FAP linked to significant changes in intestinal bacteria in Taiwan study

Gut microbiota composition also tied to nerve damage severity in patients

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by Steve Bryson, PhD |

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Taiwanese people with familial amyloid polyneuropathy (FAP) have a significantly altered composition of intestinal bacteria relative to their unrelated healthy family members, a new study showed.

In addition, the composition of gut microbiota, or bacteria living in the intestines, was associated not only with the severity of nerve damage in patients, but with heart involvement, according to the researchers.

These findings suggest potential contributions of gut microbiota to the development or severity of FAP, the team noted.

Details of the analysis were outlined in “Altered gut microbiota in Taiwanese A97S predominant transthyretin amyloidosis with polyneuropathy,” a study published in the journal Nature Scientific Reports.

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Seeking data on the composition of intestinal bacteria in FAP

FAP is a progressive disease marked by the accumulation of toxic clumps of the transthyretin protein mainly in the nerves outside the brain and spinal cord, causing damage to several nerves, or polyneuropathy. In some patients, the disease also can lead to the buildup of toxic transthyretin clumps in the heart, resulting in heart damage, or cardiomyopathy.

The rare condition is caused by mutations in the TTR gene, which encodes transthyretin, with Val30Met, known as V30M, as the most common disease-causing mutation worldwide. In Taiwan and Southeast Asia, however, the most common TTR mutation is Ala97Ser, known as A97S, which usually presents as a late-onset disease between the ages of 40 and 75.

Microbes inhabiting the intestines — referred to as the gut microbiota — play various biological roles, including the breakdown of food, nutrient processing, and regulating immune responses. Many studies have found links between gut microbiota changes and various neurological conditions, including Parkinson’s and Alzheimer’s diseases.

However, “the alteration of the gut microbiota in [FAP] has not been well explored before,” according to the researchers, based at the National Taiwan University Hospital in Taipei.

To learn more about this specific patient population, the team examined microbiota composition in fecal samples from 38 Taiwanese people with FAP. The patients ranged in age from 52 to 78 and 76% were men. Fecal samples from 39 age-matched unrelated family members, such as spouses, were used as controls.

The researchers also assessed the potential link between gut microbiota changes and the patients’ clinical characteristics.

Among the FAP patients, A97S was the most common TTR mutation, present in 36 or 94.7%. The age at polyneuropathy symptom onset ranged from 50 to 70 years. At enrollment, 17 patients had not yet received treatment, while 21 were treated with diflunisal, a nonsteroidal anti-inflammatory drug that has shown some promise in slowing FAP progression.

A total of 13 patients (34.2%) could walk independently, 18 (47.4%) needed some kind of assistance for walking, and seven (18.4%) were dependent on wheelchairs to move around.

All patients experienced sensory symptoms, with nearly all (92.1%) showing limb weakness and about two-thirds (68.4%) experiencing neuropathic, or nerve damage-related pain.

Most (92.1%) also had impairment of the autonomic nervous system, which controls involuntary bodily processes such as heart rate, blood pressure, and gastrointestinal function — which was affected in 34 patients (89.5%). Constipation and/or diarrhea were reported in 32 patients.

All 36 patients with evaluable heart data showed transthyretin clumps in the heart.

The results showed that the FAP patients had a significantly greater abundance of gut microbiota and significantly different gut microbiota composition relative to the control group. There were no significant differences in gut microbiota richness and compositions between FAP patients with and without treatment, diarrhea, or constipation, per the data.

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More gut microbiota richness, diversity linked to more heart involvement

Most strains of bacteria that differed between FAP patients and controls fell into two major groups, or phyla, called Firmicutes and Bacteroidetes. These are the two most common bacterial groups in the human gut. The ratio of Firmicutes to Bacteroidetes is considered a marker of healthy intestinal function, and it was significantly higher in FAP patients than in controls.

“All these observations strongly suggested that the gut microbiota was altered in patients with [FAP],” the researchers wrote.

In addition, more damage to small nerve fibers, which detect pain, heat, and itching sensations in the skin, significantly correlated with a lower abundance of two gut bacterial types: Eubacterium oxidoreducens and the family XIII AD3011 group. Both belonged to the class Clostridia, which falls into the phylum Firmicutes.

A lower abundance of Eubacterium oxidoreducens and six other groups of the Clostridia class also was significantly associated with more severe damage to large nerve fibers, which carry the pain signals to the brain and spinal cord and control muscle movement.

Moreover, a greater gut microbiota richness and diversity were associated with more heart involvement.

We found that the gut microbiota in [FAP was] significantly altered not only in [its] richness and evenness but also in the variability of species compared to the control group, especially in the components of Firmicutes and Bacteroidetes.

No clinical measures correlated with the Firmicutes to Bacteroidetes ratio.

“We found that the gut microbiota in [FAP was] significantly altered not only in [its] richness and evenness but also in the variability of species compared to the control group, especially in the components of Firmicutes and Bacteroidetes,” the researchers wrote.

Given that this study could not determine whether gut microbiota changes contribute to FAP or the other way around, “further elucidation of the interaction between gut microbial and host immunometabolic responses may lead to a better understanding of the [underlying mechanisms] of [FAP],” the team wrote.

Such future studies should involve patients with other ethnicities and FAP-causing mutations, and consider all possible simultaneous health conditions and gastrointestinal symptoms, the scientists concluded.