Gut microbes impact stroke severity via the trimethylamine N-oxide pathway

Zhu, Weifei; Romano, Kymberleigh A.; Lin, Li; Buffa, Jennifer A.; Sangwan, Naseer; Prakash, Prem; Tittle, Aaron N; Li, Xinmin S.; Fu, Xiaoming; Androjna, Charlie; DiDonato, Anthony J.; Brinson, Kimberly; Trapp, Bruce D.; Fischbach, Michael A.; Rey, Federico E.; Hajjar, Adeline M.; DiDonato, Joseph A.; Hazen, Stanley L.

doi:10.1016/j.chom.2021.05.002

Cited by 98 publications

(65 citation statements)

References 58 publications

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“…An engineered strain Escherichia coli BL21 equipped with high β-galactosidase activity could play a role in lactose intolerance alleviation [ 27 ]. Furthermore, transplantation of defined microbial communities with genetically human commensals with engineered microbial cutC gene (an enzymatic source of choline-to-trimethylamine transformation) into germ-free mice is sufficient to transmit trimethylamine-N-oxide production, heighten cerebral infarct size, and lead to functional impairment [ 28 ]. And for that, transplantation of engineered bacteria equipped with upregulated-SCFA synthetic function, such as some decreased SCFA-synthesis enzymatic genes in AF as described in the current study, might contribute to SCFA production, and play a beneficial regulatory role in disease progression.…”

Section: Discussionmentioning

confidence: 99%

Altered synthesis of genes associated with short-chain fatty acids in the gut of patients with atrial fibrillation

et al. 2021

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Background The gut microbiota provides health benefits in humans by producing short-chain fatty acids (SCFAs), whose deficiency causes multiple disorders and inflammatory diseases. However, gut bacteria producing SCFAs in patients with atrial fibrillation (AF), an arrhythmia with increasing prevalence, have not been reported. To investigate major gut microbial organisms related to SCFA synthesis, SCFAs-associated KEGG orthologues (KOs), enzymatic genes, and potential producers were examined according to metagenomic data-mining in a northern Chinese cohort comprising 50 non-AF control and 50 AF patients. Results Compared with non-AF controls, individuals with AF had marked differences in microbial genes involved in SCFA-related synthesis, including 125 KOs and 5 SCFAs-related enzymatic genes. Furthermore, there were 10 species that harbored SCFA-synthesis related enzymatic genes, and were markedly decreased in the gut of AF patients. Notably, discriminative features about SCFA-synthesis related function, including 8 KOs (K01752, K01738, K00175, K03737, K01006, K01653, K01647 and K15023), 4 genes (menI, tesB, yciA and CO dehydrogenase acetyl-CoA synthase complex) and 2 species (Coprococcus catus and Firmicutes bacterium CAG:103), were selected as key factors based on LASSO analysis. Furthermore, PLS-SEM analysis showed that 72.8 and 91.14 % of the overall effects on gut microbiota diversity and key species on AF, respectively, were mediated by the key KOs. Meanwhile, 46.31 % of the total effects of SCFA-synthesis related function on left atrial enlargement was mediated by hsCRP. Upon incorporation of clinical properties in AF, the KO score was still significantly associated with AF incidence (OR = 0.004, P = 0.001). Conclusions The current study revealed that dysbiotic gut microbiota in AF is coupled with disrupted SCFA-synthesis related genes, characterized by decreased abundances of KEGG orthologues, synthesis enzymatic genes and harboring species.

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Section: Discussionmentioning

confidence: 99%

Altered synthesis of genes associated with short-chain fatty acids in the gut of patients with atrial fibrillation

et al. 2021

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“…A meta-analysis also showed that compared with non-stroke controls, TMAO increased the stroke risks by 68% and accreted 2.201 umol/L on the average level of TMAO in stroke patients (82). Zhu et al's study also suggested gut microbiota can impact stroke severity via the gut microbial CutC-mediated TMAO pathway, which exacerbated cerebral infarct size and functional deficits (74).…”

Section: Ischemic Strokementioning

confidence: 97%

Gut Microbiota and Acute Central Nervous System Injury: A New Target for Therapeutic Intervention

Yuan

2021

Front. Immunol.

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Acute central nervous system (CNS) injuries, including stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), are the common causes of death or lifelong disabilities. Research into the role of the gut microbiota in modulating CNS function has been rapidly increasing in the past few decades, particularly in animal models. Growing preclinical and clinical evidence suggests that gut microbiota is involved in the modulation of multiple cellular and molecular mechanisms fundamental to the progression of acute CNS injury-induced pathophysiological processes. The altered composition of gut microbiota after acute CNS injury damages the equilibrium of the bidirectional gut-brain axis, aggravating secondary brain injury, cognitive impairments, and motor dysfunctions, which leads to poor prognosis by triggering pro-inflammatory responses in both peripheral circulation and CNS. This review summarizes the studies concerning gut microbiota and acute CNS injuries. Experimental models identify a bidirectional communication between the gut and CNS in post-injury gut dysbiosis, intestinal lymphatic tissue-mediated neuroinflammation, and bacterial-metabolite-associated neurotransmission. Additionally, fecal microbiota transplantation, probiotics, and prebiotics manipulating the gut microbiota can be used as effective therapeutic agents to alleviate secondary brain injury and facilitate functional outcomes. The role of gut microbiota in acute CNS injury would be an exciting frontier in clinical and experimental medicine.

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“…230 Importantly, the detrimental effects of TMAO on stroke severity and outcomes can be transferred through FMT, provided that microbial lyases are present to convert choline to TMA. 231 Another study showed that levels of proinflammatory Ly6C high monocytes were higher in mice fed with choline-rich diet to increase TMAO synthesis, but this increase in inflammatory monocytes was abolished if mice received antibiotics with the choline-rich diet. 232 FMT studies have shown that stroke severity is transmissible and the TMAO pathway may be a mediator of this transmissibility.…”

Section: Microbiota-based Treatments For Strokementioning

confidence: 99%

Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome

Honarpisheh

Bryan

McCullough

2022

Circulation Research

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The microbiota-gut-brain-axis (MGBA) is a bidirectional communication network between gut microbes and their host. Many environmental and host-related factors affect the gut microbiota. Dysbiosis is defined as compositional and functional alterations of the gut microbiota that contribute to the pathogenesis, progression and treatment responses to disease. Dysbiosis occurs when perturbations of microbiota composition and function exceed the ability of microbiota and its host to restore a symbiotic state. Dysbiosis leads to dysfunctional signaling of the MGBA, which regulates the development and the function of the host’s immune, metabolic, and nervous systems. Dysbiosis-induced dysfunction of the MGBA is seen with aging and stroke, and is linked to the development of common stroke risk factors such as obesity, diabetes, and atherosclerosis. Changes in the gut microbiota are also seen in response to stroke, and may impair recovery after injury. This review will begin with an overview of the tools used to study the MGBA with a discussion on limitations and potential experimental confounders. Relevant MGBA components are introduced and summarized for a better understanding of age-related changes in MGBA signaling and its dysfunction after stroke. We will then focus on the relationship between the MGBA and aging, highlighting that all components of the MGBA undergo age-related alterations that can be influenced by or even driven by the gut microbiota. In the final section, the current clinical and preclinical evidence for the role of MGBA signaling in the development of stroke risk factors such as obesity, diabetes, hypertension, and frailty are summarized, as well as microbiota changes with stroke in experimental and clinical populations. We conclude by describing the current understanding of microbiota-based therapies for stroke including the use of pre-/pro-biotics and supplementations with bacterial metabolites. Ongoing progress in this new frontier of biomedical sciences will lead to an improved understanding of the MGBA’s impact on human health and disease.

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Gut microbes impact stroke severity via the trimethylamine N-oxide pathway

Cited by 98 publications

References 58 publications

Altered synthesis of genes associated with short-chain fatty acids in the gut of patients with atrial fibrillation

Altered synthesis of genes associated with short-chain fatty acids in the gut of patients with atrial fibrillation

Gut Microbiota and Acute Central Nervous System Injury: A New Target for Therapeutic Intervention

Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome

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