Histamine can be secreted by many bacteria, but the particular microbes responsible for histamine overproduction in the gut have remained a mystery – until now. Read on as I break down the findings from a long-awaited study that uncovers the role of bacterial histamine in irritable bowel syndrome, and the gut bacteria involved!
Histamine is a compound released by immune cells and involved in the local immune response. It is also a known mediator of pain.
In recent years, histamine has become increasingly implicated in irritable bowel syndrome (IBS). It is also thought that the various symptoms characteristic of “histamine intolerance” might be due to an overproduction of histamine in the gut, overwhelming the body’s ability to break down and metabolize histamine.
Now, a new study published in Science Translational Medicine suggests that bacterial histamine can induce abdominal pain in a subset of patients with IBS.1 Moreover, it identifies the bacterium Klebsiella aerogenes as the primary producer of gut histamine!
In this article, I break down these new findings and discuss the implications. First, some quick background to explain the motivation for this latest study.
Low FODMAP diets reduce urine histamine in patients with IBS
Low FODMAP diets have long been recognized for their ability to help mitigate symptoms in patients with IBS. However, the exact mechanism by which these carbohydrates worsen gut symptoms has been unclear.
In 2017, a group of researchers at McMaster University randomly assigned IBS patients to consume a low or high FODMAP diet.2 After the dietary intervention, they measured a variety of metabolites in the urine.
They found that about a third of the IBS patients had high urine histamine levels at baseline, and that urine histamine was 8 times lower after the low FODMAP diet.
Diet – microbiota interactions lead to increased gut sensitivity
Building on these findings in their most recent study, the researchers transplanted the gut microbiota from (1) an IBS patient with high urine histamine, (2) an IBS patient with low urine histamine, and (3) a healthy control subject into three separate groups of germ-free mice.
After a colonization period to allow the microbiotas to take hold in the mice, they further split each group of mice in two, to receive a low or high fermentable carbohydrate diet.
Lo and behold, only the group of mice colonized with the microbiota from the IBS patient with high urine histamine and fed the high fermentable carbohydrate diet had increased gut sensitivity!
Klebsiella aerogenes is the main histamine producer in patients with IBS
The researchers then went back to analyze the donor stool more closely. IBS patients with high urine histamine had a gut microbiome that produced significantly more histamine. They set out to determine which microbes might be responsible.
In total, they isolated 164 different gut microbes and tested their capacity to produce histamine. The authors reported that:
- In IBS patients with high urine histamine, Klebsiella aerogenes was the main histamine producer. In fact, aerogenes produced 100 times more histamine than any other bacterial isolate!
- In IBS patients and low urine histamine, Enterococcus faecium and Enterococcus faecalis were the primary producers of histamine.
Unfortunately, the paper did not include a complete list of the bacteria tested and their histamine-producing capacity. For instance, previous research has highlighted Morganella morganii as a potential producer of gut histamine,3,4 but there was no mention of this microbe in the results or discussion.
It’s also entirely possible that other histamine producers (perhaps those less easily cultured) may have been missed in the selection of microbes tested.
Nevertheless, K. aerogenes was highly abundant in three different cohorts of IBS patients and was reduced on a low FODMAP diet. Additionally, germ-free mice colonized with K. aerogenes produced 77 times more histamine than those colonized with another species of Klebsiella.
pH matters: Why the acidity of the colon is essential
So how does K. aerogenes produce histamine? It uses an enzyme called histamine decarboxylase, or hdc. The hdc enzyme converts histidine, an essential amino acid found in the diet, into histamine.
Since previous studies had found the activity of this enzyme to be affected by pH, the researchers decided to test to whether histamine production by K. aerogenes was dependent on the acidity of the environment. Indeed, K. aerogenes produced the most histamine at a pH of 7.0 and almost no histamine at a pH below 6.0 or above 8.0.
This is key, as the pH of the colon ranges from 5.5 to 7.5, depending on fermentation levels. A pH at the lower end of this range is typically associated with better health. In other words, reducing the pH of the colon (increasing its acidity) could be one way to reduce gut histamine production by K. aerogenes.
Lactobacilli: a way to keep Klebsiella at bay
Of course, one of the primary determinants of colonic pH is lactic acid levels. When the researchers looked at gut samples from the “humanized” mice, they found that lactic acid levels were much lower in mice that had received a microbiota from IBS patients with high urine histamine. This was accompanied by lower levels of lactic-acid-producing bacteria like lactobacilli.
To further examine this relationship, the researchers cultured K. aerogenes with or without a mixture of lactobacilli. As expected, the lactobacilli decreased histamine production! The lab also confirmed these results in a mouse model.
Unfortunately, the two lactobacilli used in this study are not well-characterized. The first is thought to be a strain of either L. animalis or L. murinus, while the second is more closely related to L. acidophilus and L. lactis.
Nonetheless, this suggests that some lactobacilli can modulate histamine production by K. aerogenes, most likely by producing lactic acid, thereby decreasing the pH and the activity of the hdc enzyme.
Of course, many lactobacilli can be problematic for those with symptoms of histamine intolerance or mast cell activation. But more on that later.
What about Klebsiella in the small intestine?
So far, we’ve been talking about Klebsiella activity in the colon. But what about Klebsiella in the small intestine?
While the small intestine does not normally harbor much Klebsiella, at least one study has shown that Klebsiella species are more prevalent in the duodenum (upper third of the small intestine) of individuals with GI symptoms and that they can disrupt the overall small intestinal microbial community structure.5
Preliminary evidence suggests that some of these Klebsiella species may originate from the oral cavity.5 In other words, saliva may act as a reservoir for continued Klebsiella transmission to the gut, where they will flourish if the gut environment allows.6
Portions of the small intestine are also much less acidic than the colon. Recent reports suggest pH levels as high as pH 7.4-7.8 in the ileum (the most distal part of the small intestine),7 levels that could certainly support histamine production by K. aerogenes.
In other words, an opportunistic overgrowth of K. aerogenes in the small intestine could contribute to overall high levels of histamine.
Bacterial histamine attracts mast cells to the gut
Last but not least, the researchers again turned to mice to determine how bacterial histamine might cause visceral pain.
They found that bacterial histamine signals through the histamine 4 receptor to activate mast cells and attract them to the colon. These mast cells contribute even more histamine and other pain-signaling molecules, triggering nerve cells in the gut and causing abdominal pain.
Blocking H4 receptors may, therefore, represent a strategy to mitigate symptoms in patients with high histamine. This would prevent the recruitment of mast cells to the colon and additional histamine production by the host.
How to test for bacterial histamine-related IBS
So how do you know if you’re in this particular subset of IBS patients? While more studies are needed to precisely define the features of this type of IBS, it is likely that indicators will include:
- High urine histamine levels. This can be measured through a 24-hour urine histamine test, available from Quest, LabCorp, or DirectLabs.
- A high abundance of K. aerogenes on a sequence-based stool test. This can be found in the raw data of the Thorne Gut Health test or similar metagenomics tests. (Note: I’d also look for a high abundance of M. morganii, which other studies have identified as a potentially significant histamine producer.)
- Other symptoms of mast cell activation, “histamine intolerance”, or sensitivity to FODMAPs. If testing is not feasible but you have other symptoms of mast cell activation, you might be more likely to be in this subset of IBS patients.
If you have two or more of these, it might be worth trying some of the strategies I have compiled below.
Strategies to target bacterial histamine-related IBS
Below is a list of potential interventions that may be helpful for those with this particular subset of IBS.
Note: This information should not be taken as medical advice. Always consult with your personal physician about whether a particular intervention is appropriate for you.
- A low FODMAP diet: a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can acutely decrease gut histamine levels, reduce the abundance of K. aerogenes, and offer temporary relief from abdominal pain.
- Restore gut acidity: a lower pH was shown to significantly reduce histamine production by K. aerogenes.
The following are likely most effective for increasing gut acidity, but may not be tolerated by histamine-sensitive individuals; only use if well-tolerated:
- Lactobacilli – most lactobacilli produce some lactic acid and will reduce gut pH. For those who are histamine sensitive, Lactobacillus plantarum 299v has shown benefits in clinical trials for IBS8 and may be better tolerated by those who are sensitive to histamine.9
- Vinegar – vinegar is 5% percent acetic acid and has been shown to decrease colonic pH in an animal model.10
- Lacto-fermented foods – traditionally fermented dairy products and vegetables contain high amounts of lactobacilli, lactic acid, and other organic acids that can reduce gut pH.
Other interventions that are likely to be better tolerated in histamine-sensitive individuals:
- Butyrate – SCFA levels are a key factor in determining colonic pH. Supplementing with butyrate may help to promote acidity and has the added benefit of suppressing mast cell activation.11,12
- Betaine HCl – supplemental HCl may help reduce the pH of the stomach and small intestine around meals when dietary histidine is present.
- Reduce colon transit time – faster transit time has been linked to a more acidic gut pH.13 Both magnesium and vitamin C can accelerate transit time and are also helpful for supporting histamine turnover.
- Reduce gut oxygen: K. aerogenes is a member of the Enterobacteriaceae family and can utilize oxygen. This means that the strategies outlined in my article on the oxygen-dysbiosis connection might be helpful for reducing the abundance of K. aerogenes. The PPAR-gamma activating herbs silymarin and curcumin are also effective mast cell stabilizers.
- Time-restricted eating: K. aerogenes has been shown to have a circadian rhythm and proliferates more rapidly in the presence of melatonin.14 This suggests that aligning meals with the circadian clock (i.e. don’t eat late at night) or even a time-restricted eating window may be helpful.
- Low histamine diet: While we don’t have any studies on a ‘low histamine diet’, I have seen this to be beneficial in my work with clients with IBS and symptoms of mast cell activation. It seems reasonable that reducing dietary sources of histidine, the substrate for the hdc enzyme, would reduce histamine production by K. aerogenes.
- Quercetin: A natural histamine 4 receptor antagonist,15 quercetin may help offset the effects of bacterial histamine on mast cell accumulation in the gut and thus reduce gut hypersensitivity.
Summary and takeaways
I know we covered a lot, so here are the major things to take away from this article:
1)The gut microbiota is a significant source of histamine: “Although, traditionally, mast cells have been considered to be the main source of histamine, our findings point to the gut microbiota as an important source.”
2) Klebsiella aerogenes is a major (if not the) culprit for elevated histamine in patients with IBS. Bacterial histamine from K. aerogenes can recruit and activate mast cells in the gut, leading to abdominal pain. K. aerogenes may also be involved in other conditions characterized by high histamine levels, but more studies are needed.
3) A subset of IBS patients with high histamine may benefit from targeted therapies that reduce K. aerogenes or inhibit histamine signaling: “The identification of K. aerogenes, or bacteria with similar hdc activity, as a source of histamine in the gut may guide dietary recommendations, microbiota-directed therapies, or use of H4 receptor antagonists in a subset of patients with IBS with chronic abdominal pain.” I discussed many such strategies above.
That’s all for now! Let me know if you enjoyed this article and share your thoughts in the comments below.
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- Mast cells and food-induced abdominal pain
- The dual effects of histamine
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