  Citation: Park, D.-Y.; Park, J.Y.; Lee, D.; Hwang, I.; Kim, H.-S. Leaky Gum: The Revisited Origin of Systemic Diseases. Cells 2022, 11, 1079. https://doi.org/10.3390/ cells11071079 Academic Editor: Özlem Yilmaz Received: 17 February 2022 Accepted: 22 March 2022 Published: 23 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Review Leaky Gum: The Revisited Origin of Systemic Diseases Do-Young Park 1 , Jin Young Park 2 , Dahye Lee 3,4 , Inseong Hwang 1, * and Hye-Sung Kim 3,4, * 1 DOCSmedi Co., Ltd., 4F, 143, Gangseong-ro, Ilsanseo-gu, Goyang-si 10387, Korea; pdy@docsmedi.kr 2 Department of Gastrointestinal Endoscopy, Apple Tree Healthcare Center, 1450, Jungang-ro, Ilsanseo-gu, Goyang-si 10387, Korea; baadaak@appleden.com 3 Department of Orthodontics, Apple Tree Dental Hospital, 1450, Jungang-ro, Ilsanseo-gu, Goyang-si 10387, Korea; drdahaelee@appleden.com 4 Apple Tree Institute of Biomedical Science, Apple Tree Medical Foundation, 1450, Jungang-ro, Ilsanseo-gu, Goyang-si 10387, Korea * Correspondence: his@docsmedi.kr (I.H.); hyesungk2008@appleden.com (H.-S.K.) Abstract: The oral cavity is the gateway for microorganisms into your body where they disseminate not only to the directly connected respiratory and digestive tracts but also to the many remote organs. Oral microbiota, travelling to the end of the intestine and circulating in our bodies through blood vessels, not only affect a gut microbiome profile but also lead to many systemic diseases. By gathering information accumulated from the era of focal infection theory to the age of revolution in microbiome research, we propose a pivotal role of “leaky gum”, as an analogy of “leaky gut”, to underscore the importance of the oral cavity in systemic health. The oral cavity has unique structures, the gingival sulcus (GS) and the junctional epithelium (JE) below the GS, which are rarely found anywhere else in our body. The JE is attached to the tooth enamel and cementum by hemidesmosome (HD), which is structurally weaker than desmosome and is, thus, vulnerable to microbial infiltration. In the GS, microbial biofilms can build up for life, unlike the biofilms on the skin and intestinal mucosa that fall off by the natural process. Thus, we emphasize that the GS and the JE are the weakest leaky point for microbes to invade the human body, making the leaky gum just as important as, or even more important than, the leaky gut. Keywords: biofilm; gingival sulcus; junctional epithelium; leaky gum; leaky gut; mucosal barrier; oral microbiome; systemic disease 1. Introduction Humans internalize the microbiota of this planet through the oral cavity, either tem- porarily or permanently. The oral cavity harbours the second most abundant microorgan- isms after the gastrointestinal (GI) tract in a variety of distinct habitats, such as teeth, tongue, gingival sulcus (GS), palate, saliva, buccal mucosa, and throat. The expanded Human Oral Microbiome Database (eHOMD v3, http://homd.org, accessed on 16 February 2022) established during the Human Microbiome Project enlists at least 774 microbial species to date. As the old dogma that the lungs and placenta are sterile becomes obsolete [1–5], the oral microbiota has proven to be the primary source of the bacterial microbiota in human organs [6]. For one, microaspiration during respiratory activity, such as oral breathing, affects the lung microbiota [7]. In addition, dietary patterns dynamically affect the microbiome profile of the GI tract either by microbial contamination or by supplying specific nutrients for microbial commensals, even manipulating the pathophysiology of cancerous diseases [8,9] as well as regulating immune responses across the gut–brain axis [10,11]. As such, along with the revolution of human microbiome research, much effort has been dedicated to figuring out the relationship between the oral and gut microbiota, which has been dubbed the “oral–gut–brain axis” [12–17]. Cells 2022, 11, 1079. https://doi.org/10.3390/cells11071079 https://www.mdpi.com/journal/cells