Short Chain Fatty Acids Taken at Time of Thrombectomy in Acute Ischemic Stroke Patients Are Independent of Stroke Severity But Associated With Inflammatory Markers and Worse Symptoms at Discharge

Abstract

IntroductionShort chain fatty acids (SCFA) are gut microbiota-derived metabolites that contribute to the gut-brain axis and may impact stroke outcomes following gut dysbiosis. We evaluated plasma SCFA concentrations against stroke severity parameters and identified SCFA-associated protein networks.MethodsThe Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC), a continuously enrolling tissue bank, was used to obtain stroke samples. Arterial blood distal and proximal to the thrombus was obtained from Acute Ischemic Stroke (AIS) Patients (n=53) during thrombectomy. Patient demographics, stroke presentation and outcome parameters were reported. The SCFAs were isolated from proximal plasma via chemical derivatization UHPLC coupled tandem mass spectrometry using electrospray ionization and multiple reaction monitoring. Proteomic levels for 184 cardioembolic and inflammatory proteins was quantified from systemic and intracranial plasma by Olink. Arterial blood from cerebrovascular patients undergoing elective neurointerventional procedures was used as controls.ResultsAcetate positively correlated with time from last known normal (LKN) and was significantly lower in stroke patients compared to control. Isobutyrate, Butyrate and 2-Methylbutyrate negatively correlated with %ΔNIHSS. Isobutyrate and 2-Methylbutyrate positively correlated with NIHSS discharge. SCFA concentrations were not associated with NIHSS admission, infarct volume, or edema volume. Multiple SCFAs positively associated with systemic and pro-inflammatory cytokines, most notably IL-6, TNF-α, VCAM1, IL-17, and MCP-1.ConclusionsPlasma SCFA concentrations taken at time of stroke are not associated with stroke severity at presentation. However, higher levels of SCFAs at the time of stroke are associated with increased markers of inflammation, less recovery from admission to discharge, and worse symptom burden at discharge.

Ischemic stroke and concomitant gastrointestinal complications- a fatal combination for patient recovery

“…Interestingly, intestinal microbiota of stroke patients is enriched with SCFA-producing bacteria Odoribacter, Akkermansia, Ruminococcaceae and Victivallis ( 12 ). Higher levels of SCFAs in stroke patients who underwent thrombectomy were associated with increased systemic inflammation and poor stroke outcomes ( 12 , 31 ). However, different studies on analyzing the plasma or fecal levels of SCFAs in stroke patients and underlying outcomes have derived variable results.…”

Gut microbes in cerebrovascular diseases: Gut flora imbalance, potential impact mechanisms and promising treatment strategies

“…SCFA supplementation can improve post-stroke recovery, cortical reconfiguration, and synaptic plasticity ( 81 ). Butyrate is an essential SCFA; its bacterial abundance corresponds to stroke severity ( 33 , 43 , 45 ). Roseburia was considerably enriched in butyrate in mild stroke patients (NIHSS score <4); conversely, Erysipelotrichaceae incertae sedis was abundant in non-mild stroke patients ( 43 , 45 ).…”

“…In addition, isobutyric acid, butyric acid, and 2-methyl butyric acid were negatively associated with the percentage change in NIHSS scores. Furthermore, isobutyric acid and 2-methyl butyric acid were favorably linked with NIHSS discharge ( 33 ). The abundance of butyrate-producing bacteria was also associated with post-stroke infection ( 29 ).…”

“…Except the direct effect, metabolites of dysbiosis, also promote the release of inflammatory factors, and the indirect effect of IS cannot be ignored. SCFAs have been associated with elevated levels of systemic proinflammatory markers IL-6, TNF-α, vascular cell adhesion molecule-1(VCAM-1), IL-17, and MCP-1 after stroke, which was associated with a high disease burden at discharge and the duration of inpatient recovery ( 33 ). Moreover, butyrate-producing bacterial abundance is an independent predictor of post-stroke infection ( 29 ).…”

“…The release of these inflammatory factors results in intestinal permeability changes, barrier dysfunction, extravasation of inflammatory substances into peripheral blood, and transportation to the blood-brain barrier (BBB). Ultimately, they act on the cerebrovascular system and play a crucial role in CeVD occurrence, development, and prognosis (30)(31)(32)(33). In CeVD research (34)(35)(36)(37), the clinical efficacy of fecal bacterial transplantation (FMT), traditional Chinese medicine i n t e r v e n t i o n , a n t i b i o t i c i n t e r v e n t i o n , a n d S C F A supplementation remains contentious.…”