Supporting Digestion & The Breakdown of Exogenous Histamine | Diamine Oxidase

Supporting Digestion and The Breakdown of Exogenous Histamine: Overview

In this article, we discuss histamine, focusing on how exogenous histamine is broken down within the gastrointestinal tract during digestion. Furthermore, we detail how diamine oxidase—a copper-dependent enzyme that aids in metabolizing biogenic amines, such as histamine—is produced, as well as potential symptoms of insufficient diamine oxidase production by small intestinal enterocytes. We will finish the conversation by going through histamine intolerance and an absolutely phenomenal tool to support digestion and the breakdown of this biogenic amine.

Histamine | A Biogenic Amine

Histamine is a biologically active biogenic amine. Expanding upon this notion, biogenic amines are nitrogen-containing organic molecules, typically formed through the enzymatic decarboxylation of amino acids or their derivatives; furthermore, enzymatic decarboxylation is a process in which specialized enzymes remove a carboxyl group (–COOH). Narrowing focus to histamine, specifically: histamine is synthesized through the action of the enzyme histidine decarboxylase (HDC) on the amino acid L-histidine, producing a low-molecular-weight, nitrogen-containing compound with the chemical formula C₅H₉N₃.

Within the body, histamine can arise from both endogenous biosynthesis and exogenous exposure. In the case of endogenous production, histamine can be produced within several regions of the body by cells that express the enzyme histidine decarboxylase (HDC). Key histamine-producing cell types include mast cells and basophils (types of immune cells), enterochromaffin-like (ECL) cells in the gastric mucosa (detailed further below), histaminergic neurons in the central nervous system, and more. Once released, histamine may exert local or systemic effects via interactions with H₁–H₄ receptors.

In the stomach, specialized cells in the gastric lining called enterochromaffin-like (ECL) cells can produce and store histamine. These cells are located in close proximity to specialized cells called parietal cells, which produce hydrochloric acid (HCl) and respond to histamine signaling through the H₂ receptors expressed on their surface. As a result, histamine can be regarded as playing a key physiological role in supporting gastric acid secretion, and it may be further noted that this process is tightly regulated through local cell-to-cell communication, known as paracrine signaling.

In the case of exogenous exposure, histamine can be obtained through dietary sources, such as through aged, fermented, or possibly improperly stored foods—resulting from microbial decarboxylation of histidine by bacteria through histidine decarboxylase activity (Histidine decarboxylase is the enzyme that catalyzes the conversion of L-histidine into histamine.). Furthermore, bacterial production of histamine may also occur within the gut lumen and can be relevant in the context of intestinal dysbiosis, which will be detailed more fully below.

Intestinal Barrier Anatomy and Diamine Oxidase

The intestinal barrier serves as a dynamic and selective interface separating the intestinal lumen—the inner space that houses digestive enzymes, dietary components, microbes, and microbial metabolites—from the systemic environment of the body. Structurally, the intestinal wall is composed of several layers, beginning with the mucosa. The mucosa consists of three key sublayers: the epithelium, the lamina propria, and the muscularis mucosae. Furthermore, the mucosa is covered by a superficial mucus layer, a layer which aids in limiting microbial contact with the epithelial surface and which is thinner and more penetrable in the small intestines than in the colon.

Just beneath this layer of protective mucus lies the intestinal epithelium, composed of a monolayer of epithelial cells including enterocytes, the main absorptive cells. Enterocytes are joined by specialized secretory and immune-modulating cell types including goblet cells, enteroendocrine cells, Paneth cells, and more. Moreover, these epithelial cells are interconnected by tight junctions, composed of proteins including claudins and occludin which are anchored by cytoplasmic scaffolds such as zonula occludens-1 (ZO-1), and these tight junctions aid in restricting paracellular transport of substances, preserving the gut's semipermeable nature and barrier integrity. It may also be noted that the epithelium undergoes continuous renewal, and any disruption to the epithelium, whether through inflammation, oxidative stress, or infection, can compromise barrier function, leading to increased intestinal permeability.

Diamine oxidase (DAO), a copper-dependent enzyme encoded by the AOC1 gene, plays a central role in metabolizing biogenic amines, such as histamine. Furthermore, diamine oxidase (DAO) is most highly expressed in the small intestine (such as by mature enterocytes), followed by notable expression in the ascending colon, placenta, kidneys, and more.

Digestion and DAO

Diamine oxidase (DAO) plays a critical role in regulating luminal histamine levels during digestion. As histamine is introduced into the gastrointestinal (GI) tract from dietary sources as well as from local production by intestinal microbes, its concentration is carefully controlled through enzymatic activity in order to prevent accumulation, excess stimulation of histamine receptors, and possible subsequent pathological effects. DAO is the primary enzyme responsible for the oxidative deamination, a biochemical reaction in which an amine group (–NH₂) is removed from an organic molecule, of extracellular histamine in the small intestine. As noted previously, DAO is largely produced by mature enterocytes, and once synthesized, it can catalyze the conversion of histamine into imidazole acetaldehyde, hydrogen peroxide (H₂O₂), and ammonia.

The proper functioning of histamine degradation pathways plays a key role in preventing its accumulation, and the enzymatic clearance of histamine at the level of the intestinal mucosa is particularly crucial; as histamine, if absorbed unchecked, may contribute to harmful subsequent effects and/or manifestations within the body. In more detail, when DAO activity is insufficient or overwhelmed, unmetabolized histamine may enter systemic circulation, bypassing intestinal degradation and possibly triggering receptor-mediated effects throughout the body. Moreover, histamine intolerance (HIT) is the name given to this non-immunologic condition characterized by an imbalance between accumulated histamine—such as that which can be derived from high-histamine foods or microbial metabolism—and the body's ability to degrade it, primarily via the enzyme diamine oxidase (DAO). Thus, it can be noted that histamine intolerance is distinct from allergy, the latter of which can be characterized by IgE-mediated immune activation. Symptoms of histamine intolerance may include headaches, gastrointestinal motility disruption, hypotension, flushing, and more. Likewise, manifestations of histamine intolerance may encompass a wide range of nonspecific gastrointestinal and extraintestinal symptoms, attributable to the distribution of the four histamine receptors (H₁–H₄) across various organs and tissues throughout the body.

As noted above, diamine oxidase (DAO) deficiency can impact the body’s ability to degrade histamine; more narrowly, insufficient diamine oxidase production in the intestines may impact the body's ability to break down exogenous histamine, such as that which is derived from dietary sources as well as from the intestinal microbiota. This may arise from a variety of factors, including those which can be genetic as well as acquired. Genetically, single nucleotide polymorphisms (SNPs) in the AOC1 gene, for instance—which encodes DAO—can potentially have an impact upon enzyme expression or activity. In addition, damage to small intestinal enterocytes or underlying gastrointestinal disorders, as well as an array of other factors which may be examined, can potentially impact DAO production and play a role in its availability.

Supporting the Breakdown of Exogenous Histamine with DAO

A diamine oxidase (DAO) supplement can be an exceptional tool to aid in breaking down dietary histamine, particularly in individuals with reduced endogenous DAO activity. Additionally, Histamine Degrading Units (HDU) are standardized units used to quantify the enzymatic activity of diamine oxidase (DAO). In more detail, HDU reflects how much histamine a given amount of DAO can break down within a set timeframe under defined conditions, aiding in characterizing the enzyme’s activity and biological effectiveness.

OmneDiem®

OmneDiem® has a phenomenal line of diamine oxidase supplements offering exceptional support for breaking down histamine within the gut. They have demonstrated exceptional innovation and scientific rigor in the extraction and stabilization of their DAO supplements, focusing meticulous attention on enzyme preservation, reflected by their exceptional enzymatic potency and levels of Histamine Digesting Units. OmneDiem®'s Histamine Digest® and Histamine Digest® PureMAX supplements contain 30,000 and 40,000 HDU, respectively; and their natural-source DAO is delivered in capsules designed to release the enzyme specifically in the small intestines. This targeted release mechanism allows the enzyme to act at the critical site of absorption, supporting digestive comfort and aiding in reducing the histamine burden.

In addition to OmneDiem®'s Histamine Digest® and Histamine Digest® PureMAX, OmneDiem® has a remarkable line of supplements utilizing DAO combined with a phenomenal array of supportive compounds including polyphenols, vitamins, and more. Their Histamine Digest® Histamine Complete contains DAO combined with Vitamin C, Quercetin, Bromelain, and Stinging Nettle Root Extract; and it is a truly remarkable blend for supporting the breakdown of histamine in the gastrointestinal tract derived from exogenous sources as well as supporting the regulation of histamine released through mast cell degranulation.

A true embodiment of exceptional digestive support, seamlessly blending science, unparalleled enzyme preservation, and an unwavering commitment to research: OmneDiem® undoubtedly sets the standard in supporting those with Histamine Intolerance.

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