The gut that we took for granted in the critically ill, as just a conduit for food passage has over the decade or so shown us that it is an active endocrine and exocrine organ with over 40 trillion microorganisms living commensally within it. This cosmos of microorganisms that is called the gut microbiome comprises roughly 1,000 different species and put together is more DNA than the entire human genome. Under normal circumstances, in a healthy individual multiple elements of the gut viz intestinal epithelium, gut barrier function, the microbiomes, all put together offer protection against infection and this is crucial in maintenance of health. Any change to the norm, be it in the form of surgical interventions, the introduction of medications, or the pathophysiological effects of systemic disease leads to a 360° alteration in this finely construed ecosystem leading to devastating effects that go beyond the boundaries of the gut itself. Intestinal epithelium helps to absorb nutrients as well as acts as the coordinator of mucosal immunity (first line of immune defense). During ill health, gut epithelial apoptosis occurs, alterations happen in the tight epithelial junctions leading to loss of gut barrier function and loss of the mucosal immunity leading to mucosal damage and hyperpermeability. Lastly, the microbiome is transformed into a pathobiome, with resultant increase in pathogenic bacteria and induction of virulence in commensal gut bacteria. Multiple organ damage starts to set in, caused by toxins leaving the intestine via both portal blood flow and mesenteric lymph. This review article traces the gut microbiomic ecology in health and sickness, modern tools that are used to manipulate gut microbiome in the search for the prevention and treatment of critical illness and will explore if appropriate manipulation of gut microbiome can influence or modulate the course of critical illness.