<p>Why targeting the microbiome is not so successful: can randomness overcome the adaptation that occurs following gut manipulation?</p>

The microbiome is explored as a potential target for therapy of bowel and systemic diseases. Fecal microbiota transplantation (FMT) has demonstrated efficacy in Clostridium difficile infection. However, clinical results regarding other diseases are modest, despite the abundant research on the microbiome over the last decade. Both high rate variability of the microbiome and adaptation to gut manipulations may underlie the lack of ultimate effects of FMT, probiotics, prebiotics, synbiotics, and antibiotics, which are aimed at restoring a healthier microbiome. The present review discusses the inherent variability of the microbiome and multiple factors that affect its diversity, as possible causes of the adaptation of the gut microbiome to chronic manipulation. The potential use of randomness is proposed, as a means of overcoming the adaptation and of restoring some of the inherent variability, with the goal of improving the long-term efficacy of these therapies.