Sex Differences in Stroke Outcome Are Associated With Constitutive Gut Dysbiosis and Stroke-induced Gut Permeability

Abstract Background: Sex differences in experimental stroke are well documented, such that adult males show worse outcomes compared to adult females, including greater infarct volume, increased stroke-induced mortality and more severe sensory-motor impairment. Based on recent evidence that gut dysbiosis may be an early response to stroke, the present study tested the hypothesis that in the acute phase, stroke will result in greater permeability of the gut blood barrier and gut dysbiosis in males as compared to females. Method: Male and female Sprague Dawley rats (5-7 months of age) were subject to endothelin (ET)-1-induced middle cerebral artery occlusion (MCAo). Fecal samples, blood draws and sensory motor tests were conducted pre and 2d after MCAo. Fecal samples were analyzed for 16s sequencing and short chain fatty acids (SCFAs). Gut permeability was assessed in serum samples using biomarkers of gut permeability as well as functional assays using size-graded dextrans. Results: We confirmed stroke-induced sex differences, including greater mortality and sensory motor deficit in males as compared to age-matched female rats. Remarkably, fecal 16s sequencing showed greater bacterial diversity in females at baseline (prior to stroke) while 2 days after stroke, these measures were similar between the sexes. In contrast, fecal levels of short chain fatty acids (SCFAs) which are usually beneficial, were higher in males. MCAo-induced gut permeability was much worse in males as compared to females, as indicated by histological analysis, biochemical markers in serum, and serum measurement of fluorescent-labeled dextrans following oral gavage. Additionally, males had higher serum levels of proinflammatory cytokines IL-17A, MCP-1, IL-5 and EGF compared to females after stroke. Predictive modeling indicated that markers of gut permeability were associated with stroke-induced sensory-motor impairment. Conclusions: Poor stroke outcomes in adult males is mirrored by increased gut permeability in this group. Additionally, these data suggest that constitutive sex differences in the diversity and richness of gut microbial communities may predispose better functional outcomes after stroke in females, and support the idea that preventative modification of the gut microbiome may reduce the risk for stroke in vulnerable populations such as the elderly or those with co-morbid conditions.

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Abstract MP57: Sex Differences in Stroke Outcome Are Associated With Constitutive Gut Dysbiosis and Stroke-Induced Gut Permeability

Stroke ◽

10.1161/str.52.suppl_1.mp57 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Yumna El-Hakim ◽

Kathiresh Kumar Mani ◽

Amir Eldouh ◽

Alan Dabney ◽

Rachel Pilla ◽

...

Keyword(s):

Sex Differences ◽

Female Rats ◽

Male Rats ◽

Experimental Stroke ◽

Motor Deficit ◽

Gut Permeability ◽

Fecal Samples ◽

16S Sequencing ◽

Gut Dysbiosis ◽

Sensory Motor

Sex differences in experimental stroke are well documented, such that adult males show worse outcomes compared to adult females, including greater infarct volume, increased stroke-induced mortality and more severe sensory-motor impairment. Based on recent evidence that gut dysbiosis may be an early response to stroke, the present study tested the hypothesis that in the acute phase, stroke will result in greater gut dysbiosis and greater permeability of the gut blood barrier in males as compared to females. Male and female Sprague Dawley rats (5-7 months of age) were subject to endothelin-1-induced middle cerebral artery occlusion (MCAo). Fecal samples, blood draws and sensory motor tests were collected/conducted pre and 2d after MCAo. Fecal samples were subject to 16s sequencing. Serum samples were subject to gas chromatography for short chain fatty acid (SCFA) analysis. Gut permeability was assessed by histology, biochemical markers in serum and functional assays using oral dextran gavage. We confirmed stroke-induced sex differences, including increased mortality and more severe sensory motor deficit in males as compared to age-matched female rats. Fecal 16s sequencing showed greater bacterial diversity in females at baseline (pre stroke) while 2 days after stroke, these measures were similar between the sexes. Fecal levels of SCFAs, which are usually beneficial, were higher in males. In contrast, MCAo-induced gut permeability was much worse in males as compared to females. Male rats had a decreased villus length to crypt length ratio, higher levels of biochemical gut permeability markers in serum and higher levels of fluorescent-labeled dextrans following oral gavage in serum. Additionally, males had higher serum levels of proinflammatory cytokines IL-17A, MCP-1, IL-5 and EGF compared to females after stroke. Collectively, these results indicate that the worse stroke outcomes seen in males is associated with increased gut permeability in this group. These data suggest that therapeutics that target the gut epithelium in order to reinforce the gut-blood barrier post stroke may be an effective intervention especially in populations such as the elderly or those with co-morbid conditions who have already been shown to have more permeable barriers.

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Gut dysbiosis and lack of short chain fatty acids in a Chinese cohort of patients with multiple sclerosis

Neurochemistry International ◽

10.1016/j.neuint.2019.104468 ◽

2019 ◽

Vol 129 ◽

pp. 104468 ◽

Cited By ~ 22

Author(s):

Qin Zeng ◽

Junli Gong ◽

Xiyuan Liu ◽

Chen Chen ◽

Xiaobo Sun ◽

...

Keyword(s):

Multiple Sclerosis ◽

Fatty Acids ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Gut Dysbiosis ◽

Chinese Cohort ◽

Chain Fatty Acids

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Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats

Biology of Sex Differences ◽

10.1186/s13293-020-00352-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yumna El-Hakim ◽

Kathiresh Kumar Mani ◽

Amir Eldouh ◽

Sivani Pandey ◽

Maria T. Grimaldo ◽

...

Keyword(s):

Sex Differences ◽

Tight Junction ◽

Infarct Volume ◽

Motor Impairment ◽

Gut Permeability ◽

Sprague Dawley ◽

Stroke Outcomes ◽

Sprague Dawley Rats ◽

Junction Protein ◽

Sensory Motor

Abstract Background Sex differences in experimental stroke outcomes are well documented, such that adult males have a greater infarct volume, increased stroke-induced mortality, and more severe sensory-motor impairment. Based on recent evidence that the gut is an early responder to stroke, the present study tested the hypothesis that sex differences in stroke severity will be accompanied by rapid and greater permeability of the gut-blood barrier and gut dysbiosis in males as compared to females. Method Male and female Sprague-Dawley rats (5–7 months of age) were subject to endothelin (ET)-1-induced middle cerebral artery occlusion (MCAo). Sensory-motor tests were conducted pre- and 2 days after MCAo. Gut permeability was assessed in serum samples using biomarkers of gut permeability as well as functional assays using size-graded dextrans. Histological analysis of the gut was performed with H&E staining, periodic acid-Schiff for mucus, and immunohistochemistry for the tight junction protein, ZO-1. Fecal samples obtained pre- and post-stroke were analyzed for bacterial taxa and short-chain fatty acids (SCFAs). Results After stroke, males displayed greater mortality, worse sensory-motor deficit, and higher serum levels of proinflammatory cytokines IL-17A, MCP-1, and IL-5 as compared to females. MCAo-induced gut permeability was rapid and severe in males as indicated by dextran extravasation from the gut to the blood in the hyperacute (< 2 h) and early acute (2 days) phase of stroke. This was accompanied by dysmorphology of the gut villi and dysregulation of the tight junction protein ZO-1 in the acute phase. Fecal 16s sequencing showed no differences in bacterial diversity in the acute phase of stroke. Predictive modeling indicated that markers of gut permeability were associated with acute sensory-motor impairment and infarct volume. Conclusions These data show that extensive leakiness of the gut barrier is associated with severe post-stroke disability and suggest that reinforcing this barrier may improve stroke outcomes.

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Ground flaxseed reverses protection of a reduced-fat diet against Citrobacter rodentium-induced colitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00101.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. G788-G798 ◽

Cited By ~ 5

Author(s):

Pekka Määttänen ◽

Eberhard Lurz ◽

Steven R. Botts ◽

Richard Y. Wu ◽

C. William Yeung ◽

...

Keyword(s):

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Citrobacter Rodentium ◽

Gut Dysbiosis ◽

Reduced Fat ◽

Ground Flaxseed ◽

Pathogen Burden ◽

Chain Fatty Acids

Flaxseed is high in ω-3 polyunsaturated fatty acids, fiber, and lignans known to lower cholesterol levels. However, its use for prevention or treatment of inflammatory bowel diseases has yielded mixed results, perhaps related to dietary interactions. In this study, we evaluated the impact of ground flaxseed supplementation on the severity of Citrobacter rodentium-induced colitis in the setting of either a high-fat (HF, ~36%kcal) or reduced-fat (RF, ~12%kcal) diet. After weaning, C57BL/6 mice ( n = 8–15/treatment) were fed ground flaxseed (7 g/100 g diet) with either HF (HF Flx) or RF (RF Flx) diets for 4 wk before infection with C. rodentium or sham gavage. Weight changes, mucosal inflammation, pathogen burden, gut microbiota composition, tissue polyunsaturated fatty acids, and cecal short-chain fatty acids were compared over a 14-day infection period. The RF diet protected against C. rodentium-induced colitis, whereas the RF Flx diet increased pathogen burden, exacerbated gut inflammation, and promoted gut dysbiosis. When compared with the RF diet, both HF and HF Flx diets resulted in more severe pathology in response to C. rodentium infection. Our findings demonstrate that although an RF diet protected against C. rodentium-induced colitis and associated gut dysbiosis in mice, beneficial effects were diminished with ground flaxseed supplementation. NEW & NOTEWORTHY Our results demonstrate a strong protective effect of a reduced-fat diet against intestinal inflammation, dysbiosis, and pathogen burden during Citrobacter rodentium-induced colitis. However, ground flaxseed supplementation in the setting of a reduced-fat diet exacerbated colitis despite higher levels of intestinal n-3 polyunsaturated fatty acids and cecal short-chain fatty acids.

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Dietary fructose-induced gut dysbiosis promotes mouse hippocampal neuroinflammation: a benefit of short-chain fatty acids

Microbiome ◽

10.1186/s40168-019-0713-7 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 35

Author(s):

Jian-Mei Li ◽

Rong Yu ◽

Li-Ping Zhang ◽

Shi-Yu Wen ◽

Shui-Juan Wang ◽

...

Keyword(s):

Fatty Acids ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Gut Dysbiosis ◽

Dietary Fructose ◽

Chain Fatty Acids

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Cefazolin Improves Anesthesia and Surgery-Induced Cognitive Impairments by Modulating Blood-Brain Barrier Function, Gut Bacteria and Short Chain Fatty Acids

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.748637 ◽

2021 ◽

Vol 13 ◽

Author(s):

Ailin Luo ◽

Shan Li ◽

Xuan Wang ◽

Zheng Xie ◽

Shiyong Li ◽

...

Keyword(s):

Fatty Acids ◽

Gut Microbiota ◽

Blood Brain Barrier ◽

Short Chain Fatty Acids ◽

Gut Bacteria ◽

Short Chain ◽

Brain Barrier ◽

Gut Dysbiosis ◽

Blood Brain ◽

Chain Fatty Acids

Emerging evidence suggests that anesthesia and surgery may induce gut dysbiosis. Gut dysbiosis leads to imbalance in circulating contents of microbiota-derived metabolites and disrupts the integrity of the blood-brain barrier (BBB), contributing to postoperative cognitive dysfunction (POCD). The composition of gut microbiota may be influenced by various antibiotics. However, how perioperative use of antibiotics affects POCD needs more explorations. In the present study, we explored the effect of cefazolin, a common antibiotic used in perioperative period, on cognitive function, BBB integrity, gut bacteria and short chain fatty acids (SCFAs), a group of widely studied metabolites in aged mice, using 18-month-old male mice. Significant BBB disruptions and decreased levels of tight junction proteins, zonula occludens-1 (ZO-1) and Occludin (OCLN) were seen in the mice of POCD model. Cefazolin treatment attenuated these changes induced by anesthesia and surgery. Furthermore, cefazolin reversed the changes in several fecal bacteria (β-, γ/δ-, ε-Proteobacteria, and Bacteroidetes) as determined by qPCR tests. Analysis of plasma SCFAs showed that almost all types of SCFAs were reduced in POCD and cefazolin administration reversed the changes in expression of the two most abundant SCFAs (acetic and propionic acids). In conclusion, this study demonstrated that cefazolin improved POCD. Mechanistically, cefazolin suppressed the disruption of BBB, gut microbiota or SCFAs, thereby ameliorating POCD.

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Excessive Consumption of the Sugar Rich Longan Fruit Promoted the Development of Non-alcoholic Fatty Liver Disease via Mediating Gut Dysbiosis

10.21203/rs.3.rs-683396/v1 ◽

2021 ◽

Author(s):

Huimin Huang ◽

Mingxing Li ◽

Yi Wang ◽

Xiaoxiao Wu ◽

Qin Wang ◽

...

Keyword(s):

Fatty Acids ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Alcoholic Fatty Liver ◽

Free Sugars ◽

Gut Dysbiosis ◽

Alcoholic Fatty Liver Disease

Abstract Background: Controversy exists as towards the association of excessive fruits intake and certain disease risks. Longan is an edible fruit rich in high levels of fructose, glucose and sucrose. The aim of this study was to provide direct evidence on the effect of the sugar rich longan fruit on the development of non-alcoholic fatty liver disease (NAFLD). Chemical profiling of longan fruit was conducted using LC-HRMS and HPLC-ELSD.Results: Longan extracts at the doses of 4.0 g/kg, 8.0 and 16.0 g/kg were orally administered for 4 weeks to healthy C57BL/6J mice or to C57BL/6J mice fed with a HFD diet. Fecal microbiome was analyzed by 16S rRNA sequencing. The amounts of short chain fatty acids (SCFAs) in colonic contents were determined by GC-MS. Colon and liver tissues were used for histopathological examination after H&E, Masson’s trichrome, and Oil-red O staining. ELISA method was used for biochemical analysis in serum. In mice fed a normal diet, repeated longan intake for 4 weeks at excess doses (8 or 16 g/kg), but not the normal dose (4 g/kg), promoted inflammation and gut dysbiosis-like status and reduced short-chain fatty acids (SCFAs) production. In high-fat diet (HFD)-fed mice, longan intake at 4 g/kg hardly influenced the NAFLD development. In contrast, excess longan intake (8 or 16 g/kg) promoted NAFLD pathogenesis, including increased abnormality in hepatic indices, elevated inflammation, and gut permeability associated with more severe liver steatosis and fibrosis. Moreover, the exacerbated pathogenic markers were positively correlated with increased blood sugar, aggravated HFD-associated microbial dysbiosis. Conclusions: Effects mediated by excess longan intake resembled that of equivalent free sugars supplementation, suggesting that high level of free sugars in fruits contributed to the promotion of NAFLD development as demonstrated in case of excessive longan intake.

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Short-Chain Fatty Acids: A Soldier Fighting Against Inflammation and Protecting From Tumorigenesis in People With Diabetes

Frontiers in Immunology ◽

10.3389/fimmu.2020.590685 ◽

2020 ◽

Vol 11 ◽

Author(s):

Qiyu Yang ◽

Jing Ouyang ◽

Fengjun Sun ◽

Jiadan Yang

Keyword(s):

Fatty Acids ◽

Inflammatory Responses ◽

Intestinal Barrier ◽

Short Chain Fatty Acids ◽

Microbial Translocation ◽

Short Chain ◽

Fermentation Products ◽

Gut Dysbiosis ◽

Risk Of Cancer ◽

Chain Fatty Acids

Converging evidences showed that people with diabetes mellitus (DM) have significantly higher risk for different cancers, of which the exact mechanism underlying the association has not been fully realized. Short-chain fatty acids (SCFAs), the fermentation products of the intestinal microbiota, are an essential source for energy supply in gut epithelial cells. They have been reported to improve intestinal barrier integrity, prevent microbial translocation, and further dampen inflammation. Gut dysbiosis and reduction in SCFA-producing bacteria as well as SCFAs production in the intestine are commonly seen in metabolic disorders including DM and obesity. Moreover, inflammation can contribute to tumor initiation and progression through multiple pathways, such as enhancing DNA damage, accumulating mutations in tumor suppressor genes Tp53, and activating nuclear factor-kappa B (NF-κB) signaling pathways. Based on these facts, we hypothesize that lower levels of microbial SCFAs resulted from gut dysbiosis in diabetic individuals, enhance microbial translocation, and increase the inflammatory responses, inducing tumorigenesis ulteriorly. To this end, we will discuss protective properties of microbial SCFAs and explore the pivotal roles SCFAs played in the link of DM with cancer, so as to take early precautions to reduce the risk of cancer in patients with DM.

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Manipulation of Alcohol and Short-Chain Fatty Acids in the Metabolome of Commensal and Virulent Klebsiella pneumoniae by Linolenic Acid

Microorganisms ◽

10.3390/microorganisms8050773 ◽

2020 ◽

Vol 8 (5) ◽

pp. 773

Author(s):

Ryan Yuki Huang ◽

Deron Raymond Herr ◽

Shabbir Moochhala

Keyword(s):

Fatty Acids ◽

Klebsiella Pneumoniae ◽

Linolenic Acid ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Glucose Fermentation ◽

Alcohol Production ◽

Gut Dysbiosis ◽

Harmful Alcohol ◽

Chain Fatty Acids

Endogenous alcohol produced by the gut microbiome is transported via the bloodstream to the liver for detoxification. Gut dysbiosis can result in chronic excess alcohol production that contributes to the development of hepatic steatosis. The aim of this study was to examine whether linolenic acid can manipulate the production of harmful alcohol and beneficial short-chain fatty acids (SCFAs) in the metabolome of commensal Klebsiella pneumoniae (K. pneumoniae) and the virulent K. pneumoniae K1 serotype. Glucose fermentation by the K. pneumoniae K1 serotype yielded increased production of alcohol and decreased SCFAs (especially acetate and propionate) compared to those of commensal K. pneumoniae. However, the use of linolenic acid instead of glucose significantly reduced alcohol and increased SCFAs in the fermentation media of the K. pneumoniae K1 serotype. The work highlights the value of shaping the microbial metabolome using linolenic acid, which can potentially regulate the gut–liver axis for the prevention and treatment of alcohol-induced liver diseases.

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