Metabolite produced by bacteria in the gut promotes neural cell death resulting in cognitive decline

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A team of researchers from the Brown Cancer Center, the University of Louisville, Peak Neuromonitoring Associates, the University of Texas and the University of Louisville has found that a metabolite produced by bacteria in the gut promotes neural cell death resulting in cognitive decline in mice.

In their paper published in the journal Cell Host & Microbe, the group describes their study of the metabolite isoamylamine (IAA) and its impact on cognitive decline.

Prior research has suggested a strong link between gut bacteria and brain health. In this new effort, the researchers looked into the possible impact on the brain of just one metabolite produced by one family of bacteria in the gut, Ruminococcaceae.

They found first that IAA becomes more prevalent in the gut as people age due to the presence of more Ruminococcaceae. Their interest in IAA grew when they learned it could pass through the blood-brain barrier.

In order to trace the path of IAA from the gut into the brain to see what impact it might have, they had to develop a new technique – a modification of electrophoresis that allowed for the tracking of DNA mobility shifts – which they called single-strand gel shift. They next incubated the gene responsible for sensing and responding to aging in mice (S100A8) with IAA.

They found the metabolite binds to a promoter region of S100A8, which allowed for expression of the gene, resulting in production of apoptotic bodies, which lead to cell death.

To learn more about what happens when such bindings occur, the researchers fed IAA to young healthy mice and determined that this resulted in a loss of cognitive function. They next blocked production of the metabolite in the guts of older mice and found that it led to improvements in cognitive performance.

They state more research needs to be done to find out if the production of IAA in the human gut biome also results in cognitive decline, and if so, whether blocking its production would prevent cognitive decline as people age.


Heart failure

Altered gut microbiome in HF with reduced capacity for butyrate production

The last two years, several sequencing-based studies have reported that the gut microbiota composition and functions differ between patients with HF and healthy subjects, with some common findings, but also considerable variation between studies (Table 2). Luedde and colleagues observed a reduced abundance of Ruminococcaceae on the family level and reduced abundance of Blautia from the Lachnospiracea family on the genus level in 20 patients with HF [[42]].

In a similar-sized study, Kamo et al. found a reduced relative abundance of Eubacterium rectale and Dorea longicatena from the Lachnospiracea family, and levels of Faecalibacterium from the Ruminococcaceae family were lower in older patients [[43]].

Furthermore, Cui et al. reported reduced levels of Faecalibacterium prausnitzii in patients with HF [[44]]. A common finding in these studies is the relative reduction in taxa from the Lachnospiracea or Ruminococcacea families, known for their capacity for butyrate production.

Table 2 Contemporary gut microbiota sequencing studies in patients with heart failure (HF).

StudyLuedde et al. [42]Kamo et al. [43]Cui et al. [44]Kummen et al. [45]
Mayerhofer et al. [66]
PatientsChronic HF: 70% exacerbation, 30% stableAcute HF or exacerbation of chronic HFStable chronic HF: Ischaemic or dilated cardiomyopathyStable systolic HF
Age patients65 ± 3.2 yearsTwo strata: 47.4 ± 2.8 years 73.8 ± 2.8 years58.1 ± 13.3 years58.9 (39–74) years
Gender% (f/m)45/5518/8217/8359/41
Sample sizen = 20 HFn = 12 HF <60yearsn = 53 HFn = 84 HF (discovery- validation)
n = 20 controlsn = 10 HF >60yearsn = 41 controlsn = 266 controls
n = 12 controls
Methods16 s rRNA16 s rRNA16 s rRNA16 s rRNA
Parallel plasma/serumNoNoYesYes
Dietary dataNoNoNoYes
Increased relative abundance in patientsRuminococcus gnavusPrevotella, Hungatella, Succinclasticum
Decreased relative abundance in patientsCoriobacteriaceae, Erysipelotrichaceae, Ruminococcaceae (family level)-Eubacterium rectale, Dorea longicatenaFaecalibacterium prausnitzii-Lachnospiracea family: 9 different genera, including Blautia and Eubacterium halli
Blautia (genus level)-Depletion of Faecalibacterium in older patients– Ruminococcaceae: Faecalibacterium
Bifidobacteriaceae: Bifidobacterium
Functional findings-Increased capacity for lipopolysaccharide biosynthesis and TMA production and reduced capacity for butyrate production in HF microbiomesLower genetic potential for butyrate production in HF microbiomes
-Eubacterium halli associated with soluble CD25 and mortality
-Dysbiosis related to dietary fiber intake

In order to define a more robust HF-related gut microbiota signature, we investigated two independent cross-sectional cohorts, finding that patients with HF had reduced biodiversity in the gut microbiome, as well as altered abundance of 15 core taxa. Most of the microbes that were depleted in HF belonged to the Lachnospiracea family, in addition to Faecalibacterium from the Ruminococcacea family [[45]], again pointing to reduced capacity for butyrate production as a key element, supported by a lower predicted genetic potential for butyrate production (genes encoding butyrate-acetoacetate CoA-transferase). Of relevance, the abundance of several members of the Lachnospiracea family correlated with soluble CD25, a marker of T cell activation, and depletion of the known butyrate producer Eubacterium Halli and increased plasma levels of soluble CD25 were associated with death or heart transplantation [[45]].

reference link : https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(20)30024-4/fulltext


More information: Yun Teng et al, Gut bacterial isoamylamine promotes age-related cognitive dysfunction by promoting microglial cell death, Cell Host & Microbe (2022). DOI: 10.1016/j.chom.2022.05.005

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