A key role of the gut microbiota in the establishment and maintenance of health, as well as in the pathogenesis of disease, has been identified over the past two decades. One of the primary modes by ...which the gut microbiota interacts with the host is by means of metabolites, which are small molecules that are produced as intermediate or end products of microbial metabolism. These metabolites can derive from bacterial metabolism of dietary substrates, modification of host molecules, such as bile acids, or directly from bacteria. Signals from microbial metabolites influence immune maturation, immune homeostasis, host energy metabolism and maintenance of mucosal integrity. Alterations in the composition and function of the microbiota have been described in many studies on IBD. Alterations have also been described in the metabolite profiles of patients with IBD. Furthermore, specific classes of metabolites, notably bile acids, short-chain fatty acids and tryptophan metabolites, have been implicated in the pathogenesis of IBD. This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation.
The gut microbiota is implicated in immune system functions. Regulation of the metabolic processes occurring in immune cells is crucial for the maintenance of homeostasis and immunopathogenesis. ...Emerging data demonstrate that the gut microbiota is an actor in immunometabolism, notably through the effect of metabolites such as short-chain fatty acids, bile acids, and tryptophan metabolites. In this Perspective, we discuss the impact of the gut microbiota on the intracellular metabolism of the different subtypes of immune cells, including intestinal epithelial cells. Besides the effects on health, we discuss the potential consequences in infection context and inflammatory bowel diseases.
The gut microbiota is implicated in immune system functions. At the same time, regulation of metabolic processes in immune cells is crucial for the maintenance of homeostasis and immunopathogenesis. In this Perspective, Michaudel and Sokol focus on emerging data demonstrating that the gut microbiota is an actor in immunometabolism, notably through the effect of metabolites.
Metabolic disorders represent a growing worldwide health challenge due to their dramatically increasing prevalence. The gut microbiota is a crucial actor that can interact with the host by the ...production of a diverse reservoir of metabolites, from exogenous dietary substrates or endogenous host compounds. Metabolic disorders are associated with alterations in the composition and function of the gut microbiota. Specific classes of microbiota-derived metabolites, notably bile acids, short-chain fatty acids, branched-chain amino acids, trimethylamine N-oxide, tryptophan and indole derivatives, have been implicated in the pathogenesis of metabolic disorders. This review aims to define the key classes of microbiota-derived metabolites that are altered in metabolic diseases and their role in pathogenesis. They represent potential biomarkers for early diagnosis and prognosis as well as promising targets for the development of novel therapeutic tools for metabolic disorders.
The gut microbiota is a crucial actor in human physiology. Many of these effects are mediated by metabolites that are either produced by the microbes or derived from the transformation of ...environmental or host molecules. Among the array of metabolites at the interface between these microorganisms and the host is the essential aromatic amino acid tryptophan (Trp). In the gut, the three major Trp metabolism pathways leading to serotonin (5-hydroxytryptamine), kynurenine (Kyn), and indole derivatives are under the direct or indirect control of the microbiota. In this review, we gather the most recent advances concerning the central role of Trp metabolism in microbiota-host crosstalk in health and disease. Deciphering the complex equilibrium between these pathways will facilitate a better understanding of the pathogenesis of human diseases and open therapeutic opportunities.
Many metabolites are involved in host-microbiota interactions. Agus et al. review recent advances concerning the central role of tryptophan metabolism in microbiota-host crosstalk in health and disease. This review examines the direct effect of the gut microbiota in producing tryptophan-derived bioactive molecules and its indirect control of host tryptophan metabolism.
Tryptophan Metabolism as a Pharmacological Target Modoux, Morgane; Rolhion, Nathalie; Mani, Sridhar ...
Trends in pharmacological sciences (Regular ed.),
January 2021, 2021-01-00, 20210101, 2021-01, Letnik:
42, Številka:
1
Journal Article
Recenzirano
Odprti dostop
L-Tryptophan is an essential amino acid required for protein synthesis. It undergoes an extensive and complex metabolism along several pathways, resulting in many bioactive molecules acting in ...various organs through different action mechanisms. Enzymes involved in its metabolism, metabolites themselves, or their receptors, represent potential therapeutic targets, which are the subject of dynamic research. Disruptions in L-tryptophan metabolism are reported in several neurological, metabolic, psychiatric, and intestinal disorders, paving the way to develop drugs to target it. This review will briefly describe L-tryptophan metabolism and present and discuss the most recent pharmacological developments targeting it.
L-Tryptophan (L-Trp) is metabolized via three pathways: the indole pathway in bacteria and the kynurenine and serotonin pathways in mammalian cells.Disruptions in L-Trp metabolism are reported in several diseases making L-Trp metabolism a promising therapeutic target.Manipulating L-Trp metabolism is an attractive therapeutic strategy.Key enzymes of L-Trp metabolism are targets of inhibitors currently undergoing clinical trials in cancerology, dermatology, and gastroenterology.Serotonin and aryl hydrocarbon receptor (AhR) receptors are targeted in the treatment of gastrointestinal diseases, inflammation, and many cancers.Next-generation probiotics producing indoles are being developed for their ability to activate AhR in the gut.
Fecal microbiota transplantation (FMT) has demonstrated efficacy in treating inflammatory bowel diseases and irritable bowel syndrome in an increasing number of randomized controlled trials. Recently ...published data gives striking insights into the factors associated with FMT success paving the road for the use of precision medicine in gastrointestinal disorders.
The implication of gut microbiota in the control of brain functions in health and disease is a novel, currently emerging concept. Accumulating data suggest that the gut microbiota exert its action at ...least in part by modulating neuroinflammation. Given the link between neuroinflammatory changes and neuronal activity, it is plausible that gut microbiota may affect neuronal functions indirectly by impacting microglia, a key player in neuroinflammation. Indeed, increasing evidence suggests that interplay between microglia and synaptic dysfunction may involve microbiota, among other factors. In addition to these indirect microglia-dependent actions of microbiota on neuronal activity, it has been recently recognized that microbiota could also affect neuronal activity directly by stimulation of the vagus nerve.
The putative mechanisms of the indirect and direct impact of microbiota on neuronal activity are discussed by focusing on Alzheimer's disease, one of the most studied neurodegenerative disorders and the prime cause of dementia worldwide. More specifically, the mechanisms of microbiota-mediated microglial alterations are discussed in the context of the peripheral and central inflammation cross-talk. Next, we highlight the role of microbiota in the regulation of humoral mediators of peripheral immunity and their impact on vagus nerve stimulation. Finally, we address whether and how microbiota perturbations could affect synaptic neurotransmission and downstream cognitive dysfunction.
There is strong increasing evidence supporting a role for the gut microbiome in the pathogenesis of Alzheimer's disease, including effects on synaptic dysfunction and neuroinflammation, which contribute to cognitive decline. Putative early intervention strategies based on microbiota modulation appear therapeutically promising for Alzheimer's disease but still require further investigation.
Patients with extensive or complicated Crohn＇s disease（CD） at diagnosis should be treated straightaway with immunosuppressive therapy according to the most recent guidelines.In patients with ...localized and uncomplicated CD at diagnosis,early use of immunosuppressive therapy is debated for preventing disease progression and limiting the disabling clinical impact.In this context,there is a need for predictors of benign or unfavourable subsequent clinical course,in order to avoid over-treating with risky drugs those patients who would have experienced spontaneous mid-term asymptomatic disease without progression towards irreversible intestinal lesions.At diagnosis,an age below 40 years,the presence of perianal lesions and the need for treating the first flare with steroids have been consistently associated with an unfavourable subsequent 5-year or 10-year clinical course.The positive predictive value of unfavourable course in patients with 2 or 3 predictors ranges between 0.75 and 0.95 in population-based and referral centre cohorts.Consequently,the use of these predictors can be integrated into the elements that influence individual decisions.In the CD postoperative context,keeping smoking and history of prior resection are the stron-gest predictors of disease symptomatic recurrence.However,these clinical predictors alone are not as reliable as severity of early postoperative endoscopic recurrence in clinical practice.In ulcerative colitis（UC）,extensive colitis at diagnosis is associated with unfavourable clinical course in the first 5 to 10 years of the disease,and also with long-term colectomy and colorectal inflammation-associated colorectal cancer.In patients with extensive UC at diagnosis,a rapid step-up strategy aiming to achieve sustained deep remission should therefore be considered.At the moment,no reliable serological or genetic predictor of inflammatory bowel disease clinical course has been identified.
Dietary lipids favor the growth of the pathobiont Bilophila wadsworthia, but the relevance of this expansion in metabolic syndrome pathogenesis is poorly understood. Here, we showed that B. ...wadsworthia synergizes with high fat diet (HFD) to promote higher inflammation, intestinal barrier dysfunction and bile acid dysmetabolism, leading to higher glucose dysmetabolism and hepatic steatosis. Host-microbiota transcriptomics analysis reveal pathways, particularly butanoate metabolism, which may underlie the metabolic effects mediated by B. wadsworthia. Pharmacological suppression of B. wadsworthia-associated inflammation demonstrate the bacterium's intrinsic capacity to induce a negative impact on glycemic control and hepatic function. Administration of the probiotic Lactobacillus rhamnosus CNCM I-3690 limits B. wadsworthia-induced immune and metabolic impairment by limiting its expansion, reducing inflammation and reinforcing intestinal barrier. Our results suggest a new avenue for interventions against western diet-driven inflammatory and metabolic diseases.
Antimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G ...suppression during experimental alcoholic liver disease.
Interleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic-binge ethanol feeding (NIAAA model).
In a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL-22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL-22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered
to produce IL-22 (
/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However,
/IL-22 did not reduce ethanol-induced liver disease in
mice.
Ethanol-associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol-induced steatohepatitis.
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