Why Flore Cares About Histamine (and Screens Every Probiotic Strain for It)

By Craig Rouskey, MSc, Co-founder and CEO of Flore. Craig is a molecular medical microbiologist and immunologist who has spent years unpacking how the gut microbiota shapes the immune system.

Most people meet histamine through antihistamines: hay fever, hives, an itchy reaction to something they ate. In the lab, histamine looks very different. It is a messenger that immune cells, gut lining cells and nerves all listen to, and a meaningful share of it can come from the bacteria living in your gut. Once you see that, you can't look at a probiotic label the same way. Here is why histamine sits near the top of the list when we design a Flore formula.

What does histamine actually do in the body?

Histamine acts through four receptors, H1 through H4. They sit on immune cells, on the cells lining the gut, on smooth muscle and on nerves. Each receptor sends a different instruction:

• H1 drives the classic allergic picture: swelling, itch, flushing, airway tightening.
• H2 controls stomach acid, and on immune cells it often works as a brake on inflammation.
• H3 works mainly in the nervous system, adjusting how much histamine and other neurotransmitters nerves release.
• H4 sits mostly on immune cells and pulls them, including mast cells, toward a site. It also plays a part in itch and pain.

Researchers reviewing histamine's role in gut immunity point out that its net effect on inflammation in the gut is still poorly defined. The same molecule can protect or harm depending on where it lands (Smolinska et al., Allergy, 2014). For an immunologist, that is the key point. Histamine is a context-dependent signal, not simply a "bad" chemical, and context is exactly what a generic probiotic ignores.

Do gut bacteria really make histamine?

Yes. Bacteria make histamine with an enzyme called histidine decarboxylase, which strips a carbon group off the amino acid histidine. Two families of this enzyme exist. One is found in various Gram-negative bacteria. The other, encoded by a gene called hdcA, is found in Gram-positive bacteria, especially lactic acid bacteria, the group many probiotics come from (Landete et al., Crit Rev Food Sci Nutr, 2008). It is the main reason fermented foods such as aged cheese, wine and sauerkraut can carry high histamine loads.

Human studies now link histamine-producing gut bacteria to real conditions:

• Asthma: adults with asthma had more histamine-secreting microbes in their gut than people without asthma (Barcik et al., J Allergy Clin Immunol, 2016).
• IBS pain: in a subset of people with irritable bowel syndrome, gut bacteria produced large amounts of histamine. The researchers traced this to a strain of Klebsiella aerogenes that was more common in IBS patients across three separate groups of people. In germ-free mice given these patients' gut bacteria, the bacterial histamine drew mast cells into the colon through the H4 receptor and made the gut more sensitive to pain (De Palma et al., Sci Transl Med, 2022). That is a mouse finding for a subset of patients, not proof for everyone with IBS, but it shows the pathway is real.
• Histamine intolerance: people with histamine intolerance had a different gut microbiome from healthy controls, with more histamine-producing Enterobacteriaceae. Most of them also had low activity of DAO, the enzyme that breaks histamine down (Sánchez-Pérez et al., Nutrients, 2022). We go deeper on that link in Can Histamine Cause Anxiety?

If histamine can calm inflammation, why screen for it?

Because the calming effect depends on conditions you can't count on. The most-cited example is Lactobacillus reuteri. Researchers found that strains carrying the histamine-making gene cluster reduced TNF, a major inflammatory signal, by acting on the H2 receptor (Thomas et al., PLoS One, 2012). In a mouse model of colitis, only the gene-carrying strains reduced the inflammation. Even then, the effect depended on the mice eating histidine and having working H2 receptors (Gao et al., mBio, 2015).

That is a striking result, and it shows the problem. The same histamine that calms one pathway through H2 can act on H1 or H4 in someone else. How much histamine a person can tolerate also varies: it depends on their DAO activity, how reactive their mast cells are, what they ate, and how leaky their gut lining is. A finding that holds in a controlled mouse study does not make a histamine-producing strain safe for a person who flushes after a glass of wine.

So our rule is simple: we don't add histamine production to someone's gut by accident. If a person's results point toward a histamine problem, that is something to address on purpose, not something to make worse with a probiotic.

Why doesn't a probiotic label tell you this?

Because making histamine is a trait of the individual strain, not the species. Within the same species, one strain can carry the histamine genes and the next one may not. In some lactic acid bacteria the genes sit on plasmids, small loose pieces of DNA that a strain can gain or lose; in one Lactobacillus hilgardii strain the cluster was on an unstable 80-kb plasmid (Lucas et al., Appl Environ Microbiol, 2005). A label that just says "Lactobacillus", or even names the species, tells you nothing about histamine.

Very few probiotic labels disclose histamine production at all. High-dose, many-strain products multiply the uncertainty: every extra strain is one more you know nothing about. We cover that problem in When High CFU Backfires.

What does Flore actually do about histamine?

1. Every strain is screened. Before a probiotic strain can be used in a Flore formula, it is screened for its histamine-producing capability. A strain that would add to your histamine load doesn't make the cut.
2. Your formula starts from your own gut. Flore builds each formula from your microbiome test results, not from a one-size-fits-all blend. If your results and symptoms point toward histamine, which we describe as the Histamine-Leaning phenotype, strain selection takes that into account.
3. We treat histamine as an immune question. Histamine is never handled as a single number. It sits inside the bigger picture of how your microbiome talks to your immune system, which is the work Flore was built on.

Who should pay the most attention to histamine?

Histamine is worth discussing with your clinician if you notice any of these:

• flushing, headaches, hives or a racing heart after aged, fermented or leftover foods, or after wine
• bloating or abdominal pain that flares with those same foods
• allergies or asthma alongside gut symptoms
• a reaction to a probiotic or fermented-food routine that was supposed to help

For you, a probiotic that hasn't been screened for histamine production is a gamble.

This article is for education and is not medical advice. Flore probiotics are not intended to diagnose, treat, cure or prevent any disease. If your symptoms are persistent or severe, talk to a qualified healthcare provider.

Frequently asked questions

Can probiotics produce histamine?

Some can. Strains that carry histidine decarboxylase genes, including some lactic acid bacteria, can turn histidine into histamine. It varies from strain to strain, which is why Flore screens every strain it uses for histamine-producing capability.

Which gut bacteria make histamine?

Many kinds, including Gram-negative bacteria such as some Enterobacteriaceae (for example, certain Klebsiella and Proteus) and Gram-positive lactic acid bacteria that carry the hdcA gene. Higher levels of histamine-producing gut bacteria have been reported in asthma, in histamine intolerance and in a subset of IBS patients.

Are Flore probiotics screened for histamine?

Yes. Every probiotic strain Flore uses is screened for its histamine-producing capability before it goes into a formula. Each formula is then matched to the person's own microbiome results.

Can gut bacteria cause histamine intolerance?

Research links histamine intolerance to gut changes: more histamine-producing bacteria, low DAO activity and a leakier gut lining. That doesn't mean bacteria are the only cause, but it makes the gut a real part of the picture.

Sources

1. Smolinska S, Jutel M, Crameri R, O'Mahony L. Histamine and gut mucosal immune regulation. Allergy. 2014;69(3):273–281.
2. Landete JM, de las Rivas B, Marcobal A, Muñoz R. Updated molecular knowledge about histamine biosynthesis by bacteria. Crit Rev Food Sci Nutr. 2008;48(8):697–714. PMID 18756395.
3. Barcik W, Pugin B, Westermann P, et al. Histamine-secreting microbes are increased in the gut of adult asthma patients. J Allergy Clin Immunol. 2016;138(5):1491–1494.e7.
4. De Palma G, Shimbori C, Reed DE, et al. Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice. Sci Transl Med. 2022;14(655):eabj1895. doi:10.1126/scitranslmed.abj1895
5. Sánchez-Pérez S, et al. Intestinal dysbiosis in patients with histamine intolerance. Nutrients. 2022. PMC9102523
6. Thomas CM, Hong T, van Pijkeren JP, et al. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One. 2012;7(2):e31951. PMC3285189
7. Gao C, Major A, Rendon D, et al. Histamine H2 receptor-mediated suppression of intestinal inflammation by probiotic Lactobacillus reuteri. mBio. 2015;6(6):e01358-15. PMC4701830
8. Lucas PM, Wolken WAM, Claisse O, Lolkema JS, Lonvaud-Funel A. Histamine-producing pathway encoded on an unstable plasmid in Lactobacillus hilgardii 0006. Appl Environ Microbiol. 2005;71(3):1417–1424. PMC1065165