A Novel Combination of Probiotic Supplements Reduces Gut Permeability, Oxidative Stress, and Inflammation in Undernourished Adults: A Randomized Controlled Trial

ABSTRACT Undernutrition is associated with intestinal barrier dysfunction, oxidative stress, and systemic inflammation. This randomized controlled trial investigated the effects of an 8‐week multi‐strain probiotic supplementation combined with an energy‐surplus diet in underweight adults. In this double‐blind, placebo‐controlled trial (IRCT20230310057667N1), 100 underweight adults (BMI < 18.5 kg/m 2 , aged 18–60 years) were randomized (1:1) using sex‐stratified block randomization (block size 4) to receive either two daily probiotic capsules ( Lactobacillus acidophilus LA5 10 9 CFU, Lactobacillus rhamnosus GG 10 9 CFU, Lactobacillus casei 10 9 CFU) plus a 500 kcal/day energy‐surplus diet, or identical placebo plus the same diet. Primary outcome was change in serum zonulin concentration. Secondary outcomes included markers of oxidative stress and inflammation. Per‐protocol analysis was conducted on 95 participants who completed the study. Serum zonulin concentration decreased by a mean of 0.98 ± 1.61 ng/mL in the probiotic group versus 0.22 ± 1.12 ng/mL in the placebo group ( p = 0.047). Median changes in secondary outcomes (probiotic versus placebo) were as follows: total antioxidant capacity +0.40 versus −0.01 mmol/L, total oxidant status −4.22 versus +0.79 μmol/L, glutathione peroxidase +4.0 versus −0.8 nmol/mL, malondialdehyde −0.046 versus +0.006 nmol/mL, C‐reactive protein −0.50 versus +0.10 mg/L, and 1‐h erythrocyte sedimentation rate −1 versus +1 mm/h. The between‐group differences were statistically significant for all outcomes ( p < 0.001 for secondary outcomes; p = 0.047 for serum zonulin). Multi‐strain probiotic supplementation combined with a weight‐gain diet significantly improves gut barrier integrity, reduces oxidative stress and attenuates systemic inflammation in undernourished adults, offering a promising adjunctive nutritional intervention.