Imbalances in gut bacteria have been associated with multiple diseases. However, whether there are disease-specific changes in gut microbial metabolism remains unknown. Here, we demonstrate that human immunodeficiency virus (HIV) infection (n = 33) changes, at quantifiable levels, the metabolism of gut bacteria. These changes are different than those observed in patients with the auto-immune disease systemic lupus erythaematosus (n = 18), and Clostridium difficile-associated diarrhoea (n = 6). Using healthy controls as a baseline (n = 16), we demonstrate that a trend in the nature and directionality of the metabolic changes exists according to the type of the disease. The impact on the gut microbial activity, and thus the metabolite composition and metabolic flux of gut microbes, is therefore disease-dependent. Our data further provide experimental evidence that HIV infection drastically changed the microbial community, and the species responsible for the metabolism of 4 amino acids, in contrast to patients with the other two diseases and healthy controls. The identification in this present work of specific metabolic deficits in HIV-infected patients may define nutritional supplements to improve the health of these patients.