High Kynurenine:Tryptophan Ratio Is Associated With Liver Fibrosis in HIV-Monoinfected and HIV/Hepatitis C Virus–Coinfected Women

Abstract

Background Tryptophan catabolism, measured by the kynurenine:tryptophan (kyn/trp) ratio, is associated with gut microbiota alterations in people with HIV (PWH). We examined the association of the kyn/trp ratio with liver fibrosis in women with/without HIV infection. Methods The plasma kyn/trp ratio was measured in 137 HIV-monoinfected, HIV/hepatitis C virus (HCV)–coinfected, and uninfected women in the Women’s Interagency HIV Study. Fibrosis was estimated using FIB-4 in all participants and vibration-controlled transient elastography liver stiffness measurement (LSM) in a subset (n = 83). We used multivariable linear regression to evaluate the associations of infection status and kyn/trp ratio with relative differences in fibrosis estimates. Results The median kyn/trp ratio (interquartile range) was 0.056 (0.045–0.066) in HIV/HCV-coinfected, 0.038 (0.032–0.046) in HIV-monoinfected, and 0.031 (0.025–0.034) in uninfected women (P < .001). After adjustment for sociodemographic, lifestyle, and metabolic factors, HIV monoinfection and HIV/HCV coinfection were associated with 37% (95% confidence interval [CI], 9% to 73%) and 164% (95% CI, 100% to 250%) greater FIB-4, respectively. When kyn/trp ratio was included, higher kyn/trp ratio was associated with greater FIB-4 (27% per kyn/trp doubling; 95% CI, 5% to 53%), and the associations of HIV monoinfection (29% per kyn/trp doubling; 95% CI, 2% to 63%) and HIV/HCV coinfection (123% per kyn/trp doubling; 95% CI, 63% to 203%) with greater FIB-4 were attenuated. Among those with LSM, higher kyn/trp ratio was associated with greater LSM (43% per kyn/trp doubling; 95% CI, 15% to 79%) in multivariable analysis. Conclusions The kyn/trp ratio is elevated in PWH and is associated with greater liver fibrosis. Tryptophan catabolism may modify the relationships between HIV, HCV, and fibrosis.

The Pathogenesis of Liver Disease in People Living With Human Immunodeficiency Virus: The Emerging Role of the Microbiome

“…39 Higher KTR, a measure of tryptophan catabolism, was strongly associated with increased liver fibrosis in a recent cross-sectional study of a prospectively followed cohort of 137 women with and without HIV and HCV infections. 38 Moreover, in that study, the association of HIV infection with greater liver fibrosis was attenuated after controlling for KTR, suggesting that altered microbial metabolism through tryptophan breakdown may mediate fibrosis development in PLWH. 38 The hepatotoxic effects of gut dysbiosis may be particularly pronounced in the setting of viral hepatitis coinfection.…”

“…38 Moreover, in that study, the association of HIV infection with greater liver fibrosis was attenuated after controlling for KTR, suggesting that altered microbial metabolism through tryptophan breakdown may mediate fibrosis development in PLWH. 38 The hepatotoxic effects of gut dysbiosis may be particularly pronounced in the setting of viral hepatitis coinfection. In a retrospective study of 98 ART-treated individuals with HIV/HCV coinfection, sCD14 levels were increased in persons with HCV genotypes 1 and 4 or those with cirrhosis.…”

“…These tryptophan catabolites further reduce the pool of gut CD4 + T cells, promoting gut “leakiness” and release of LPS, activating a cycle of immune dysregulation in HIV . Higher KTR, a measure of tryptophan catabolism, was strongly associated with increased liver fibrosis in a recent cross‐sectional study of a prospectively followed cohort of 137 women with and without HIV and HCV infections . Moreover, in that study, the association of HIV infection with greater liver fibrosis was attenuated after controlling for KTR, suggesting that altered microbial metabolism through tryptophan breakdown may mediate fibrosis development in PLWH …”

“…A growing body of literature implicates crosstalk between gut flora and innate immunity in the pathogenesis of liver disease among PLWH. Prospective human cohort studies have provided the most compelling evidence for an association between MT and liver fibrosis in PLWH 15,[34][35][36][37][38] (Table 1). In one study of individuals with and without HIV or HCV infection, greater LPS and sCD14 levels were evident after CD4 + T cell depletion in individuals who experienced HIV seroconversion.…”

NAD+ Metabolism, Metabolic Stress, and Infection

“…For example, kynurenine (KYN) pathway metabolites, which are produced during de novo NAD + biosynthesis ( Figure 2 ), have been linked to brain disorders independent of NAD + levels ( Schwarcz et al, 2012 ; Amaral et al, 2013 ; Badawy, 2017 ; Braidy and Grant, 2017 ; Katsyuba et al, 2018 ; Castro-Portuguez and Sutphin, 2020 ). Interestingly, several pathogens also appear to target the NAD + metabolic network upon infection including Mycobacterium tuberculosis ( Sun et al, 2015 ; Pajuelo et al, 2020 ), Aspergillus fumigatus ( Choera et al, 2017 ; Zelante et al, 2021 ), Toxoplasma gondii ( Majumdar et al, 2019 ; Abo-Al-Ela, 2020 ), SARS-CoV-2 (COVID-19) ( Heer et al, 2020 ; Martorana et al, 2020 ; Thomas et al, 2020 ), and HIV ( Bipath et al, 2015 ; Kardashian et al, 2019 ). Aberrations of NAD + and KYN metabolites homeostasis are observed during infections, which may play a role in the modulation of host’s immune response and inflammatory signaling.…”