<p>Both conventional and next-generation probiotics play a crucial role in maintaining host homeostasis. They modulate insulin sensitivity, immune-regulation, lipid metabolism, and trimethylamine synthesis. In recent years, probiotics have emerged as an effective and safe alternative to antibiotics for treating chronic life-style disorders via gut-organ-axis. Accounting for that, they contributed a market size of 71.2&#xa0;billion USD in the year 2024. However, effective consortia that can completely address all the symptoms of a particular disease are still lacking. Further, natural probiotics also face the issues of low survival rate and transfer of antibiotic resistance genes. Thus, postbiotics, which act as the ultimate mediators of gut-organ-axis have gained recognition over probiotics. They bind with multiple receptors present in host organs and modulate their functioning. This suggests the multilayer-multichannel axis between postbiotics and host vital organs. However, postbiotics cannot colonize the gut, and dosage and time also need optimization. Hence, engineered probiotics are being developed for efficient self-regulatory release of postbiotics at the target site. There are a few reviews on the topic of probiotics and lifestyle diseases; however, there is an urgent need for a critical appraisal synchronous with the fast-evolving technology, including omics and artificial intelligence. Thus, our article discusses advancements in technology to address the shortcomings of probiotics and postbiotics using genome editing, machine learning, and functional genomics techniques. It also covers the detailed application of artificial intelligence in probiotic consortia formulation, disease diagnosis, novel postbiotics detection, genetically engineered probiotics, and personalized therapies.</p> Graphical Abstract <p></p>