Retinitis pigmentosa (RP) is a photoreceptor-degenerative disease caused by various mutations and is characterized by death of rod photoreceptor cell followed by gradual death of cone photoreceptors. The molecular mechanisms that lead to rod and cone death are not yet fully understood. Neuroinflammation contributes to the progression of many chronic neurodegenerative disorders. However, it remains to be determined how microglia contribute to photoreceptor disruption in RP. In this study, we explored the role of microglia as a contributor to photoreceptor degeneration in the rd10 mouse model of RP. First, we demonstrated that microglia activation was an early alteration in RP retinas. Inhibition of microglia activation by minocycline reduced photoreceptor apoptosis and significantly improved retinal structure and function and visual behavior in rd10 mice. Second, we identified that minocycline exerted its neuroprotective effects through both anti-inflammatory and anti-apoptotic mechanisms. Third, we found that Cx3cr1 deficiency dysregulated microglia activation and subsequently resulted in increased photoreceptor vulnerability in rd10 mice, suggesting that the Cx3cl1/Cx3cr1 signaling pathway might protect against microglia neurotoxicity. We concluded that suppression of neuroinflammatory responses could be a potential treatment strategy aimed at improving photoreceptor survival in human RP.

Suppression of microglial activation is neuroprotective in a mouse model of human retinitis pigmentosa

Early life gut microbiota have been increasingly recognized as major contributors to short and/or long-term human health and diseases. Numerous studies have demonstrated that human gut microbial colonization begins at birth, but continues to develop a succession of taxonomic abundances for two to three years until the gut microbiota reaches adult-like diversity and proportions. Several factors, including gestational age (GA), delivery mode, birth weight, feeding types, antibiotic exposure, maternal microbiome, and diet, influence the diversity, abundance, and function of early life gut microbiota. Gut microbial life is essential for assisting with the digestion of food substances to release nutrients, exerting control over pathogens, stimulating or modulating the immune system, and influencing many systems such as the liver, brain, and endocrine system. Microbial metabolites play multiple roles in these interactions. Furthermore, studies provide evidence supporting that imbalances of the gut microbiota in early life, referred to as dysbiosis, are associated with specific childhood or adult disease outcomes, such as asthma, atopic dermatitis, diabetes, allergic diseases, obesity, cardiovascular diseases (CVD), and neurological disorders. These findings support that the human gut microbiota may play a fundamental role in the risk of acquiring diseases that may be programmed during early life. In fact, it is critical to explore the role of the human gut microbiota in early life.

https://www.mdpi.com/2077-0383/10/3/459/pdf

The Association between Early-Life Gut Microbiota and Long-Term Health and Diseases.

Background Parkinson's disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently, it has been increasingly evident that gut microbiota affects the communication between the gut and the brain in PD pathogenesis, known as the microbiota-gut-brain axis. As an approach to re-establishing a normal microbiota community, fecal microbiota transplantation (FMT) has exerted beneficial effects on PD in recent studies. Here, in this study, we established a chronic rotenone-induced PD mouse model to evaluate the protective effects of FMT treatment on PD and to explore the underlying mechanisms, which also proves the involvement of gut microbiota dysbiosis in PD pathogenesis via the microbiota-gut-brain axis. Results We demonstrated that gut microbiota dysbiosis induced by rotenone administration caused gastrointestinal function impairment and poor behavioral performances in the PD mice. Moreover, 16S RNA sequencing identified the increase of bacterial genera Akkermansia and Desulfovibrio in fecal samples of rotenone-induced mice. By contrast, FMT treatment remarkably restored the gut microbial community, thus ameliorating the gastrointestinal dysfunctions and the motor deficits of the PD mice. Further experiments revealed that FMT administration alleviated intestinal inflammation and barrier destruction, thus reducing the levels of systemic inflammation. Subsequently, FMT treatment attenuated blood-brain barrier (BBB) impairment and suppressed neuroinflammation in the substantia nigra (SN), which further decreased the damage of dopaminergic neurons. Additional mechanistic investigation discovered that FMT treatment reduced lipopolysaccharide (LPS) levels in the colon, the serum, and the SN, thereafter suppressing the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products both in the SN and the colon. Conclusions Our current study demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, we prove that rotenone-induced microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axis. Video abstract.

Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. The discovery of genes associated with amyotrophic lateral sclerosis, commencing with SOD1 in 1993, started fairly gradually. Recent advances in genetic technology have led to the rapid identification of multiple new genes associated with the disease, and to a new understanding of oligogenic and polygenic disease risk. The overlap of genes associated with amyotrophic lateral sclerosis with those of other neurodegenerative diseases is shedding light on the phenotypic spectrum of neurodegeneration, leading to a better understanding of genotype-phenotype correlations. A deepening knowledge of the genetic architecture is allowing the characterisation of the molecular steps caused by various mutations that converge on recurrent dysregulated pathways. Of crucial relevance, mutations associated with amyotrophic lateral sclerosis are amenable to novel gene-based therapeutic options, an approach in use for other neurological illnesses. Lastly, the exposome-the summation of lifetime environmental exposures-has emerged as an influential component for amyotrophic lateral sclerosis through the gene-time-environment hypothesis. Our improved understanding of all these aspects will lead to long-awaited therapies and the identification of modifiable risks factors. 

Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis

http://manuscript.elsevier.com/S0140673622012727/pdf/S0140673622012727.pdf

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease. Genetic predisposition, epigenetic changes, aging and accumulated life-long environmental exposures are known ALS risk factors. The complex and dynamic interplay between these pathological influences plays a role in disease onset and progression. Recently, the gut microbiome has also been implicated in ALS development. In addition, immune cell populations are differentially expanded and activated in ALS compared to healthy individuals. However, the temporal evolution of both the intestinal flora and the immune system relative to symptom onset in ALS is presently not fully understood. To better elucidate the timeline of the various potential pathological factors, we performed a longitudinal study to simultaneously assess the gut microbiome, immunophenotype and changes in ileum and brain epigenetic marks relative to motor behavior and muscle atrophy in the mutant superoxide dismutase 1 (SOD1G93A) familial ALS mouse model. We identified alterations in the gut microbial environment early in the life of SOD1G93A animals followed by motor dysfunction and muscle atrophy, and immune cell expansion and activation, particularly in the spinal cord. Global brain cytosine hydroxymethylation was also altered in SOD1G93A animals at disease end-stage compared to control mice. Correlation analysis confirmed interrelationships with the microbiome and immune system. This study serves as a starting point to more deeply comprehend the influence of gut microorganisms and the immune system on ALS onset and progression. Greater insight may help pinpoint novel biomarkers and therapeutic interventions to improve diagnosis and treatment for ALS patients.This article has an associated First Person interview with the joint first authors of the paper.

/pdf/temporal-evolution-of-the-microbiome-immune-system-and-522mfpnz25.pdf

Temporal evolution of the microbiome, immune system and epigenome with disease progression in ALS mice.

NK cells are innate immune cells implicated in ALS; whether NK cells impact ALS in a sex- and age-specific manner was investigated. Herein, NK cells were depleted in male and female SOD1G93A ALS mice, survival and neuroinflammation were assessed, and data were stratified by sex. NK cell depletion extended survival in female but not male ALS mice with sex-specific effects on spinal cord microglia. In humans, NK cell numbers, NK cell subpopulations, and NK cell surface markers were examined in prospectively blood collected from subjects with ALS and control subjects; longitudinal changes in these metrics were correlated to revised ALS functional rating scale (ALSFRS-R) slope and stratified by sex and age. Expression of NK cell trafficking and cytotoxicity markers was elevated in subjects with ALS, and changes in CXCR3+ NK cells and 7 trafficking and cytotoxicity markers (CD11a, CD11b, CD38, CX3CR1, NKG2D, NKp30, NKp46) correlated with disease progression. Age affected the associations between ALSFRS-R and markers NKG2D and NKp46, whereas sex impacted the NKp30 association. Collectively, these findings suggest that NK cells contribute to ALS progression in a sex- and age-specific manner and demonstrate that age and sex are critical variables when designing and assessing ALS immunotherapy.

/pdf/nk-cells-associate-with-als-in-a-sex-and-age-dependent-2dvvtfl2mw.pdf

NK cells associate with ALS in a sex- and age-dependent manner

Modeling glioblastoma complexity with organoids for personalized treatments.

Spinal cord injury (SCI) affects approximately 1.3 million people living in the United States. Most research efforts have been focused on reversing paralysis, as this is arguably the most defining feature of SCI. The damage due to SCI, however, extends past paralysis and includes other debilitating outcomes including immune dysfunction and gut dysbiosis. Recent efforts are now investigating the pathophysiology of and developing therapies for these more distal manifestations of SCI. One exciting avenue is the spinal cord-gut-immune axis, which proposes that gut dysbiosis amplifies lesion inflammation and impairs SCI recovery. This review will highlight the most recent findings regarding gut and immune dysfunction following SCI, and discuss how the CNS, gut, and immune system all coalesce to form a bidirectional axis that can impact SCI recovery. Finally, important considerations into how the spinal cord-gut-immune axis fits within the larger framework of therapeutic development (i.e., probiotics, fecal transplants, dietary modifications) will be discussed, emphasizing the lack of interdepartmental investigation and the missed opportunity to maximize therapeutic benefit in SCI.

The spinal cord-gut-immune axis and its implications on therapeutic development for spinal cord injury.

Abstract Intraoperative neuromonitoring is recommended as standard practice for corrective scoliosis surgery. Common methods include somatosensory-evoked potentials (SSEPs) and transcranial motor-evoked potentials (TcMEPs), which have been shown to have a high diagnostic accuracy in detecting new neurological deficits postoperatively. Sequential compression devices (SCDs) are a common method for thromboprophylaxis in spine surgery and are not known to have many device-related complications. To date, there have been no reports of lower extremity ischemia secondary to SCD deflation failure detected by multimodality neuromonitoring during minimally invasive posterior spine surgery. We, therefore, present a case report of an 18-year-old male with adolescent idiopathic scoliosis who underwent minimally invasive posterior spinal fusion with instrumentation. Intraoperative decrease in SSEPs and TcMEPs were noted in the left leg shortly after incision before any instrumentation or reduction occurred. Further examination revealed that the left leg was hypoperfused compared with the right leg and that the left SCD was not properly deflating. Bilateral SCDs were removed, and perfusion and neuromonitoring returned to baseline immediately. Bilateral SCDs and the machine were replaced, and neuromonitoring remained within normal limits for the rest of the surgery. The patient had no postoperative neurologic or vascular deficits. Early detection of lower extremity ischemia by neuromonitoring resulted in the prompt identification and addressing of SCD malfunction, sparing devastating neurological and vascular injury to the patient's leg. This case reinforces the importance of neuromonitoring within spine surgery.

Kristen D. Raue

Papers

Temporal evolution of the microbiome, immune system and epigenome with disease progression in ALS mice.

NK cells associate with ALS in a sex- and age-dependent manner

Modeling glioblastoma complexity with organoids for personalized treatments.

The spinal cord-gut-immune axis and its implications on therapeutic development for spinal cord injury.

Failure of Sequential Compression Device Detected by Neuromonitoring during Minimally Invasive Posterior Scoliosis Surgery