The stunning complexity of the resident microbiota and the intricate pathways of microbial and host interactions provide a massive adaptive capacity for mammals. In this addendum we reflect on our recent publication on Toll-like receptor 2 deficiency related colonic mucosal epigenetic, immunologic and microbiomic changes. Our findings underscored the tremendous flexibility of the gut and its microbiota. This flexibility can provide means to overcome significant environmental or genetic challenges. In the meantime, the challenged intestinal system may become vulnerable to otherwise tolerable insults. In such instances, the fine-tuned mutualistic balance between the gut and its microflora may collapse leading to dysbiosis and disease. The ultimate challenge for biomedical research in these cases is to find optimal means for the restoration and maintenance of healthy host physiology.