Background: The aim of the study was to investigate the association between human immunodeficiency virus (HIV)-related gut microbiota changes, alterations in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism, and visceral adipose tissue in the context of HIV infection. Methods: Three hundred eighty-Three people with HIV (PWH) were included from the Copenhagen comorbidity in HIV infection (COCOMO) study. Gut microbiota composition was analyzed by 16S ribosomal ribonucleic acid sequencing. Plasma metabolites were analyzed by liquid chromatography-Tandem mass spectrometry. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by single-slice computed tomography (CT) scan (4th lumbar vertebra). Results: The HIV-related gut microbiota alterations were associated with lower Trp (β-.01; 95% confidence interval [CI],-0.03 to-0.00) and higher Kyn-To-Trp ratio (β 0.03; 95% CI, 0.01-0.05), which in turn was associated with higher VAT-To-SAT ratio (β 0.50; 95% CI, 0.10-0.90) and larger VAT area (β 30.85; 95% CI, 4.43-57.28). In mediation analysis, the Kyn-To-Trp ratio mediated 10% (P =. 023) of the association between the VAT-To-SAT ratio and HIV-related gut microbiota. Conclusions: Our data suggest HIV-related gut microbiota compositional changes and gut microbial translocation as potential drivers of high Kyn-To-Trp ratio in PWH. In turn, increased activity in the Kyn pathway of Trp metabolism was associated with larger visceral adipose tissue area. Taken together, our findings suggest a possible role for this pathway in the gut-Adipose tissue axis in the context of HIV infection.