Changes In Tryptophan Metabolism Research Articles

Neuroimmune modulation by tryptophan derivatives in neurological and inflammatory disorders

The nervous and immune systems are highly developed, and each performs specialized physiological functions. However, they work together, and their dysfunction is associated with various diseases. Specialized molecules, such as neurotransmitters, cytokines, and more general metabolites, are essential for the appropriate regulation of both systems. Tryptophan, an essential amino acid, is converted into functional molecules such as serotonin and kynurenine, both of which play important roles in the nervous and immune systems. The role of kynurenine metabolites in neurodegenerative and psychiatric diseases has recently received particular attention. Recently, we found that hyperactivity of the kynurenine pathway is a critical risk factor for septic shock. In this review, we first outline neuroimmune interactions and tryptophan derivatives and then summarized the changes in tryptophan metabolism in neurological disorders. Finally, we discuss the potential of tryptophan derivatives as therapeutic targets for neuroimmune disorders.

Exploring the interplay between running exercises, microbial diversity, and tryptophan metabolism along the microbiota-gut-brain axis.

The emergent recognition of the gut-brain axis connection has shed light on the role of the microbiota in modulating the gut-brain axis's functions. Several microbial metabolites, such as serotonin, kynurenine, tryptamine, indole, and their derivatives originating from tryptophan metabolism have been implicated in influencing this axis. In our study, we aimed to investigate the impact of running exercises on microbial tryptophan metabolism using a mouse model. We conducted a multi-omics analysis to obtain a comprehensive insight into the changes in tryptophan metabolism along the microbiota-gut-brain axis induced by running exercises. The analyses integrated multiple components, such as tryptophan changes and metabolite levels in the gut, blood, hippocampus, and brainstem. Fecal microbiota analysis aimed to examine the composition and diversity of the gut microbiota, and taxon-function analysis explored the associations between specific microbial taxa and functional activities in tryptophan metabolism. Our findings revealed significant alterations in tryptophan metabolism across multiple sites, including the gut, blood, hippocampus, and brainstem. The outcomes indicate a shift in microbiota diversity and tryptophan metabolizing capabilities within the running group, linked to increased tryptophan transportation to the hippocampus and brainstem through circulation. Moreover, the symbiotic association between Romboutsia and A. muciniphila indicated their potential contribution to modifying the gut microenvironment and influencing tryptophan transport to the hippocampus and brainstem. These findings have potential applications for developing microbiota-based approaches in the context of exercise for neurological diseases, especially on mental health and overall well-being.

Magnolol-driven microbiota modulation elicits changes in tryptophan metabolism resulting in reduced skatole formation in pigs

Skatole of gut origin has garnered significant attention as a malodorous pollutant due to its escalating emissions, recalcitrance to biodegradation and harm to animal and human health. Magnolol is a health-promoting polyphenol with potential to considerably mitigate the skatole production in the intestines. To investigate the impact of magnolol and its underlying mechanism on the skatole formation, in vivo and in vitro experiments were conducted in pigs. Our results revealed that skatole concentrations in the cecum, colon, and faeces decreased by 58.24% (P = 0.088), 44.98% (P < 0.05) and 43.52% (P < 0.05), respectively, following magnolol supplementation. Magnolol supplementation significantly decreased the abundance of Lachnospira, Faecalibacterium, Paramuribaculum, Faecalimonas, Desulfovibrio, Bariatricus, and Mogibacterium within the colon (P < 0.05). Moreover, a strong positive correlation (P < 0.05) between skatole concentration and Desulfovibrio abundance was observed. Subsequent in silico studies showed that magnolol could dock well with indolepyruvate decarboxylase (IPDC) within Desulfovibrio. Further in vitro investigation unveiled that magnolol addition led to less indole-3-pyruvate diverted towards the oxidative skatole pathway by the potential docking of magnolol towards IPDC, thereby diminishing the conversion of substrate into skatole. Our findings offer novel targets and strategies for mitigating skatole emission from the source.

Patients with Neurodegenerative Proteinopathies Exhibit Altered Tryptophan Metabolism in the Serum and Cerebrospinal Fluid.

Some pathological conditions affecting the human body can also disrupt metabolic pathways and thus alter the overall metabolic profile. Knowledge of metabolic disturbances in specific diseases could thus enable the differential diagnosis of otherwise similar conditions. This work therefore aimed to comprehensively characterize changes in tryptophan metabolism in selected neurodegenerative diseases. Levels of 18 tryptophan-related neuroactive substances were determined by high throughput and sensitive ultrahigh-performance liquid chromatography-tandem mass spectrometry in time-linked blood serum and cerebrospinal fluid samples from 100 age-matched participants belonging to five cohorts: healthy volunteers (n = 21) and patients with Lewy body disease (Parkinson's disease and dementia with Lewy bodies; n = 31), four-repeat tauopathy (progressive supranuclear palsy and corticobasal syndrome; n = 10), multiple system atrophy (n = 13), and Alzheimer's disease (n = 25). Although these conditions have different pathologies and clinical symptoms, the discovery of new biomarkers is still important. The most statistically significant differences (with p-values of ≤0.05 to ≤0.0001) between the study cohorts were observed for three tryptophan metabolites: l-kynurenine in cerebrospinal fluid and 3-hydroxy-l-kynurenine and 5-hydroxy-l-tryptophan in blood serum. This led to the discovery of distinctive correlation patterns between the profiled cerebrospinal fluid and serum metabolites that could provide a basis for the differential diagnosis of neurodegenerative tauopathies and synucleinopathies. However, further large-scale studies are needed to determine the direct involvement of these metabolites in the studied neuropathologies, their response to medication, and their potential therapeutic relevance.

Tryptophan Metabolism in Postmenopausal Women with Functional Constipation.

Constipation belongs to conditions commonly reported by postmenopausal women, but the mechanism behind this association is not fully known. The aim of the present study was to determine the relationship between some metabolites of tryptophan (TRP) and the occurrence and severity of abdominal symptoms (Rome IV) in postmenopausal women with functional constipation (FC, n = 40) as compared with age-adjusted postmenopausal women without FC. All women controlled their TRP intake in their daily diet. Urinary levels of TRP and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), and 3-indoxyl sulfate (indican, 3-IS), were determined by liquid chromatography/tandem mass spectrometry. Dysbiosis was assessed by a hydrogen-methane breath test. Women with FC consumed less TRP and had a lower urinary level of 5-HIAA, but higher levels of KYN and 3-IS compared with controls. The severity of symptoms showed a negative correlation with the 5-HIAA level, and a positive correlation with the 3-IS level. In conclusion, changes in TRP metabolism may contribute to FC in postmenopausal women, and dysbiosis may underlie this contribution.

Changes in Tryptophan Metabolism on Serotonin and Kynurenine Pathways in Patients with Irritable Bowel Syndrome

(1) Background: L-tryptophan is a substrate for the synthesis of many biological compounds through the serotonin and kynurenine pathways. These compounds have a significant influence on gastrointestinal functions and mental processes. The aim of the study was to evaluate the urinary excretion of selected tryptophan metabolites in patients with constipation-predominant and diarrhoea-predominant irritable bowel syndrome (IBS-C and IBS-D, respectively), related to somatic and mental symptoms. (2) Methods: 120 people were included in the study and three groups were distinguished, with 40 individuals each, including healthy subjects (controls), patients with IBS-C and patients with IBS-D. The Gastrointestinal Symptoms Rating Scale (GSRS-IBS) was used to assess the severity of abdominal symptoms. The Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D) were used to evaluate the mental state of patients. Using liquid chromatography tandem mass spectrometry (LC-MS/MS), L-tryptophan and the following metabolites in urine, related to the creatinine level, were measured: 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA). (3) Results: In both groups of patients with IBS, changes in tryptophan metabolism were found as compared to the control group. We observed an increase in the activity of the serotonin pathway and a positive correlation between the 5-HIAA level and the GSRS score (p < 0.01) and HAM-A score (p < 0.001) in IBS-D patients. The IBS-C group was characterized by a higher concentration of kynurenines (KYN, QA) in urine. Moreover, the QA (p < 0.001) and KYNA (p < 0.05) levels were correlated with the HAM-D score among IBS-C patients. (4) Conclusions: Various changes in the tryptophan metabolism pathway can determine the differences in the clinical picture of irritable bowel syndrome. These results should be included in the nutritional and pharmacological treatment of this syndrome.

Metabolomic Profiling of Lungs from Mice Reveals the Variability of Metabolites in Pneumocystis Infection and the Metabolic Abnormalities in BAFF-R-Deficient Mice.

The incidence of Pneumocystis pneumonia (PCP) in patients without human immunodeficiency virus (HIV) has been increasing. In this study, we aimed to investigate the metabolic changes in Pneumocystis infection and the metabolic abnormalities in B-cell-activating factor receptor (BAFF-R)-deficient mice with Pneumocystis infection. The important function of B cells during Pneumocystis infection is increasingly recognized. In this study, a Pneumocystis-infected mouse model was constructed in BAFF-R-/- mice and wild-type (WT) mice. Lungs of uninfected WT C57BL/6, WT Pneumocystis-infected, and BAFF-R-/- Pneumocystis-infected mice were used for metabolomic analyses to compare the metabolomic profiles among the groups, with the aim of exploring the metabolic influence of Pneumocystis infection and the influence of mature B-cell deficiency during infection. The results indicated that many metabolites, mainly lipids and lipid-like molecules, were dysregulated in Pneumocystis-infected WT mice compared with uninfected WT C57BL/6 mice. The data also demonstrated significant changes in tryptophan metabolism, and the expression levels of key enzymes of tryptophan metabolism, such as indoleamine 2,3-dioxygenase 1 (IDO1), were significantly upregulated. In addition, B-cell development and function might be associated with lipid metabolism. We found a lower level of alitretinoin and the abnormalities of fatty acid metabolism in BAFF-R-/- Pneumocystis-infected mice. The mRNA levels of enzymes associated with fatty acid metabolism in the lung were upregulated in BAFF-R-/- Pneumocystis-infected mice and positively correlated with the level of IL17A, thus suggesting that the abnormalities of fatty acid metabolism may be associated with greater inflammatory cell infiltration in the lung tissue of BAFF-R-/- Pneumocystis-infected mice compared with the WT Pneumocystis-infected mice. Our data revealed the variability of metabolites in Pneumocystis-infected mice, suggesting that the metabolism plays a vital role in the immune response to Pneumocystis infection.

The Kynurenine Pathway in Healthy Subjects and Subjects with Obesity, Depression and Chronic Obstructive Pulmonary Disease

Changes in tryptophan metabolism through the kynurenine pathway (KP) are observed in several disorders and coupled with pathophysiological deviations. This study retrospectively compared the KP in serum in healthy subjects (108) with subjects with obesity (141), depression (49), and chronic obstructive pulmonary disease (COPD) (22) participating in four clinical studies and explored predictors of the changes in the KP metabolites. Compared with the healthy group, the KP was upregulated in the disease groups with high kynurenine, quinolinic acid (QA), kynurenine/tryptophan-ratio and QA/xanthurenic acid-ratio and low kynurenic acid/QA-ratio. Tryptophan and xanthurenic acid were upregulated in the depressed group compared with the groups with obesity and COPD. The covariates BMI, smoking, diabetes, and C-reactive protein explained the significant differences between the healthy group and the group with obesity but not between the healthy group and the groups with depression and COPD, indicating that different pathophysiological conditions result in the same changes in the KP. The KP was significantly upregulated in the disease groups compared with the healthy group, and there were significant differences between the disease groups. Different pathophysiological abnormalities seemed to result in the same deviations in the KP.

Effect of pharmacological modulation of the kynurenine pathway on pain-related behavior and opioid analgesia in a mouse model of neuropathic pain

Dysfunction of the central nervous system are accompanied by changes in tryptophan metabolism, with the kynurenine pathway (KP) being the main route of its catabolism. Recently, KP metabolites, which are collectively called kynurenines, have become an area of intense research due to their ability to directly and indirectly affect a variety of classic neurotransmitter systems. However, the significance of KP in neuropathic pain is still poorly understood. Therefore, we designed several experiments to verify changes in the mRNA levels of KP enzymes in parallel with other factors related to this metabolic route after chronic constriction injury of the sciatic nerve (CCI model) in mice. The analysis revealed an increase in, Kmo, Kynu and Haoo mRNA levels in the spinal cord on the 7th day after CCI, while Kat1, Kat2, Tdo2, Ido2 and Qprt mRNA levels remain unchanged. Subsequent pharmacological studies provided evidence that modulation of KP by single intrathecal administration of 1-D-MT, UPF468 or L-kynurenine attenuates mechanical and thermal hypersensitivity and increases the effectiveness of selected opioids in mice as measured on day 7 after CCI. Moreover, our results provide the first evidence that the injection of L-kynurenine preceded by UPF468 (KMO inhibitor) is more effective at reducing hypersensitivity in animals with neuropathic pain. Importantly, L-kynurenine also exerts an analgesic effect after intravenous injections, which is enhanced by the administration of minocycline, an inhibitor of microglial activation. Additionally, L-kynurenine administered intrathecally and intravenously enhances analgesia evoked by all tested opioids (morphine, buprenorphine and oxycodone). Overall, our results indicate that the modulation of KP at different levels might be a new pharmacological tool in neuropathy management.

Mechanism of interventional effect and targets of Zhuyu pill in regulating and suppressing colitis and cholestasis.

Zhuyu pill (ZYP) is a traditional Chinese medicine prescription composed of two drugs, Coptis chinensis Franch. and Tetradium ruticarpum (A. Jussieu) T. G. Hartley, and is commonly used in the clinical treatment of diseases of the digestive system. However, the mechanism underlying the effect of ZYP on colitis remains unclear. In this study, a colitis rat model was induced with 2,4,6-trinitro-benzenesulfonic acid (TNBS, 100mg/kg) and treated with ZYP (low dose: 0.6g/kg, high dose: 1.2g/kg). Disease activity index, colonic weight index, and weight change ratio were used to evaluate the model and efficacy. LC-MS and 16S rRNA gene sequencing were used to measure differences in fecal metabolism and microorganism population among the control, model, low-dose ZYP, and high-dose ZYP groups. To elucidate the mechanism of interventional effect of ZYP, Spearman correlation analysis was used to analyze the correlation between fecal metabolism and fecal microbial number. High-dose and low-dose ZYP both exhibited significant interventional effects on colitis rat models, and high-dose ZYP produced a better interventional effect compared with low-dose ZYP. Based on a metabolomics test of fecal samples, significantly altered metabolites in the model and high-dose ZYP treatment groups were identified. In total, 492 metabolites were differentially expressed. Additionally, sequencing of the 16S rRNA gene in fecal samples revealed that the high-dose ZYP could improve TNBS-induced fecal microbiota dysbiosis. Ultimately, changes in tryptophan metabolism and Firmicutes and Gammaproteobacteria populations were detected after ZYP treatment in both colitis and cholestasis. Therefore, we conclude that tryptophan metabolism and Firmicutes and Gammaproteobacteria populations are the core targets of the anti-inflammatory effect of ZYP. These findings provide a scientific basis for further investigation of the anti-inflammatory mechanism of ZYP in the future.

Direct Effects of Vitamin D Supplementation on Ultramarathon-Induced Changes in Kynurenine Metabolism.

In humans, most free tryptophan is degraded via kynurenine pathways into kynurenines. Kynurenines modulate the immune system, central nervous system, and skeletal muscle bioenergetics. Consequently, kynurenine pathway metabolites (KPMs) have been studied in the context of exercise. However, the effect of vitamin D supplementation on exercise-induced changes in KPMs has not been investigated. Here, we analyzed the effect of a single high-dose vitamin D supplementation on KPMs and tryptophan levels in runners after an ultramarathon. In the study, 35 amateur runners were assigned into two groups: vitamin D supplementation group, administered 150,000 IU vitamin D in vegetable oil 24 h before the run (n = 16); and control (placebo) group (n = 19). Blood was collected for analysis 24 h before, immediately after, and 24 h after the run. Kynurenic, xanthurenic, quinolinic, and picolinic acids levels were significantly increased after the run in the control group, but the effect was blunted by vitamin D supplementation. Conversely, the decrease in serum tryptophan, tyrosine, and phenylalanine levels immediately after the run was more pronounced in the supplemented group than in the control. The 3-hydroxy-l-kynurenine levels were significantly increased in both groups after the run. We conclude that vitamin D supplementation affects ultramarathon-induced changes in tryptophan metabolism.

Characterizing the influence of gut microbiota on host tryptophan metabolism with germ-free pigs.

Intestinal microbes are closely associated with host health, depending on metabolic crosstalk between the microbiota and host. Tryptophan metabolism is one of the best examples of metabolic crosstalk between intestinal microbiota and host; however, our understanding about the influence of intestinal microbiota on host tryptophan metabolism is limited. Thus, we established germ-free (GF) pig models to systemically explore the influence of intestinal microbiota on tryptophan metabolism. Five GF pigs were kept in GF conditions throughout the experiment (GF group). Six GF pigs were transplanted with fecal microbiota from donor sows to act as control pigs. Compared with control pigs, the GF pigs had remarkable alterations in tryptophan metabolism. The differential metabolites (P < 0.05) were mainly found in the liver, circulation system and large intestine. Notably, the alteration of metabolites in tryptophan metabolism varied among organs, especially for the serotonin pathway. In GF pigs, tryptophan and kynurenine in the large intestine and 5-hydroxytryptophan in most organs were increased (P < 0.05), while metabolites in the indole pathway in most organs were decreased (P < 0.05). Collectively, our study reveals changes in tryptophan metabolism in GF pigs, highlighting the critical role of gut microbes in shaping host tryptophan metabolism.

An Emerging Cross-Species Marker for Organismal Health: Tryptophan-Kynurenine Pathway.

Tryptophan (TRP) is an essential dietary amino acid that, unless otherwise committed to protein synthesis, undergoes metabolism via the Tryptophan-Kynurenine (TRP-KYN) pathway in vertebrate organisms. TRP and its metabolites have key roles in diverse physiological processes including cell growth and maintenance, immunity, disease states and the coordination of adaptive responses to environmental and dietary cues. Changes in TRP metabolism can alter the availability of TRP for protein and serotonin biosynthesis as well as alter levels of the immune-active KYN pathway metabolites. There is now considerable evidence which has shown that the TRP-KYN pathway can be influenced by various stressors including glucocorticoids (marker of chronic stress), infection, inflammation and oxidative stress, and environmental toxicants. While there is little known regarding the role of TRP metabolism following exposure to environmental contaminants, there is evidence of linkages between chemically induced metabolic perturbations and altered TRP enzymes and KYN metabolites. Moreover, the TRP-KYN pathway is conserved across vertebrate species and can be influenced by exposure to xenobiotics, therefore, understanding how this pathway is regulated may have broader implications for environmental and wildlife toxicology. The goal of this narrative review is to (1) identify key pathways affecting Trp-Kyn metabolism in vertebrates and (2) highlight consequences of altered tryptophan metabolism in mammals, birds, amphibians, and fish. We discuss current literature available across species, highlight gaps in the current state of knowledge, and further postulate that the kynurenine to tryptophan ratio can be used as a novel biomarker for assessing organismal and, more broadly, ecosystem health.

Changes in tryptophan metabolism after bariatric surgery

Rationale: Bariatric surgery can affect amino acids metabolism, which might contribute to postoperative metabolic improvements. We evaluated changes in tryptophan and its metabolites three months after of Roux-en-Y gastric by-pass surgery (RYGB).

Indole-3-acetate is associated with improvements of glycemic control biomarkers after bariatric surgery

Rationale: Indole-3-acetate (IAA) is a tryptophan metabolite produced by gut microbiota and has been associated with glucose homeostasis in preclinical studies. Since bariatric surgery can promote changes in tryptophan metabolism, we evaluated the associations between IAA and biomarkers of glycemic control before and three months after of Roux-en-Y gastric by-pass surgery (RYGB).

Kynurenine inhibits melanogenesis in human melanocyte-keratinocyte co-cultures and in a reconstructed 3D skin model.

Kynurenine (KYN), the most abundant metabolite of tryptophan, is classically associated with immune tolerance and tumor immune escape. In the last years, KYN is in the spotlight in other biological processes. Here, we showed that KYN inhibited tyrosinase expression and melanin content in primary human melanocyte and keratinocyte co-cultures. Furthermore, KYN decreased melanosome content in a 3D human skin reconstruction model. In these experiments, we used tyrosine + NH4 Cl to induce pigmentation. We compared the inhibitory effect of KYN on melanogenesis with the already known inhibitory effect promoted by IFN-γ. Since increased KYN production depends on theIFN-γ-inducibleenzyme indoleamine-2,3-dioxygenase (IDO), we propose that part of the effect of IFN-γ on melanogenesis involves KYN production. From that, we tested if, during melanogenesis, changes in tryptophan metabolism would occur. For this purpose, we measured tryptophan, KYN and downstream products along with pigmentation. There were no significant changes in Trp metabolism, except for the high consumption of kynurenic acid. Our data identify the skin as a potential target for the action of KYN relevant for skin physiology and pigmentation. The results are discussed concerning the high production of KYN in skin inflammatory disorders and cancer.

Chronic Unpredictable Stress Alters Brain Tryptophan Metabolism and Impairs Working Memory in Mice without Causing Depression-Like Behaviour.

Chronic stress is a well-known risk factor in major depressive disorder and disrupts the kynurenine and serotonin pathways of tryptophan metabolism. Here, we characterize the temporal central and peripheral changes in tryptophan metabolism and concomitant depressive-like behavioural phenotype induced during the progression of chronic unpredictable stress (CUS). Mice were exposed to 0, 10, 20, or 30 days of CUS followed by a panel of behavioural assays to determine depressive-like phenotypes. Immediately after behavioural testing, plasma and brain tissue were collected for metabolic analysis. While anhedonia-like and anxiety-like behaviours were unaffected by stress, nesting behaviour and cognitive deficits became apparent in response to CUS exposure. While CUS caused a transient reduction in circulating quinolinic acid, no other tryptophan metabolites significantly changed in response to CUS. In the brain, tryptophan, kynurenine, picolinic acid, and 5-hydroxyindoleacetic acid concentrations were significantly elevated in CUS-exposed mice compared with non-stress control animals, while kynurenic acid, xanthurenic acid, and serotonin decreased in CUS-exposed mice. Metabolic turnover of serotonin to the major metabolite 5- hydroxyindoleacetic acid was markedly increased in response to CUS. These results suggest that CUS impairs hippocampal-dependent working memory and enhances nascent nesting behaviour in C57BL/6J male mice, and these behaviours are associated with increased brain kynurenine pathway metabolism leading to accumulation of picolinic acid and a significant reduction in serotonin levels.

Effect of aprepitant on kynurenine to tryptophan ratio in cART treated and cART naïve adults living with HIV.

Changes in tryptophan metabolism affect human physiology including the immune system, mood, and sleep and are associated with human immunodeficiency virus (HIV) pathogenesis. This study investigates whether the treatment of HIV-infected individuals with the neurokinin-1 receptor antagonist, aprepitant, alters tryptophan metabolism.This study utilized archival samples from 3 phase 1B clinical trials “Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 Antagonist Aprepitant”-2 double-blinded, placebo-controlled, and 1 open-label study. We tested samples from a total of 57 individuals: 26 combination antiretroviral therapy (cART) naïve individuals receiving aprepitant, 19 cART naïve individuals receiving placebo, and 12 individuals on a ritonavir-containing cART regimen receiving aprepitant. We evaluated the effect of aprepitant on tryptophan metabolism by measuring levels of kynurenine and tryptophan in archival plasma samples and calculating the kynurenine to tryptophan ratio.Aprepitant treatment affected tryptophan metabolism in both cART treated and cART naïve individuals with more profound effects in patients receiving cART. While aprepitant treatment affected tryptophan metabolism in all HIV-infected patients, it only significantly decreased kynurenine to tryptophan ratio in cART treated individuals. Aprepitant treatment offers an opportunity to target inflammation and mood disorders frequently co-existing in chronic HIV infection.

Lack of Skeletal Muscle Serotonin Impairs Physical Performance.

Low levels of the neurotransmitter serotonin have been associated with the onset of depression. While traditional treatments include antidepressants, physical exercise has emerged as an alternative for patients with depressive disorders. Yet there remains the fundamental question of how exercise is sensed by the brain. The existence of a muscle–brain endocrine loop has been proposed: according to this scenario, exercise modulates metabolization of tryptophan into kynurenine within skeletal muscle, which in turn affects the brain, enhancing resistance to depression. But the breakdown of tryptophan into kynurenine during exercise may also alter serotonin synthesis and help limit depression. In this study, we investigated whether peripheral serotonin might play a role in muscle–brain communication permitting adaptation for endurance training. We first quantified tryptophan metabolites in the blood of 4 trained athletes before and after a long-distance trail race and correlated changes in tryptophan metabolism with physical performance. In parallel, to assess exercise capacity and endurance in trained control and peripheral serotonin–deficient mice, we used a treadmill incremental test. Peripheral serotonin–deficient mice exhibited a significant drop in physical performance despite endurance training. Brain levels of tryptophan metabolites were similar in wild-type and peripheral serotonin–deficient animals, and no products of muscle-induced tryptophan metabolism were found in the plasma or brains of peripheral serotonin–deficient mice. But mass spectrometric analyses revealed a significant decrease in levels of 5-hydroxyindoleacetic acid (5-HIAA), the main serotonin metabolite, in both the soleus and plantaris muscles, demonstrating that metabolization of tryptophan into serotonin in muscles is essential for adaptation to endurance training. In light of these findings, the breakdown of tryptophan into peripheral but not brain serotonin appears to be the rate-limiting step for muscle adaptation to endurance training. The data suggest that there is a peripheral mechanism responsible for the positive effects of exercise, and that muscles are secretory organs with autocrine-paracrine roles in which serotonin has a local effect.

Multi-omics: Differential expression of IFN-γ results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases

Low grade, chronic inflammation is a critical risk factor for immunologic dysfunction including autoimmune diseases. However, the multiplicity of complex mechanisms and lack of relevant murine models limit our understanding of the precise role of chronic inflammation. To address these hurdles, we took advantage of multi-omics data and a unique murine model with a low but chronic expression of IFN-γ, generated by replacement of the AU-rich element (ARE) in the 3’ UTR region of IFN-γ mRNA with random nucleotides. Herein, we demonstrate that low but differential expression of IFN-γ in mice by homozygous or heterozygous ARE replacement triggers distinctive gut microbial alterations, of which alteration is female-biased with autoimmune-associated microbiota. Metabolomics data indicates that gut microbiota-dependent metabolites have more robust sex-differences than microbiome profiling, particularly those involved in fatty acid oxidation and nuclear receptor signaling. More importantly, homozygous ARE-Del mice have dramatic changes in tryptophan metabolism, bile acid and long-chain lipid metabolism, which interact with gut microbiota and nuclear receptor signaling similarly with sex-dependent metabolites. Consistent with these findings, nuclear receptor signaling, encompassing molecules such as PPARs, FXR, and LXRs, was detectable as a top canonical pathway in comparison of blood and tissue-specific gene expression between female homozygous vs heterozygous ARE-Del mice. Further analysis implies that dysregulated autophagy in macrophages is critical for breaking self-tolerance and gut homeostasis, while pathways interact with nuclear receptor signaling to regulate inflammatory responses. Overall, pathway-based integration of multi-omics data provides systemic and cellular insights about how chronic inflammation driven by IFN-γ results in the development of autoimmune diseases with specific etiopathological features.