Gut dysbiosis impairs recovery after spinal cord injury

Kigerl, Kristina A.; Hall, Jodie C. E.; Wang, Lingling; Mo, Xiaokui; Yu, Zhongtang; Popovich, Phillip G.

doi:10.1084/jem.20151345

Cited by 255 publications

(304 citation statements)

References 124 publications

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“…It has recently been postulated that a better understanding of the contributions and responses by the brain-gut-microbiota axis to chronic inflammation and brain injury would expand opportunities for therapeutics interventions for the long-term sequelae of TBI 69 . Acute and chronic changes in the gut microbiome following CNS injuries such as spinal cord injury and ischemic brain injury are associated with intestinal barrier dysfunction, immune dysregulation, and functional neurologic deficits 70,71 . Moreover, induction of gut dysbiosis has been demonstrated to have deleterious effects on the outcome of acute ischemic brain injury, including increased lesion volume and neuroinflammation 72–74 .…”

Section: Discussionmentioning

confidence: 99%

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

Elise

Smith

Desai

et al. 2017

Brain, Behavior, and Immunity

128

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Objectives Traumatic brain injury (TBI) has complex effects on the gastrointestinal tract that are associated with TBI-related morbidity and mortality. We examined changes in mucosal barrier properties and enteric glial cell response in the gut after experimental TBI in mice, as well as effects of the enteric pathogen Citrobacter rodentium (Cr) on both gut and brain after injury. Methods Moderate-level TBI was induced in C57BL/6 mice by controlled cortical impact (CCI). Mucosal barrier function was assessed by transepithelial resistance, fluorescent-labelled dextran flux, and quantification of tight junction proteins. Enteric glial cell number and activation were measured by Sox10 expression and GFAP reactivity, respectively. Separate groups of mice were challenged with Cr infection during the chronic phase of TBI, and host immune response, barrier integrity, enteric glial cell reactivity, and progression of brain injury and inflammation were assessed. Results Chronic CCI induced changes in colon morphology, including increased mucosal depth and smooth muscle thickening. At day 28 post-CCI, increased paracellular permeability and decreased claudin-1 mRNA and protein expression were observed in the absence of inflammation in the colon. Colonic glial cell GFAP and Sox10 expression were significantly increased 28 days after brain injury. Clearance of Cr and upregulation of Th1/Th17 cytokines in the colon were unaffected by CCI; however, colonic paracellular flux and enteric glial cell GFAP expression were significantly increased. Importantly, Cr infection in chronically-injured mice worsened the brain lesion injury and increased astrocyte- and microglial-mediated inflammation. Conclusion These experimental studies demonstrate chronic and bidirectional brain-gut interactions after TBI, which may negatively impact late outcomes after brain injury.

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Section: Discussionmentioning

confidence: 99%

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

Elise

Smith

Desai

et al. 2017

Brain, Behavior, and Immunity

128

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“…administered 6‐hydroxy‐dopamine, which results in a potent increase in systemic noradrenaline release, to mice and observed a decrease in the abundance of Prevotellaceae . Additionally, recent preclinical data suggest that the gut microbiota can influence the severity of neurological damage following spinal cord injury …”

Section: Microbiota and Neurology: Aging And Neurodegenerationmentioning

confidence: 99%

Recent developments in understanding the role of the gut microbiota in brain health and disease

Sherwin

Dinan

Cryan

2017

Annals of the New York Academy of Sciences

273

164

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There is a growing appreciation of the role of the gut microbiota in all aspects of health and disease, including brain health. Indeed, roles for the bacterial commensals in various psychiatric and neurological conditions, such as depression, autism, stroke, Parkinson's disease, and Alzheimer's disease, are emerging. Microbiota dysregulation has been documented in all of these conditions or in animal models thereof. Moreover, depletion or modulation of the gut microbiota can affect the severity of the central pathology or behavioral deficits observed in a variety of brain disorders. However, the mechanisms underlying such effects are only slowly being unraveled. Additionally, recent preclinical and clinical evidence suggest that targeting the microbiota through prebiotic, probiotic, or dietary interventions may be an effective "psychobiotic" strategy for treating symptoms in mood, neurodevelopmental disorders, and neurodegenerative diseases.

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“…), recovery from neurological injury (Kigerl et al . ), metabolic syndrome, and obesity (Tilg and Kaser ; Sanmiguel et al . ; Economopoulos et al .…”

Section: Introductionmentioning

confidence: 99%

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

et al. 2017

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Aim: To evaluate an antibiotic inactivation strategy to protect the gut microbiome from antibiotic-mediated damage. Methods and Results: SYN-004 (ribaxamase) is an orally delivered betalactamase intended to degrade penicillins and cephalosporins within the gastrointestinal tract to protect the microbiome. Pigs (20 kg, n = 10) were treated with ceftriaxone (CRO) (IV, 50 mg kg À1, SID) for 7 days and a cohort (n = 5) received ribaxamase (PO, 75 mg, QID) for 9 days beginning the day before antibiotic administration. Ceftriaxone serum levels were not statistically different in the antibiotic-alone and antibiotic + ribaxamase groups, indicating ribaxamase did not alter systemic antibiotic levels. Whole-genome metagenomic analyses of pig faecal DNA revealed that CRO caused significant changes to the gut microbiome and an increased frequency of antibiotic resistance genes. With ribaxamase, the gut microbiomes were not significantly different from pretreatment and antibiotic resistance gene frequency was not increased. Conclusion: Ribaxamase mitigated CRO-mediated gut microbiome dysbiosis and attenuated propagation of the antibiotic resistance genes in pigs. Significance and Impact of the Study: Damage of the microbiome can lead to overgrowth of pathogenic organisms and antibiotic exposure can promote selection for antibiotic-resistant micro-organisms. Ribaxamase has the potential to become the first therapy designed to protect the gut microbiome from antibiotic-mediated dysbiosis and reduce emergence of antibiotic resistance.

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Gut dysbiosis impairs recovery after spinal cord injury

Abstract: Kigerl et al. show that spinal cord injury causes profound changes in gut microbiota and that these changes in gut ecology are associated with activation of GALT immune cells. They show that feeding mice probiotics after SCI confers neuroprotection and improves functional recovery.

Cited by 255 publications

References 124 publications

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

Recent developments in understanding the role of the gut microbiota in brain health and disease

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

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