Abnormal stroke-related brain blood vessels linked to gut bacteria

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In a nationwide study, National Institutes of Health (NIH)-funded researchers found that the presence of abnormal bundles of brittle blood vessels in the brain or spinal cord, called cavernous angiomas (CA), are linked to the composition of a person’s gut bacteria. Also known as cerebral cavernous malformations, these lesions which contain slow moving or stagnant blood, can often cause haemorrhagic strokes, seizures, or headaches. Current treatment involves surgical removal of lesions when it is safe to do so. Previous studies in mice and a small number of patients suggested a link between CA and gut bacteria. This study is the first to examine the role the gut microbiome may play in a larger population of CA patients.

Led by scientists at the University of Chicago, the researchers used advanced genomic analysis techniques to compare stool samples from 122 people who had at least one CA as seen on brain scans, with those from age- and sex-matched, control non-CA participants, including samples collected through the American Gut Project. Initially, they found that on average the CA patients had more gram-negative bacteria whereas the controls had more gram-positive bacteria, and that the relative abundance of three gut bacterial species distinguished CA patients from controls regardless of a person’s sex, geographic location, or genetic predisposition to the disease. Moreover, gut bacteria from the CA patients appeared to produce more lipopolysaccharide molecules which have been shown to drive CA formation in mice. According to the authors, these results provided the first demonstration in humans of a “permissive microbiome” associated with the formation of neurovascular lesions in the brain.

Further analysis showed that some gut bacteria compositions could identify aggressive versus non-aggressive forms of the disease as well as those with recent symptomatic haemorrhages. Also, for the first time, they showed how combining gut bacteria data with results from blood plasma tests might help doctors better diagnose the severity of a brain disorder. The results support a growing body of evidence for the role of gut bacteria in brain health.

Abstract
Cavernous angiomas (CA) are common vascular anomalies causing brain hemorrhage. Based on mouse studies, roles of gram-negative bacteria and altered intestinal homeostasis have been implicated in CA pathogenesis, and pilot study had suggested potential microbiome differences between non-CA and CA individuals based on 16S rRNA gene sequencing. We here assess microbiome differences in a larger cohort of human subjects with and without CA, and among subjects with different clinical features, and conduct more definitive microbial analyses using metagenomic shotgun sequencing. Relative abundance of distinct bacterial species in CA patients is shown, consistent with postulated permissive microbiome driving CA lesion genesis via lipopolysaccharide signaling, in humans as in mice. Other microbiome differences are related to CA clinical behavior. Weighted combinations of microbiome signatures and plasma inflammatory biomarkers enhance associations with disease severity and hemorrhage. This is the first demonstration of a sensitive and specific diagnostic microbiome in a human neurovascular disease.

Authors
Sean P Polster, Anukriti Sharma, Ceylan Tanes, Alan T Tang, Patricia Mericko, Ying Cao, Julián Carrión-Penagos, Romuald Girard, Janne Koskimäki, Dongdong Zhang, Agnieszka Stadnik, Sharbel G Romanos, Seán B Lyne, Robert Shenkar, Kimberly Yan, Cornelia Lee, Amy Akers, Leslie Morrison, Myranda Robinson, Atif Zafar, Kyle Bittinger, Helen Kim, Jack A Gilbert, Mark L Kahn, Le Shen, Issam A Awa

NIH/National Institute of Neurological Disorders and Stroke
Nature Communications abstract


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