Enteric Nervous System Remodeling in a Rat Model of Spinal Cord Injury: A Pilot Study

Abstract

The physiopathology of digestive disorders in patients with spinal cord injury (SCI) remains largely unknown, particularly the involvement of the enteric nervous system (ENS). We aimed in a rat model of chronic thoracic SCI to characterize (1) changes in the neurochemical coding of enteric neurons and their putative consequences upon neuromuscular response, and (2) the inflammatory response of the colon. Ex vivo motility of proximal and distal colon segments of SCI and control (CT) rats were studied in an organ chamber in response to electrical field stimulation (EFS) and bethanechol. Immunohistochemical analysis of proximal and distal segments was performed using antibodies again Hu, neuronal nitric oxide synthase, (nNOS), and choline acetyltransferase. Colonic content of acetylcholine and acetylcholinesterase was measured; messenger RNA (mRNA) expression of inflammatory cytokines was measured using reverse transcription quantitative polymerase chain reaction (RT-qPCR) approaches. Compared with the CT rats, the contractile response to bethanechol was significantly decreased in the proximal colon of SCI rats but not in the distal colon. The proportion of nNOS immunoreactive (IR) neurons was significantly reduced in the proximal but not distal colon of SCI rats. No change in proportion of choline acetyltransferase (ChAT)-IR was reported; the tissue concentration of acetylcholine was significantly decreased in the proximal colon of SCI rats. The expression of tumor necrosis factor alpha (TNF-a) and intercellular adhesion molecule-1 (ICAM-1) was significantly reduced in the proximal and distal colon of SCI rats. This study demonstrates that functional motor and enteric neuroplastic changes affect preferentially the proximal colon compared with the distal colon. The underlying mechanisms and factors responsible for these changes remain to be discovered.

Intestinal microbiota and melatonin in the treatment of secondary injury and complications after spinal cord injury

“…The interruption of the control of the advanced center leads to the loss of gastrointestinal and bladder sympathetic control, smooth muscle dysfunction, impaired intestinal movement, fecal retention or incontinence ( Holmes et al, 2020 ), and these variables are maintained throughout the acute to chronic phase of SCI. It has been studied to exclude the influence of sympathetic and parasympathetic on intestinal tract by injuring the high level thoracic spinal cord, in the mice with T8 SCI, it found that the number of nitroergic nerve cells decreased, and the number of acetylcholine decreased although the proportion of acetylcholinergic nerve did not change significantly ( Lefèvre et al, 2020 ). Another study found that nitroergic and cholinergic neurons decreased in the mice with T3 SCI ( White et al, 2020 ).…”

Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease

“…Enumeration of enteric neurons to study alterations to ENS neuronal numbers was performed by following the well-established protocol [105][106][107][108] of counting the numbers of neurons in myenteric ganglia and comparing them between animals for statistically significant differences. Identification of myenteric ganglia was performed according to our pre-determined method published earlier 19 .…”

Stroke Alters the Function of Enteric Neurons to Impair Smooth Muscle Relaxation and Dysregulates Gut Transit

“… 56 Under pathological conditions, extrinsic signaling from the central nervous system may override intrinsic homeostatic signals in the gut, resulting in disruption of gut motility, as observed in traumatic brain injury and spinal cord injury clinically and experimentally. 22 , 23 , 24 With the middle cerebral artery being the most commonly occluded vessel in clinical stroke, 57 we demonstrated that our clinically relevant permanent MCAO stroke model resulted in slowed gut transit of the distal small intestine. We generated evidence that the underlying mechanism for poststroke gut dysmotility was not accompanied by local inflammation but was primarily driven by neurogenic factors.…”

“…The opposing regulation of gut motility by ChAT + and nNOS + neurons has been explored previously in the settings of chronic spinal cord injury, Crohn disease, and ulcerative colitis whereby imbalances in ChAT or nNOS expression can lead to gut dysmotility. 22 , 62 Although the ENS is more prone to changes after chronic conditions, specific neuronal subtypes that express nNOS can be altered as early as within 24 hours in conditions such as experimental ischemia reperfusion injury of the intestinal tract. 63 Given that the role of neuronal‐derived NO is to promote relaxation of muscle cells, our finding of unchanged neuronal ChAT but reduced nNOS expression indicates that there would be reduced inhibitory neural input to the smooth muscle following MCAO.…”

“… 21 Previous studies have shown that spinal cord injury and traumatic brain injury can lead to downstream changes in ENS function and gut motility. 22 , 23 , 24 It is notable that a reduction in gut transit has also been reported in a mouse model of experimental stroke 5 ; however, the mechanisms underlying these responses are yet to be elucidated.…”