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Scope Little is known about the changes that a very-low-calorie ketogenic diet (VLCKD) produces in gut microbiota or the effect of synbiotics during the diet. The aim of this study is to evaluate changes in gut microbiota produced by a VLCKD and synbiotic supplementation. Methods and results A randomized, single-blind, parallel-design trial is conducted in 33 obese patients who follow a weight-loss program (PnK-Method) that include a VLCKD followed by a low-calorie diet (LCD). Subjects are randomly allocated to three groups: one supplemented with synbiotics, a second group supplemented with a placebo during the VLCKD and synbiotics during the LCD phase, and a control group given a placebo. Although symbiotic administration do not produce an effect on microbial diversity, an increase in short-chain fatty aciding producing bacteria and anti-inflammatory mediator signals such as Odoribacter and Lachnospira is shown. The administration of Bifidobacterium animalis subsp. lactis and prebiotics fiber during the LCD is significantly associated with the percentage of weight loss and change in glucose, C-reactive protein and lipopolysaccharide-binding protein. Conclusions VLCKD produces important changes in gut microbiota. The administration of synbiotics during VLCKD can improve weight loss through the amelioration of inflammation, which may be mediated by the gut microbiota.