Changes in Gut Microbiota May Contribute to HAE Attacks

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

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The richness and diversity of the gut’s microbial community, or microbiota, are significantly reduced in people with hereditary angioedema (HAE) who have had recent swelling attacks, when compared with that of healthy individuals, a single-center study in China shows.

This difference was particularly pronounced among HAE patients with gastrointestinal (GI) swelling attacks, also separating this group from patients without any recent HAE attack.

In addition, recent GI attacks appeared to be associated with a reduction in beneficial bacteria and an increase in disease-causing bacteria. According to researchers, that reduction may act as a trigger for HAE attacks rather than being a consequence of such attacks.

Larger, international studies are needed to confirm these findings, as well as the value of a combined gut bacterial biomarker the researchers proposed be used to distinguish HAE patients with and without recent attacks.

The study, “Gut microbiome alterations in hereditary angioedema,” was published in the journal Annals of Allergy, Asthma & Immunology.

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Gut microbiota comprises the vast community of friendly bacteria, fungi, and viruses that colonize the gastrointestinal tract. This community helps to maintain a balanced gut function, protect against disease-causing organisms, and influence a person’s immune system.

A healthy balance of the body’s microbiota depends on environmental factors such as diet, age, exposure to microorganisms, and antibiotic therapy. A microbiota imbalance, known as dysbiosis, has been shown to trigger or worsen a number of health conditions, ranging from gastrointestinal problems to inflammatory and autoimmune diseases.

Notably, previous preclinical studies have shown that some microorganisms can directly or indirectly stimulate the production of bradykinin, the inflammatory molecule overly produced in HAE patients that causes sudden episodes of swelling and pain. However, little is known about the role of gut microbiota in HAE.

To address this, a team of researchers in China analyzed the gut microbiota of 55 HAE patients — 35 females and 20 males — from 43 unrelated families. The team also assessed 27 healthy relatives, as well as potential associations with HAE attacks.

The participants’ stool samples were collected and analyzed through a genetic sequencing method to determine the composition and diversity of their gut microbiota. None of them had taken antibiotics in the two months prior to sample collection.

The team noted that the use of patients’ healthy relatives as controls was meant to minimize potential influencing effects caused by genetic variation, diet, or living environment.

Included patients, with a median age of 40 years (12–71 years), were treated at the Peking Union Medical College Hospital between June 2020 and June 2021. Their disease was caused by mutations in the SERPING1 gene, and most (83.6%) had HAE type 1.

A total of 27 patients (49.1%) had experienced HAE attacks within the last month. Among them, 12 had abdominal symptoms (gastrointestinal attacks) upon examination. In the previous year, GI swelling attacks were frequent in nearly half (49.1%) of the patients, while laryngeal attacks were rare in most (74.5%).

More than half (54.5%) of the patients had not received prior preventive treatment — namely Danocrine (danazol) and tranexamic acid, used off-label for HAE — at the time of sample collection, while the remaining patients were on either therapy.

Results showed that HAE patients who experienced recent attacks, but not those without recent attacks, had significantly reduced gut microbiota richness and diversity relative to healthy controls. This gut dysbiosis was more pronounced among patients with recent GI attacks, who also showed a significantly poorer and less diverse gut microbiota than patients without recent HAE attacks.

Also, patients experiencing recent HAE attacks, and especially GI attacks, had a reduction in Firmicutes and an increase in Proteobacteria and overall disease-causing bacteria relative to both healthy controls and patients without recent attacks.

Firmicutes comprise a group of bacteria thought to contribute to a healthy gut and anti-inflammatory responses, while Proteobacteria is a group that comprises many disease-causing bacteria.

Notably, an expansion of Proteobacteria has been previously associated with several bowel diseases and “may represent a marker of the destruction of intestinal epithelial barriers and induction of gut inflammation,” the researchers wrote.

An increase in disease-causing bacteria may be “linked to frequent and severe abdominal swelling among these patients,” they added.

“We hypothesize that gut dysbiosis is a more likely predisposing factor for HAE, instead of the result of vomiting or diarrhea caused by gastrointestinal [attacks],” the team wrote.

Gut microbiota richness and composition were comparable between patients with frequent versus rare laryngeal swelling, but the frequencies of several groups of bacteria were significantly different between the patient groups.

Based on these findings, researchers proposed a potential combined bacterial biomarker of recent HAE attacks that included five groups of bacteria: Bifidobacterium, Lachnospira, Paraprevotella, Desulfovibrio, and Staphylococcus.

The biomarker was found to accurately distinguish between patients with and without recent attacks, but “prospective trials with larger sample sizes will be needed to further validate this hypothesis,” the team wrote.

In addition, data from nine patients whose stool samples were collected before and after a few months of regular treatment with Danocrine (eight patients) or tranexamic acid (one patient) showed that gut dysbiosis was largely resolved after treatment.

Particularly, they noticed there was a “sharp decrease in the frequency of [disease-causing] bacteria after several months of treatment,” suggesting that long-term preventive treatment “may alleviate gut dysbiosis and reduce infections [of] opportunistic [bacteria].”

These findings “may provide some clues to explain the variable clinical feature of HAE,” the researchers wrote, adding that “making use of the gut microbiome to predict HAE attacks is promising and potentially valuable to clinical practice.”