Gastrointestinal symptoms are prevalent extrapulmonary systemic manifestations of Chronic Obstructive Pulmonary Disease (COPD), but have been rarely studied. We dissected the perturbations in intestinal function in human patients with COPD using comprehensive metabolic and physiological approaches. In this observational study, small intestinal membrane integrity and active carrier-mediated glucose transport were quantified by sugar permeability test in 21 clinically stable patients with moderate to severe COPD (mean FEV1, 41.2 (3.2) % of predicted) and 16 healthy control subjects. Protein digestion and absorption was analyzed using stable tracer kinetic methods. Plasma acetate, propionate, and butyrate concentrations were measured as markers of intestinal microbial metabolism. Compared with healthy controls, non carrier-mediated permeability was higher (0.062 (95% CI 0.046, 0.078) vs. 0.037 (95% CI 0.029, 0.045), P = 0.009) and active glucose transport lower in COPD (31.4 (95% CI 23.4, 39.4)% vs. 48.0 (95% CI 37.8, 58.3)%, P = 0.010). Protein digestion and absorption was lower in COPD (0.647 (95% CI 0.588, 0.705) vs. 0.823 (95% CI 0.737, 0.909), P = 0007), and impairment greater in patients with dyspnea (P = 0.038), exacerbations in preceding year (P = 0.052), and reduced transcutaneous oxygen saturation (P = 0.051), and was associated with reduced physical activity score (P = 0.016) and lower quality of life (P = 0.0007). Plasma acetate concentration was reduced in COPD (41.54 (95% CI 35.17, 47.91) vs. 80.44 (95% CI 54.59, 106.30) μmol/L, P = 0.001) suggesting perturbed intestinal microbial metabolism. We conclude that intestinal dysfunction is present in COPD, worsens with increasing disease severity, and is associated with reduced quality of life.