The hallmark of the human oral and gastrointestinal microbiome is species diversity. Dysregulation can occur via either poor health or hygiene habits as well as inadequate nutrition. More recently, it has become apparent that changes in the microflora of the mouth and large intestine can be a major contributory factor in diseases of other organ systems of the body. Poorly managed periodontal disease is now linked to an uptick in several autoimmune conditions, cardiovascular illness, and tumors. Patients with inflammatory bowel disease conditions can also reduce their incidence of disease flares by modulating their microbiome through diet and probiotic intake. Given the important impact that the oral and intestinal flora have on these very common chronic inflammatory syndromes, this chapter will examine the mechanisms involved in health and dysregulation of their homeostatic mechanisms. The diseases in which human microbiome dysregulation plays an important role will also be discussed with reference to their pathophysiology and progression of symptoms.