Histamine, Digestion, Bloating, and the Connection to SIBO/IMO

Histamine intolerance (HIT) can be associated with various gastrointestinal symptoms, particularly abdominal pain or cramps, bloating, a feeling of fullness, diarrhea, and other digestive problems.¹˒²

Histamine acts through histamine receptors that are also present in the digestive tract. In the human intestine, H1, H2, and H4 receptors in particular have been identified, and histamine signaling is involved, among other functions, in the regulation of secretion and intestinal motility.³

In sensitive individuals, histamine may therefore contribute to digestive disturbances, abdominal pain, or changes in bowel movements. A markedly bloated or enlarged abdomen does not necessarily indicate an increase in body fat – gas, intestinal contents, and distension of the digestive tract can all contribute to an increase in abdominal volume.⁸

Histamine and the Gut Microbiota

The relationship between histamine and the gut microbiota is complex. Some intestinal bacteria possess the enzyme histidine decarboxylase, which enables them to convert the amino acid histidine into histamine. In people with symptoms of histamine intolerance, differences in the composition of the gut microbiota and a higher abundance of certain histamine-producing bacteria have been reported.⁴

From the perspective of the intestinal epithelium and the DAO enzyme, it is not decisive whether histamine comes from food or is produced by the gut microbiota. In both cases, it is the same histamine molecule present in the intestinal lumen. What matters most is the overall histamine load and whether sufficient DAO activity is available to continuously break it down.⁵

DAO present in the intestinal mucosa therefore represents an important metabolic barrier against exogenous histamine. If the amount of histamine exceeds the body's capacity to degrade it, more histamine may become available to exert effects in the intestine and subsequently be absorbed.⁵

Histamine Intolerance and SIBO

SIBO (Small Intestinal Bacterial Overgrowth) is a condition characterized by an excessive amount of bacteria in the small intestine associated with gastrointestinal symptoms. Typical symptoms include bloating, gas, abdominal pain or discomfort, diarrhea, and other changes in bowel movements.⁶

The symptoms of SIBO can therefore overlap considerably with symptoms attributed to histamine intolerance. A direct causal relationship between SIBO and HIT has not yet been sufficiently established. However, several biological mechanisms may connect the two conditions.

One of these is the production of histamine by certain intestinal bacteria.

In patients with symptoms of HIT, a significantly higher abundance of several histamine-producing microorganisms has been reported, including members of the genera Staphylococcus and Proteus, certain Enterobacteriaceae, Clostridium perfringens, and Enterococcus faecalis.⁴

Under certain conditions, SIBO may also be associated with damage to the small intestinal mucosa and impairment of its functions.⁹ This is relevant from the perspective of histamine metabolism because DAO is highly expressed in the intestinal epithelium, and intestinal DAO represents one of the main mechanisms for the degradation of exogenous histamine.⁵˒⁹

In some patients, several factors may therefore occur simultaneously:

• a higher histamine load from food,

• histamine production by intestinal microorganisms,

• changes in the gut microbiota,

• and insufficient intestinal DAO capacity to degrade the resulting amount of histamine.

In this situation, it may make sense to support histamine degradation with exogenous DAO alongside measures addressing SIBO itself.⁵˒¹⁰

DAO does not treat bacterial overgrowth. It acts on a different, parallel mechanism – the amount of histamine present in the gastrointestinal tract.

What About IMO?

With IMO (Intestinal Methanogen Overgrowth), the situation is different. Methane is produced by methanogenic archaea, not bacteria, and IMO is therefore not a classic form of bacterial SIBO.⁶˒⁷

Methanogenic archaea in the gut use products of bacterial fermentation, particularly hydrogen. Increased methane production is significantly associated with slower intestinal transit and constipation. A systematic review and meta-analysis of 19 studies involving 1,293 patients with IMO found bloating in 78%, abdominal pain in 65%, excessive gas in 56%, and constipation in 51% of patients.⁷

However, the presence of IMO does not automatically mean that histamine production is increased. IMO and an increased histamine load can coexist as two separate mechanisms.

If a person with IMO also experiences symptoms associated with histamine, it may therefore make sense to address both components in parallel:

1. IMO and its underlying cause – particularly methanogen overgrowth and impaired motility,

2. histamine load – through dietary measures and, where appropriate, DAO supplementation.

DAO does not affect methane production or the amount of archaea, but it may support the breakdown of histamine present in the gut.⁵

What About DAO in SIBO or IMO?

DAO is an enzyme found primarily in the intestinal mucosa and is involved in breaking down histamine before it is systemically absorbed.¹˒⁵

From the perspective of DAO, it is not decisive whether histamine present in the gut comes from food or is produced by the microbiota. What matters is the resulting amount of histamine and whether sufficient enzyme activity is available to continuously degrade it.⁵

Clinical data are also available for oral DAO supplementation. In an open-label intervention study involving 28 patients with histamine intolerance, taking DAO before meals for four weeks resulted in a significant reduction in the symptoms assessed. Gastrointestinal symptoms evaluated included bloating, postprandial fullness, abdominal pain and cramps, diarrhea, constipation, and belching. After DAO supplementation was discontinued, the overall symptom score increased again.¹⁰

It is important to emphasize, however, that this study was conducted in patients with HIT and not specifically in patients with SIBO or IMO. Based on the mechanism of action, DAO may therefore be considered as complementary support alongside measures targeting SIBO or IMO itself in people with SIBO or IMO who also experience symptoms consistent with an increased histamine load.

In practice, two approaches can therefore be pursued in parallel:

1. Addressing SIBO/IMO– microbial or methanogen overgrowth, motility, and other underlying causes

2. Reducing the histamine load– dietary adjustments and, where appropriate, DAO supplementation before meals

These approaches do not compete with each other because they target different mechanisms.

Why Might milDAO Be Particularly Suitable for SIBO/IMO?

milDAO contains DAO derived from pea sprouts. Pea sprouts have been described in the scientific literature as a natural source of DAO with histamine-degrading activity. In a laboratory study, lyophilized pea sprouts showed the highest histamine-degrading activity among the food sources tested.¹¹

According to the currently declared composition of milDAO, one tablet contains only 1.5 mg of plant protein and 3.5 μg of DAO, with a manufacturer-declared activity of at least 1,000,000 HDU per tablet.¹²

This may be practically relevant for people with sensitive digestion. Although the enzyme is derived from peas, 1.5 mg of protein represents a very small amount of plant material. In terms of fermentable load, one tablet therefore cannot be compared with consuming a typical serving of peas or pea sprouts.¹²

For comparison, the U.S. Dietary Supplement Label Database lists 32.1 mg of plant protein from lentils and peas per tablet for NaturDAO 1,000,000 HDU.¹³

However, the amount of protein alone is not a direct measure of efficacy. Enzyme activity and the method used to determine that activity are the key factors.

For people with SIBO or IMO who also experience histamine-related symptoms, milDAO may therefore be considered as complementary support for histamine degradation, particularly before meals where a higher histamine load is expected.

However, milDAO does not replace the treatment of SIBO or IMO. Its role is to support the enzymatic breakdown of histamine, while the underlying cause of SIBO or IMO needs to be addressed separately.

It is equally important to note that there is currently no direct clinical study of milDAO specifically in patients with SIBO or IMO.

The rationale is therefore based on the physiological role of DAO, the available clinical data on oral DAO supplementation, the experimentally demonstrated histamine-degrading activity of DAO from pea sprouts, and the composition of the product.⁵˒¹⁰˒¹¹˒¹²

Histamine, DAO, the gut microbiota, and intestinal motility can therefore be closely interconnected, but they do not represent a single mechanism.

From the perspective of the intestinal epithelium, the main question is not whether histamine comes from food or from the microbiota. What matters is the total amount of histamine and the ability of the available DAO to break it down sufficiently quickly.

---

Scientific References

1. Maintz L, Novak N.Histamine and histamine intolerance.American Journal of Clinical Nutrition. 2007;85(5):1185–1196.DOI: 10.1093/ajcn/85.5.1185PubMed

2. Schnedl WJ, Lackner S, Enko D, et al.Evaluation of symptoms and symptom combinations in histamine intolerance.Intestinal Research. 2019;17(3):427–433.DOI: 10.5217/ir.2018.00152PubMed | Full text – PMC

3. Sander LE, Lorentz A, Sellge G, et al.Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract.Gut. 2006;55(4):498–504.DOI: 10.1136/gut.2004.061762PubMed | Full text – PMC

4. Sánchez-Pérez S, Comas-Basté O, Duelo A, et al.Intestinal Dysbiosis in Patients with Histamine Intolerance.Nutrients. 2022;14(9):1774.DOI: 10.3390/nu14091774PubMed | Full text – PMC

The study reported a significantly higher abundance of several histamine-producing bacteria in patients with symptoms of HIT.

5. Comas-Basté O, Sánchez-Pérez S, Veciana-Nogués MT, Latorre-Moratalla ML, Vidal-Carou MC.Histamine Intolerance: The Current State of the Art.Biomolecules. 2020;10(8):1181.DOI: 10.3390/biom10081181PubMed | Full text – PMC

This review summarizes the key role of intestinal DAO in the degradation of ingested histamine.

6. Pimentel M, Saad RJ, Long MD, Rao SSC.ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth.American Journal of Gastroenterology. 2020;115(2):165–178.DOI: 10.14309/ajg.0000000000000501PubMed

The ACG defines SIBO as an excessive amount of bacteria in the small intestine associated with gastrointestinal symptoms.

7. Mehravar S, Takakura W, Wang J, et al.Symptom Profile of Patients With Intestinal Methanogen Overgrowth: A Systematic Review and Meta-analysis.Clinical Gastroenterology and Hepatology. 2025;23(7):1111–1122.e9.DOI: 10.1016/j.cgh.2024.07.020PubMed | Full text – journal

The meta-analysis included 19 studies, 1,293 patients with IMO, and 3,208 controls. Constipation was more common and more severe in patients with IMO.

8. Moshiree B, Drossman D, Shaukat A.AGA Clinical Practice Update on Evaluation and Management of Belching, Abdominal Bloating, and Distention: Expert Review.Gastroenterology. 2023;165(3):791–800.PubMed

9. Bushyhead D, Quigley EMM.Small Intestinal Bacterial Overgrowth—Pathophysiology and Its Implications for Definition and Management.Gastroenterology. 2022;163(3):593–607.DOI: 10.1053/j.gastro.2022.04.002PubMed | Full text – journal

This review describes the pathophysiology of SIBO, including colonization of the small intestine by potentially harmful microbiota.

10. Schnedl WJ, Schenk M, Lackner S, et al.Diamine oxidase supplementation improves symptoms in patients with histamine intolerance.Food Science and Biotechnology. 2019;28(6):1779–1784.DOI: 10.1007/s10068-019-00627-3PubMed | Full text – PMC

In this four-week open-label pilot study, the overall symptom score decreased significantly during DAO supplementation. Gastrointestinal symptoms assessed included bloating, postprandial fullness, abdominal pain, diarrhea, and other symptoms. The study included only 28 patients and was partly associated with the manufacturer of the DAO preparation used. The findings should therefore be interpreted as supportive rather than definitive clinical evidence.

11. Comas-Basté O, Latorre-Moratalla ML, Sánchez-Pérez S, et al.In vitro determination of diamine oxidase activity in food matrices by an enzymatic assay coupled to UHPLC-FL.Analytical and Bioanalytical Chemistry. 2019.PubMed

The study found high histamine-degrading DAO activity in lyophilized pea sprouts; among the sources tested, they showed the highest activity.

Supplementary paper:Comas-Basté O, Latorre-Moratalla ML, Rabell-González J, et al.Lyophilised legume sprouts as a functional ingredient for diamine oxidase enzyme supplementation in histamine intolerance.LWT – Food Science and Technology. 2020;125:109201.DOI: 10.1016/j.lwt.2020.109201Full text – University of Barcelona repository

12. milDAO – manufacturer-declared composition.

According to the current product declaration: 1.5 mg plant protein, 3.5 μg DAO, and at least 1,000,000 HDU per tablet.

Product information – milDAO

These are manufacturer-declared product specifications, not results from an independent clinical study.

13. NIH Dietary Supplement Label Database – NaturDAO 1,000,000 HDU.

The label recorded in the database lists 32.1 mg of plant protein from Lens culinaris and Pisum sativum.

NIH Dietary Supplement Label Database

This is a database of declared product-label information, not a clinical comparison between milDAO and NaturDAO.