Featured Articles

Since the discovery of IDO2 in 2007, there has been ongoing effort to understand whether this new KP enzyme functions similarly to its closely related family member, IDO1, or if there is an evolutionary or physiological need for a second IDO enzyme with distinct roles. To date, IDO2 has been implicated in immune regulation, particularly in cancer and autoimmune diseases. Despite nearly two decades of research on IDO2, much remains to be learned about its contribution to human diseases. This month, we highlight IDO2’s role in autoimmune diseases. Building on previous work, Dr. Mandik-Nayak’s team identified novel non-enzymatic functions of... read more

Anthranilic acid (AA), a downstream metabolite of the kynurenine pathway, has garnered significant research attention in recent years. It has been recognized as a derivative with immune-regulatory properties and therapeutic implications for autoimmune diseases and cancers, as seen with drugs like Tranilast. Subsequently, AA was identified as a risk factor for dementia, with higher plasma AA levels associated with an increased risk of dementia in the Framingham study. Notably, sex differences in AA levels have been observed; one study reported a correlation between AA and neocortical amyloid-β loading in females but not in males. More recently, AA has been implicated... read more

It is well appreciated that dysregulation of the kynurenine pathway (KP) has been linked to many disorders and diseases, for example depression (see 2023 September highlight), Parkinson’s, Alzheimer’s (see 2024 August highlight), various cancers (see 2023 March and 2022 July highlights), among others. Most studies investigating KP alterations rely on blood (serum or plasma) or cerebral spinal fluid (CSF) samples. While this is insightful, obtaining these samples is invasive and can often be difficult, prompting interest in less invasive alternatives like sweat.  Detection and quantitation of tryptophan (TRP) and its metabolites frequently use chromatography techniques such as high-performance liquid chromatography... read more

The kynurenine pathway (KP) plays a vital role during pregnancy by protecting the fetus from the mother’s immune system. This protective role is facilitated by trophoblast cells in the placenta, which significantly increases the expression of the enzyme IDO. This leads to a decrease in tryptophan (TRP) levels and an increase in the production of kynurenine (KYN), helping to suppress immune cell activity and creating a safe environment for fetal development. Beyond immune tolerance, the KP contributes to fetal growth. Previous research has shown distinct patterns of KP metabolites in the placenta and fetal membrane. with lower KYN levels and... read more

There is increasing evidence linking the kynurenine pathway (KP) to Alzheimer’s disease (AD) pathology, though the precise mechanisms remain elusive. Elevated KP activity in AD is associated with hallmark pathologies such as amyloid-β plaques and tau tangles. The prevailing hypothesis suggests that KP activation produces neurotoxic metabolites like quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK), which contribute to excitotoxicity and neurodegeneration (see June 2022 highlight). A recent systematic review and meta-analysis by Maes et al. (2022) found evidence of AD patients exhibiting tryptophan (TRP) depletion and an elevated kynurenine (KYN)/TRP ratio. However, the clinical relevance of targeting IDO1 in AD pathophysiology... read more

The incidence of obesity has increased over the last 30 years at a staggering rate worldwide. Eight percent of children and 16% of adults were classified as obese in 2022. Obesity increases the risk of comorbidities, including diabetes, cardiovascular disease, and steatotic liver diseases. The liver plays a major role in tryptophan metabolism and liver fibrosis is associated with increased kynurenine pathway activity. A recent study published by Dr. Carmen Arto and colleagues investigated kynurenine pathway metabolite levels in obese individuals with and without metabolic dysfunction-associated steatotic liver disease (MASLD). Body mass index (BMI) was significantly associated with quinolinic acid... read more

Several metabolites of the kynurenine pathway have been shown to have immunomodulatory effects through various mechanisms. To name a few: (1) the tryptophan depletion theory, where activation of the kynurenine pathway via IDO-1 prevents graft rejection by suppressing T-cells—highlighting the importance of the KP in immune regulation in autoimmunity and cancer immune biology; (2) the KYN-AhR pathway, which contributes to our understanding of immune tolerance against infection; and (3) new mechanistic insights into immunoregulation by neuroactive KP metabolites, such as KA (via GPR35) and QA (via Foxo-1-PPARγ, featured in March 2023). A new addition to the field is 3-hydroxykynurenine (3-HK),... read more

While we exit the COVID-19 pandemic, we are still feeling the effects of this virus. Many individuals have long COVID neurological symptoms which can include brain fog, sleep disturbances, depression and/or anxiety.  ISTRY has followed COVID-19 research and how tryptophan metabolism is altered in both acute- and long-COVID (reported in our first newsletter and in our Featured Article series – see 2022 Aug, 2023 Jul, Oct, Nov). A recent study published by Dr. Mario Gietl and colleagues followed COVID patients over a year after being hospitalized with acute COVID-19 infection to assess the long-term effects. At the initial visit kynurenine... read more

Aging-related diseases have been associated with kynurenine pathway dysregulation, which we touched on in issue 3 of our newsletter. Research has shown that with age there are increases in quinolinic acid (QUIN), suggesting that the kynurenine pathway (KP) plays a role in aging-associated diseases. The KP impacts bioenergetic activities through the reduction of nicotinamide adenine dinucleotide (NAD+) levels and ATP production, as well as impacting mitochondria function. Interestingly, longer lifespans have been correlated to suppressed kynurenine activity. Previous studies have focused on NAD+ levels and how increasing NAD+ through supplementation can impact longevity. Here, Dr. Mariann Gabrawy and colleagues combined... read more

Globally attention-deficit/hyperactivity disorder (ADHD) affects around 6% of children and around 5% of adults. While the exact cause of ADHD is unknown, a combination of factors including environmental and genetic are thought to play a role in this neurodevelopmental disorder. Like other psychiatric diseases, such as depression, individuals with ADHD have elevated inflammatory markers such as interleukin-6. Additionally, research has highlighted dysregulation of kynurenine pathway (KP) metabolite levels suggesting that KP activity may drive pathogenesis in ADHD. Therefore, in a recent meta-analysis study, Dr Daniele Cavaleri and colleagues looked at differences in the KP metabolite levels between ADHD patients and... read more

Various therapeutics can lead to drug-induced interstitial lung disease (DIILD) either via direct toxicity or from secondary effects due to immune activation. Mortality rates in DIILD have been reported as upwards of 50% and individuals who recover often have long-term effects, including lung fibrosis. Currently, patients are diagnosed by high-resolution computed tomography scans however, there is a need for a non-invasive method of diagnosis that can differentiate individuals with DILD from other pulmonary diseases while limiting radiation exposure. Dr. Yuchen Sun and colleagues sought to find new biomarkers that are specific to DIILD. In their metabolomic screening, they identified five kynurenine-derived... read more