzymes responsible for host metabolism of gut microbiota metabolites; (5) a combination of these effects. The typical metabolites modulated by dietary compounds are SCFAs, bile acids, trimethylamine, branched-chain amino acids, tryptophan and indole metabolites ( Figure 1).

SCFAs
SCFAs are a group of small organic monocarboxylic acids with one to six carbon atoms (55), and they are the most widely studied gut microbiota metabolites in recent years. SCFAs are comprised mostly of acetate (C2), propionate (C3), and butyrate (C4) with a molar rate of 60:20:20 in gastrointestinal tract (95%) (56, 57). After the production, SCFAs can be readily absorbed by colonocytes via hydrogen-coupled monocarboxylate transporters and sodiumcoupled monocarboxylate transporters, with only about 5-10 % of the SCFAs can be detected in feces (58,59). The concentration gradient of SCFAs falls from the gut lumen to the periphery tissues and organs because of the consumption of butyrate at the epithelium, propionate at the liver and acetate in the periphery (60). After absorption, part of SCFAs will be directly utilized as energy resource for gluconeogenesis and lipid synthesis, while the remaining SCFAs play important roles in regulating various host biological responses such as inflammation and oxidative stress. SCFAs can activate several G protein-coupled receptors (GPCRs) directly, such as GPR43 (free fatty acid receptor 2, FFAR2) and GPR41 (FFAR3), GPR109a/HCAR2 (hydrocarboxylic acid receptor) and GPR164, and thus regulate energy metabolism, inflammation, oxidative stress, and other reactions (16,61). SCFAs can also inhibit nuclear class I histone deacetylases (HDACs) including HDAC1 and HDAC3, and thus end up with regulation of inflammatory signaling pathways (16,62). Under physiological condition, SCFAs can regulate gut microbiota composition, gut barrier, gut hormone, appetite, energy homeostasis, and immune function, and circadian clocks (18). On the contrary, disturbance of SCFAs is associated with a group of diseases such as diabetes, obesity, non-alcoholic fatty liver disease, hypertension, ulcerative colitis, Parkinson's disease, and colorectal cancer (18, 63).
Dietary compounds can directly modulate the production of SCFAs by serving as the resource for SCFAs synthesis. Non-digestible dietary carbohydrates such as fibers that escape the digestion and absorption of small intestine can be partially or completely fermented by gut microbiota and produce SCFAs. During fermentation, acetate can be produced by acetyl-CoA pathway or via the Wood-Ljungdahl pathway under the action of bacteria such as Bifidobacterium spp., Lactobacillus spp., and Akkermansia muciniphila (64). Propionate can be produced by succinate pathway, propanediol pathway, or acrylate pathway under the action of bacteria such as Megasphaera elsdenii, Veillonella spp. and Roseburia inulinivorans (65). Butyrate can be produced by butyryl-CoA:acetate CoA-transferase routes or phosphotransbutyrylase/butyrate kinase routes under the action of bacteria such as Eubacterium rectale, and Faecalibacterium prausnitzii (64,65). In addition to carbohydrates, proteins or peptides that contain branchedchain amino acids and escape the digestion and absorption of small intestine can be fermented to SCFAs as well. However, the SCFAs produced from proteins and peptides are typically branched-chain fatty acids, such as 2-methylbutyrate, isobutyrate, and iso-valerate (66). Polyphenols can affect the SCFAs production as well. For example, the sugar moiety of quercetin-3-glucoside can be fermented to formate and acetate by Enterococcus casseliflavus, and the resulting quercetin can be further degraded into 3,4-dihydroxyphenylacetic acid, phloroglucinol, butyrate and acetate by Eubacterium ramulus (67).
The type of food and the intake amount can affect the types and amounts of SCFAs significantly. Dietary fiber, according to the definition by CODEX Alimentarius Commission, are carbohydrate polymers with ten or more monomeric units that are not hydrolyzed by the endogenous enzymes in the small intestine of humans (68). In animal models, the addition of fiber can lead to increase of cecal SCFAs in comparison with control diets. However, no significant linear correlation between fiber intake amount and SCFA concentrations can be observed (69). The study of SCFA concentrations in human is mainly carried by measuring the fecal SCFAs because of the convenience of the sampling method. However, concentrations of fecal SCFAs reflect little information on actual intestinal SCFA concentrations since SCFAs are readily absorbed by host after production. Therefore, in vitro fermentation is widely used to study the relationship between diet and SCFAs, and it was found out that different fiber showed significant difference in production of SCFAs (56). Specifically, the physical form and chemical properties of fibers including monosaccharide compositions, linkage of monosaccharide, molecular size and arrangements of the sugars are important factors influencing the production of SCFAs (70). For example, in vitro fermentation of polysaccharide from the seeds of Plantago asiatica L.  . Polyphenols can modulate the composition of gut microbiota to a ect SCFAs production or be directed degraded into SCFAs. Polyphenols can also a ect α-dehydroxylase activity to influence BA pool. Carbohydrates can be directly fermented into SCFAs. Proteins can be degraded into peptides and amino acids, which can further be transformed into TMA, tryptophan metabolites, and others. Please refer to main text for detailed metabolites and targets. AhR, aryl hydrocarbon receptor; BAs, bile acids; BCAAs, branched-chain amino acids; CAR, constitutive androstane receptor; FXR, farnesoid X receptor; GPR , G protein-coupled receptor ; GPR , G protein-coupled receptor ; HDAC , histone deacetylase ; HDAC , histone deacetylase ; NLPR , inflammasome NOD-like receptor protein ; PXR, pregnane X receptor; RORγt, retinoid-related orphan receptor gamma-t; SCFAs, short-chain fatty acids; TMA, trimethylamine; TGR , Takeda G-protein receptor ; VDR, vitamin D receptor.
showed that acetic and butyric acids are produced mainly due to the fermentation of aldehydes and xylose, whereas propionic acid is mainly generated by fermentation of arabinose and xylose (71). Flammulina velutipes polysaccharide with the monosaccharide composition at the ratio of glucose: galactose: mannose = 60.66:19.96:19.38 can increase the levels of isobutyric and butyric acid (72). On the contrary, the Flammulina velutipes polysaccharide with the monosaccharide composition at the ratio of mannose: glucose: xylose: arabinose: fucose = 6.6:27.8:18:1.5:5.2 increased the levels of acetic, propanoic and butyric acids (73). Because SCFAs play important roles in health and the type of food can affect the production of SCFAs, modulation of SCFAs by diet has been suggested to be a good approach to maintain health and treat diseases. In Table 2, we have listed the common dietary polysaccharides on SCFAs.
In recent years, a large number of animal and clinical studies have carried to investigate the supplement of dietary compounds on diseases, especially fiber. In mice, supplement of dietary fermentable fiber changed the composition of gut and lung microbiota, especially the ratio of Firmicutes to Bacteroidetes. In addition, mice received a high-fiber diet showed increased circulating SCFAs and were protected from allergic lung inflammation (105). Compared with the animal studies, the clinical studies on supplement of dietary compounds have received more attentions. In a randomized clinical study, supplement of specifically designed isoenergetic diets showed that a high-fiber diet can change the composition of the gut microbiota and improve glucose homeostasis in patients with type 2 diabetes mellitus (T2DM). In addition, the high-fiber diet can selectively elevate bacteria producing SCFAs and the levels of bacteria producing SCFAs correlated positively with hemoglobin A1c levels in participants with T2DM (106). The results suggested that targeted promotion of bacteria producing SCFAs can be effective to treat T2DM in clinic. Considering that carbohydrates such as fibers can .

Bile acids
Bile acids (BAs) are a group of acidic, amphipathic, and water-soluble metabolites with a steroid structure that are originally produced from cholesterol in the hepatocytes. The primary BAs are synthesized mainly by classic pathway, in which 7α-hydroxylase acts as the rate-limiting enzyme, and to a lesser extent by alternative pathway (109). The main BAs synthesized in human are chenodeoxycholic acid and cholic acid whereas rodents can also produce muricholic acids, and thus BAs show evident species-specific differences (109). After the production, BAs can conjugate with taurine or glycine to form bile salts in the liver (110). When triggered by food intake, BAs are released  (113). Given that dietary compounds can affect the composition of gut microbiota, dietary supplement may alter the gut microbial BA metabolism and thus further bring beneficial effects on hosts. In fact, a group of recent studies have continuously supported this idea. Curcumin is a compound that is extracted from turmeric, and is widely used as a dietary agent and traditional medicine for many years (114). In high-fat diet-induced obese wild type mice, curcumin treatment ameliorated obesity by reconstruction of gut microbiota composition and increasing of microbial derived secondary BAs including deoxycholic acid and lithocholic acid, two potent ligands for TGR5 (115). Moreover, the enhanced effects of curcumin on thermogenesis were eliminated inTGR5 knockout mice, which further confirmed that the effects of curcumin on obesity were achieved through modulation of microbial BA metabolism. Capsaicin, a naturally occurring alkaloid that derived from chillies, are widely used as food additives due to its hot pungent taste. In type 2 diabetic db/db mice, capsaicin remarkably improved glucose tolerance and insulin sensitivity, and this process was associated with decreasing the abundance of Lactobacillus and microbial bile salt hydrolase activity (116). The modulation of microbial abundance and enzyme activity further leaded to accumulation of tauro-β-muricholic acid, an antagonist of the FXR, and thus improved glucose metabolism and insulin sensitivity in diabetic mice (116). In another study by same group, capsaicin ameliorated high fat diet-induced obesity and adipose tissue accumulation, and this process was associated with the increase of Bacteroides abundance and 7α-dehydroxylase activity and the decrease of bile salt hydrolase activity. The modulation of microbial abundance and enzyme activity further leaded to the increase of lithocholic acid, an agonist of TGR5, and thus improved glucose metabolism and insulin sensitivity (117). These two studies showed similar pharmacological effects of capsaicin, yet the mechanisms were different. The reason may be that the animal models are different as one was leptin receptor-deficient diabetic mice whereas the other was highfat diet-induced obese mice. Resveratrol, a natural polyphenol that is present largely in grapes and berries, improved glucose homeostasis by modulation of microbial BA metabolism and TGR5 in db/db mice (118). These studies suggested that the healthy effects of dietary compounds can be partly attribute to the modulation of gut microbial BA metabolism.

Trimethylamine and trimethylamine N-oxide
Under the action of gut microbial trimethylamine (TMA) lyases, dietary quaternary amines that are not absorbed such as choline, betaine, phosphatidylcholine, and L-carnitine can be transformed into TMA (119). After absorption, TMA can be oxidized to trimethylamine N-oxide TMAO under the action of hepatic flavin-containing monooxygenases (FMOs) such as FMO1 and FMO3 (120). Increased TMAO then promotes oxidative stress and inflammation of endothelial cells, activates the inflammasome NOD-like receptor protein 3 and nuclear factor kappa B signaling in vascular smooth muscle cells, promotes the transformation of macrophages into foam cells, promotes platelet hyperreactivity, and alters cholesterol transport and bile acid synthesis (121). Correspondingly, high level of blood TMAO might contribute to heart disease, diabetes, atherosclerosis, and even cancer (122, 123).
Worth notice is that while a large number of epidemiologic research have showed strong association between the increased plasma TMAO concentrations and the risk of cardiovascular diseases, the roles of dietary compounds on final concentrations of TMAO in blood and the risk of diseases are still worth investigating as controversy remains over this topic. For example, a study on a longitudinal cohort of US men showed that intake of higher levels of red meat and choline was significantly associated with higher TMAO levels in participants with rich TMAO-producing bacteria especially Alistipes shahii but not in other participants (124). On the contrary, a study comparing the TMAO levels in patients with carotid artery atherosclerosis and healthy controls showed that there was no association between the level of TMAO and carotid atherosclerosis or cardiovascular death (125). In addition, fishrich diets can lead to obvious increase of plasma TMAO; . /fnut. . however, meta-analysis, cross-sectional and prospective studies showed that fish consumption is associated with lower risk of cardiovascular diseases (126). Furthermore, some studies even reported the beneficial effects of TMAO or TMA in cardiovascular diseases (119). Nevertheless, in addition to the compounds such as choline and L-carnitine that can be metabolized to TMA directly, modulation of TMA and TMAO metabolism is still regarded as one important mechanism of other types of dietary compounds in regulation of cardiovascular diseases. For example, administration of Lonicera caerulea berry extract, which is rich in polyphenols, to high cholesterol-induced hypercholesterolemic male SD rats for 12 weeks attenuated serum dyslipidemia (127), and this process was associated with decreasing of serum TMAO levels. In mice supplemented with 1.3% carnitine, flavonoids from oolong tea and citrus peels remarkedly reduced plasma TMAO and aortic inflammation, and this process was associated with modulation of Lactobacillus and Akkermansia (128). In addition to crude extracts, pure compounds in diet can also modulate TMA and TMAO to modulate cardiovascular diseases. For example, oral resveratrol can attenuate TMAO-induced atherosclerosis in ApoE −/− mice, and this process was associated with inhibiting of gut microbial TMA production (129). Besides, treatment with antibiotics abolished the decreasing effects of resveratrol on TMAO levels and the inhibiting effects on atherosclerosis.

Branched-chain amino acids
Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids with branched aliphatic side chains. BCAAs play critical roles in nutrients metabolism such as muscle protein synthesis, glucose and lipid metabolism via phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway (130). In contrast to the beneficial effects, evidence has indicated that BCAAs can contribute to a number of diseases such as insulin resistance, type 2 diabetes mellitus, cancer, and cardiovascular diseases (26,130). Therefore, BCAAs has been suggested to be developed as biomarkers to predict the outcomes of diseases such as obesity, insulin resistance, and cardiovascular diseases (131). Although mammalians lack the enzymes needed for the de novo synthesis of BCAAs, gut microbiota contain rich enzymes responsible for synthesis of BCAAs (132). Many gut bacteria are capable of de novo synthesis of BCAAs, such as Prevotella copri, Bacteroides vulgatus, and Clostridium clusters (133). Since BCAAs can be degraded from food and synthesized by gut microbiota, both the daily supplementation of BCAAscontaining food and modulating the composition of gut microbiota can affect the circulating BCAAs and further affect the health and disease associated with BCAAs. For example, diet with specifically reduced BCAAs can reverse the dietinduced obesity and restore the glucose tolerance and insulin sensitivity (134).
In addition to the dietary proteins, peptides, and amino acids that can be directly metabolized to BCAAs by gut microbiota, other dietary compounds can also influence the levels of circulating BCAAs and thus attenuate diseases. For example, virgin olive oil and high-oleic acid peanut oil are dietary vegetable oil with a high monounsaturated fatty acid and can attenuate metabolic syndrome (135). When the two types of oils were fed to rats with a high-fat diet, the β-diversity and abundance of Bifidobacterium were increased (oleic acid peanut oil also decreased Lachnospiraceae and Blautia) and the levels of BCAAs were revised, suggesting of modulation of gut microbial BCAA metabolism as the mechanism of the two oils in attenuation of metabolic syndrome (135). As a favorite vegetable, Luffa cylindrica (L.) Roem (luffa) is a very common in daily diet, and it is rich in polyphenols, saponin, triterpenoids, flavonoids, and oleanolic acid (136). Dietary oral administration of luffa to diet-induced obese mice can reduce circulating BCAA levels and selectively decrease the relative abundances of bacteria such as Enterortabdus and Butyricicoccus positively correlated with BCAA levels (136). In addition, this effect on BCAA catabolism was not observed in antibiotictreated obese mice. The results suggested that luffa ameliorated obesity by modulation of gut microbial BCAA metabolism. In another study, citrus polymethoxyflavones ameliorated high-fat diet-induced metabolic syndrome via regulation of gut microbial BCAA metabolism (137). Antibiotic treatment, fecal microbiome transplantation, and single bacterium gavage showed that Bacteroides ovatus was responsible for the reduction of BCAA levels and alleviation of metabolic syndrome (137).

Tryptophan, indole, and indole derivatives
Tryptophan, an essential amino acid for human body, is an important metabolite that can significantly influence both the physiology and pathology of mammalians. In addition to the main role in protein synthesis, tryptophan in host cells can act as an important precursor for production of crucial metabolites following the kynurenine and serotonin pathways (28). In contrast, unabsorbed tryptophan in the colon can interact with gut microbiota and can be metabolized into indole and indole derivatives such as skatole and indole acrylic acid under the action of the tryptophanases, which are expressed in many Gram-negative and Gram-positive gut bacteria such as Clostridium spp., Bacteroides spp. and Escherichia coli (28). Many of the indole derivatives such as indole acrylic acid, indole-3-aldehyde, indole-3-propionic acid, indole-3-acetic acid, and indole-3-acetaldehyde can act as ligands for aryl hydrocarbon receptor (AhR), pregnane X receptor and retinoid-related orphan receptor gamma-t (29, 138). Among these targets, .
/fnut. . aryl hydrocarbon receptor plays important roles in intestinal homeostasis by acting on a group of cells, such as Th17 cells, macrophages, dendritic cells, neutrophils, and other cells (139). Correspondingly, microbial tryptophan metabolites can regulate the intestinal barrier integrity, epithelial proliferation, and intestinal resistance to pathogens (27, 28). Since intestinal barrier are directly associated with a number of diseases, tryptophan and tryptophan microbial metabolites have been demonstrated to be linked to a number of diseases such as ulcerative colitis, Crohn's disease, obesity, autism spectrum disorder, Alzheimer's disease, Parkinson's disease, and irritable bowel syndrome (28,140,141). As microbial tryptophan metabolism is associated with host functions and diseases, it is no wonder that dietary tryptophan is associated with health. In the aging mice, a diet containing 0.4% tryptophan significantly attenuated the inflammation and oxidative stress via increasing the colon indoles and the relative abundance of Akkermansia (142). Similarly, in non-obese diabetic mice expressing DQ8, a tryptophan-rich diet decreased gluten immunopathology via modulation of gut microbiota composition and enhancing the production of AhR ligands such as indole-3-aldehyde and indole3-lactic acid (143). On the contrary, in an aged mouse model, tryptophan-deficient diets (0.1% tryptophan) showed an elevated levels of pro-inflammatory cytokines in comparison with those fed a normal (0.2% tryptophan) and a tryptophan-rich (1.25% tryptophan) diet (144). And the effect was associated with modulation of gut bacteria such as Clostridium spp., which is involved in microbial tryptophan metabolism (144).
In addition to the diet containing tryptophan, other types of dietary compounds can modulate the gut microbiota tryptophan metabolism as well. For example, turmeric polysaccharides can improve the pathological phenotype of colitis mice via increasing the relative abundance of gut bacteria associated with tryptophan metabolism such as Lactobacillus and increasing the levels of cecal indole-3-acetic acid (145). Similarly, Fuzhuan brick tea polysaccharide ameliorated the ulcerative colitis of mice via promoting the proliferation of beneficial bacteria such as Akkermansia and increasing of fecal indole-3-acetaldehyde and indole-3-acetic acid (146). 1-Deoxynojirimycin, a major bioactive compound from functional food mulberry leaves, can ameliorate hyperlipidemia via increasing of Akkermansia and Clostridium and enhancing the microbial production of indole-3-propionic acid (147). Besides the animal-based studies, clinical studies have also suggested the beneficial effects of the other types of dietary compounds on microbial tryptophan metabolism. For instance, in a randomized, controlled, crossover trial, a polyphenol-rich diet significantly increased the microbial tryptophan metabolite indole 3propionic acid in older people with normal renal function, and this effect was associated with shift of bacteria Bacteroidales and Clostridiales (148).

Gases
Gut microbiota can produce gases (H 2 S, H 2 , CO 2 , CH 4 , NO) (6,35). CH 4 has significant effect on gastrointestinal tract as it is associated with constipation and can slow the colon motility (149). NO plays important roles in neuronal communication, modulation of blood vessels and immune response, and is possibly participated in diseases such as stroke and Parkinson's disease (150). While high concentration of H 2 S is generally believed to be toxic to hosts by inducing mucus disruption and inflammation, low levels H 2 S can be beneficial to hosts by stabilizing mucus layer, inhibiting adherence of bacteria to the epithelium, preventing the invasive bacteria, and reducing inflammation and tissue injury (151). CO 2 is mainly produced in the stomach whereas H 2 , CH 4 , CO 2 and H 2 S are mainly generated in the small intestine and colon (31). The gases H 2 and CO 2 are produced by fermentation of undigested carbohydrates and, to a much lesser extent, by dietary or hosts-released proteins, whereas the gas CH 4 is produced with the help of archaea in the colon by metabolism of CO 2 and H 2 (152). H 2 S is generated by fermentation of sulfur-containing proteins with the help of bacteria that are capable of reducing sulfates and sulfites (153). In mammalian cells, H 2 S can also be generated from L-cysteine, thio sulfate and homocysteine with the help of enzymes such as cystathionine β-and γ -lyase, aspartate aminotransferase and 3mercaptopyruvate sulfurtransferase (154, 155). Since chemical constituents and fermentable substrates are affected by dietary intake, the diet can change the production of gases. For instance, cellulose and corn bran can improve the production of H 2 , whereas the production of CH 4 was not affected (156,157). In healthy volunteers, a diet with high levels of short-chain carbohydrates that are poorly absorbed and non-digestible in the small intestine leaded to an increase of H 2 levels and a decrease of CH 4 (158). In addition, consuming of two purified fibers xylans and pectin increased the levels of CH 4 , whereas lactulose did not show this effect (156,159). Taken together, dietary compounds can be metabolized into gases and the types of diet can influence the gas production.

Others
In Table 3, we have listed the non-polysaccharide dietary compounds and extracts on aforementioned gut microbiotaderived metabolites. In addition to these metabolites, gut microbiota can also produce other metabolites such as lipids (lipopolysaccharides, conjugated fatty acids, etc.), vitamins, ethanol, triphosadenine, organic acids (such as benzoate and hippurate), polysaccharide A, imidazole propionate, dipeptide aldehydes (35,(176)(177)(178)(179). Among these metabolites, of special note are the metabolites produced from amino acids. In addition to tryptophan, other amino acids can also . /fnut. .  can be transformed into γ -aminobutyrate via the enzyme glutamate decarboxylase and bacteria such as Lactobacillus spp. and Bifidobacterium spp. (189). These gut microbiotaderived neuroactive compounds and neurotransmitters play important roles in gut motility disorders, behavioral disorders, neurodegenerative diseases, cerebrovascular diseases, and neuroimmune-mediated disorders (190). Taken together, amino acids can be transformed into neuroactive compounds, sulfide-containing metabolites (H 2 S, methanethiol), aromatic compounds (phenol, p-cresol), and polyamines, under the action of gut microbiota.

Perspectives
Because of the importance of gut microbiota metabolites in health and disease, regulation of gut microbiota metabolites by diets has received much attention in recent years. However, gut microbiota itself show great intra-and interindividual variations (1) and thus the extent of the response of gut microbiota metabolites in one person to a diet might be different from the response of another person. In this background, the concept precision nutrition or personalized nutrition has been raised in recent years following the initiative of precision medicine (191). Currently, targeted manipulating of gut microbiota has become an important approach to achieve precision medicine (43). Similar to precision medicine, precision nutrition aims to identify key characteristics of gut microbiota that can predict the response of an individual to specific dietary components, and then design of a diet that is conductive to health. In a proofof-principle study, analysis of three cohorts of obese adults from Belgium, Finland, and Britain showed that Clostridial species were indicative of the response of gut microbiota to diet, which in turn predicted the hosts' cholesterol response (192). In another study, a machine-learning approach integrating gut microbiota, blood parameters, dietary habits, anthropometrics, and physical activity showed that this approach can accurately predicts individual postprandial glycemic response after real-life meals (193). However, these studies did not correlate the levels of gut microbiota metabolites with diets and clinical outcomes, further studies are needed to identify the metabolites that are capable of predicting clinical outcomes.
After intake of a specific diet, the change of gut bacteria and gut microbiota metabolites may not be limited to a specific bacterium or metabolites. For example, in a mice model of inflammatory bowel disease, ketogenic diet altered gut bacteria such as Proteobacteria, Enterobacteriaceae, Escherichia-Shigella and changed the gut microbiota metabolites such as stearic acid, arachidic acid, and erucic acid (194). In fact, many of the changed bacteria and metabolites only show associative relationship with the change of phenotypes, and the key bacteria and metabolites with causal relationship must be determined. This idea is supported by the recent idea of keystone taxa, which drive the community composition and function of microbiota irrespective of their abundance (195). Therefore, screening of the key bacteria and gut microbiota metabolites responsible for the phenotypes is necessary. To achieve this aim, the combination of in vivo and in vitro experiments, and a variety of advanced technologies can be used. In this case, animal such as germ-free animal, gnotobiotic animal, antibiotic-treated animal and fecal bacteria culturing can be adopted to screening key bacteria. Targeted and untargeted metabolomics combined with oral supplementation or intravenous injection can be adopted to identify the key metabolites.

Conclusion
Gut microbiota-derived metabolites such as SCFAs and BAs play important roles in maintenance of host homeostasis and development of diseases. In the colon, the dietary compounds that pass small intestine can interact with gut microbiota and thus modulate the gut microbiota metabolites. In general, these metabolites can be grouped into 3 types: (I) metabolites that are produced directly from dietary compounds by gut microbiota; (II) metabolites that are originally synthesis by hosts and chemically transformed by gut microbiota; (III) metabolites that are produced by gut microbiota de novo. Depending on the types of dietary compounds, the gut microbiota metabolites affected include, but not limited to, SCFAs, BAs, TMA, BCAAs, and tryptophan metabolites. Because some dietary compounds can be metabolized to a specific group of metabolites under the action of particular bacteria, personalized diets can be applied for targeted manipulation of gut microbiota metabolites. In addition, a specific diet can influence multiple gut bacteria and metabolites, thus, identification of key bacteria and metabolites responsible to the healthy effects of diets are necessary.  . /fnut. .