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Harnessing the microbiome as a possible stroke treatment

Presented by
Prof. Louise McCullough, University of Texas Health Science Center, TX, USA
AAN 2023

One of the ‘frontiers in neuroscience’ discussed in the session of the same name was the gut microbiome as a possible therapeutic target for age-related diseases, including stroke and cognitive decline. Altering the microbiome before or after stroke has enhanced recovery in mouse models and reduced neuro-inflammation.

Prof. Louise McCullough (University of Texas Health Science Center, TX, USA) defined the microbiome as the community of microorganisms – including fungi, bacteria, and viruses – that exist in a particular environment [1]. Her talk centred on the microbiome in the gut. The gut microorganisms are dynamic and change in response to diet, medication, stressors, and environmental exposure. The bacteria in the microbiome can be helpful (commensal bacteria) or harmful (pathogenic). The microbiome produces a variety of metabolites, some of which are solely generated by the microbiome (e.g., indoles, short-chain fatty acids [SCFA]). “What we're finding now is that it is not so much the biome or the bacteria that are important but their metabolites,” highlighted Prof. McCullough.

As some of Prof. McCullough's work with mouse models has shown, the biome changes with age, with increasing dysbiosis: a pathological shift in its composition. This results in ‘bottom-up’ signalling from the gut to the brain, possibly due to circulating factors or vagal nerve function. She observed that young mice (around 12 weeks of age) recovered much quicker after an experimental stroke than older mice (16­–20 months), despite having much larger strokes. This difference was due to hypothermia, significant and persistent (up to 1-month post-stroke) inflammation, and immunosuppression in aged mice, largely caused by gut-driven bacteria. The gut structure deteriorates with age; after a stroke gut permeability worsens (especially in aged mice), which correlates with neurological deficits. The biome of aged mice was radically different from young mice and contained much more deleterious bacteria. Aged mice had fewer Bacteroidetes and more firmicutes, considered more pathogenic. Intriguingly, transplanting a young microbiome (and its metabolites) to an aged recipient replenishes the biome. A study Prof. McCullough co-authored suggested that poor stroke recovery in aged mice can be reversed via ‘bacteriotherapy’ given 3 days post-stroke via modulation of immunologic, microbial, and metabolomic profiles in the host [2].

In explaining this beneficial effect, Prof. McCullough emphasised the role of SCFA. She explained: “A drop in SCFA probably causes a lot of inflammation. So, after a stroke, there is a possible window of opportunity for treatment with SCFA.” Indeed, giving bacterial therapy increased SCFA, and this restoration of SCFA-producing bacteria was enough to improve stroke recovery to an even larger extent than a faecal transplant. Proposed mechanisms for the therapeutic effects of SCFA include beneficial effects on goblet cells, enhancement of gut barrier integrity, and enhancement of the ‘immune landscape’ in the brain.

Prof. McCullough also highlighted some of her (not yet published) research on indole, a biome-derived tryptophan metabolite. Looking for a potential role of indoles in neuroprotection, she found that indoles-producing bacteria decreased dramatically with age. Post-stroke treatment of mice with indoles decreased their neurological deficit, cerebral oedema, and infarct size. She concluded that the microbiome is malleable and thus may be an important therapeutic target for age-related diseases, including Alzheimer's disease.

  1. McCullough L. Harnessing the microbiome to treat stroke and age-related cognitive decline. PL6.006, AAN 2023 Annual Meeting, 22–27 April, Boston, USA.
  2. Lee J, et al. Circ Res. 2020;127(4):453–65.

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