Telomere elongation in the gut extends zebrafish lifespan

Telomere shortening is a hallmark of aging and is counteracted by telomerase. The gut is one of the earliest organs to exhibit short telomeres and tissue dysfunction during normal zebrafish aging. This is recapitulated in prematurely aged telomerase mutants (tert-/-). Here, we show that gut-specific telomerase activity in tert-/- zebrafish prevents premature aging. Induction of telomerase rescues gut senescence and low cell proliferation to wild-type levels, while restoring gut tissue integrity, inflammation, and age-dependent gut microbiota dysbiosis. Remarkably, averting gut dysfunction results in a systemic beneficial impact. Gut-specific telomerase activity rescues premature aging markers in remote organs, such as the reproductive (testes) and hematopoietic (kidney marrow) systems. Functionally, it also rescues age-dependent loss of male fertility and testes atrophy. Finally, we show that gut-specific telomerase activity increases the lifespan of telomerase mutants. Our work demonstrates that delaying telomere shortening in the gut is sufficient to systemically counteract aging in zebrafish.

TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

Parkinson’s disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD, especially in a subset of people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations of gut homeostasis are hypothesized to contribute to α-synuclein aggregation in enteric neurons, which may spread to the brain over decades and eventually result in the characteristic central nervous system manifestations of PD, including neurodegeneration and motor impairments. However, the mechanisms linking gut disturbances and α-synuclein aggregation are still unclear. A plethora of research indicates that toll-like receptors (TLRs), especially TLR2 and TLR4, are critical mediators of gut homeostasis. Alongside their established role in innate immunity throughout the body, studies are increasingly demonstrating that TLR2 and TLR4 signalling shapes the development and function of the gut and the enteric nervous system. Notably, TLR2 and TLR4 are dysregulated in patients with PD, and may thus be central to early gut dysfunction in PD. To better understand the putative contribution of intestinal TLR2 and TLR4 dysfunction to early α-synuclein aggregation and PD, we critically discuss the role of TLR2 and TLR4 in normal gut function as well as evidence for altered TLR2 and TLR4 signalling in PD, by reviewing clinical, animal model and in vitro research. Growing evidence on the immunological aetiology of α-synuclein aggregation is also discussed, with a focus on the interactions of α-synuclein with TLR2 and TLR4. We propose a conceptual model of PD pathogenesis in which microbial dysbiosis alters the permeability of the intestinal barrier as well as TLR2 and TLR4 signalling, ultimately leading to a positive feedback loop of chronic gut dysfunction promoting α-synuclein aggregation in enteric and vagal neurons. In turn, α-synuclein aggregates may then migrate to the brain via peripheral nerves, such as the vagal nerve, to contribute to neuroinflammation and neurodegeneration typically associated with PD.

Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice

Inflammation may contribute to multiple brain pathologies. One cause of inflammation is lipopolysaccharide/endotoxin (LPS), the levels of which are elevated in blood and/or brain during bacterial infections, gut dysfunction and neurodegenerative diseases, such as Parkinson’s disease. How inflammation causes neuronal loss is unclear, but one potential mechanism is microglial phagocytosis of neurons, which is dependent on the microglial P2Y6 receptor. We investigated here whether the P2Y6 receptor was required for inflammatory neuronal loss. Intraperitoneal injection of LPS on 4 successive days resulted in specific loss of dopaminergic neurons (measured as cells staining with tyrosine hydroxylase or NeuN) in the substantia nigra of wild-type mice, but no neuronal loss in cortex or hippocampus. This supports the hypothesis that neuronal loss in Parkinson’s disease may be driven by peripheral LPS. By contrast, there was no LPS-induced neuronal loss in P2Y6 receptor knockout mice. In vitro, LPS-induced microglial phagocytosis of cells was prevented by inhibition of the P2Y6 receptor, and LPS-induced neuronal loss was reduced in mixed glial–neuronal cultures from P2Y6 receptor knockout mice. This supports the hypothesis that microglial phagocytosis contributes to inflammatory neuronal loss, and can be prevented by blocking the P2Y6 receptor, suggesting that P2Y6 receptor antagonists might be used to prevent inflammatory neuronal loss in Parkinson’s disease and other brain pathologies involving inflammatory neuronal loss.

Sodium nitroprusside protects HFD induced gut dysfunction via activating AMPKα/SIRT1 signaling

Background Activation of Adenosine 5′-monophosphate-activated protein kinase/Sirtuin1 (AMPK/SIRT1) exerts an effect in alleviating obesity and gut damage. Sodium nitroprusside (SNP), a nitric oxide (NO) donor, has been reported to activate AMPK. This study was to investigate the effect of SNP on HFD induced gut dysfunction and the mechanism. Methods SNP was applied on lipopolysaccharide (LPS) stimulated Caco-2 cell monolayers which mimicked intestinal epithelial barrier dysfunction and HFD-fed mice which were complicated by gut dysfunction. Then AMPKα/SIRT1 pathway and gut barrier indicators were investigated. Results SNP rescued the loss of tight junction proteins ZO-1 and occludin, the inhibition of AMPKα/SIRT1 in LPS stimulated Caco-2 cell monolayers, and the effects were not shown when AMPKa1 was knocked-down by siRNA. SNP also alleviated HFD induced obesity and gut dysfunction in mice, as indicated by the decreasing of intestinal permeability, the increasing expression of ZO-1 and occludin, the decreasing levels of pro-inflammatory cytokine IL-6, and the repairing of gut microbiota dysbiosis. These effects were complicated by the increased colonic NO content and the activated AMPKα/SIRT1 signaling. Conclusions The results may imply that SNP, as a NO donor, alleviates HFD induced gut dysfunction probably by activating the AMPKα/SIRT1 signaling pathway.

Leveraging publicly available coronavirus data to identify new therapeutic targets for COVID-19

Many important questions remain regarding severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the viral pathogen responsible for COVID-19. These questions include the mechanisms explaining the high percentage of asymptomatic but highly infectious individuals, the wide variability in disease susceptibility, and the mechanisms of long-lasting debilitating effects. Bioinformatic analysis of four coronavirus datasets representing previous outbreaks (SARS-CoV-1 and MERS-CoV), as well as SARS-CoV-2, revealed evidence of diverse host factors that appear to be coopted to facilitate virus-induced suppression of interferon-induced innate immunity, promotion of viral replication and subversion and/or evasion of antiviral immune surveillance. These host factors merit further study given their postulated roles in COVID-19-induced loss of smell and brain, heart, vascular, lung, liver, and gut dysfunction.

The Role of Dietary and Microbial Fatty Acids in the Control of Inflammation in Neonatal Piglets

Excessive inflammation and a reduced gut mucosal barrier are major causes for gut dysfunction in piglets. The fatty acid (FA) composition of the membrane lipids is crucial for mediating inflammatory signalling and is largely determined by their dietary intake. Porcine colostrum and milk are the major sources of fat in neonatal piglets. Both are rich in fat, demonstrating the dependence of the young metabolism from fat and providing the young organism with the optimum profile of lipids for growth and development. The manipulation of sow’s dietary polyunsaturated FA (PUFA) intake has been shown to be an efficient strategy to increase the transfer of specific FAs to the piglet for incorporation in enteric tissues and cell membranes. n-3 PUFAs, especially seems to be beneficial for the immune response and gut epithelial barrier function, supporting the piglet’s enteric defences in situations of increased stress such as weaning. Little is known about microbial lipid mediators and their role in gut barrier function and inhibition of inflammation in neonatal piglets. The present review summarizes the current knowledge of lipid nutrition in new-born piglets, comparing the FA ingestion from milk and plant-based lipid sources and touching the areas of host lipid signalling, inflammatory signalling and microbially derived FAs.

Gut Microbiota and Probiotics/Synbiotics for Modulation of Immunity in Critically Ill Patients

Patients suffering from critical illness have host inflammatory responses against injuries, such as infection and trauma, that can lead to tissue damage, organ failure, and death. Modulation of host immune response as well as infection and damage control are detrimental factors in the management of systemic inflammation. The gut is the motor of multiple organ failure following injury, and it is recognized that gut dysfunction is one of the causative factors of disease progression. The gut microbiota has a role in maintaining host immunity, and disruption of the gut microbiota might induce an immunosuppressive condition in critically ill patients. Treatment with probiotics and synbiotics has been reported to attenuate systemic inflammation by maintaining gut microbiota and to reduce postoperative infectious complications and ventilator-associated pneumonia. The administration of prophylactic probiotics/synbiotics could be an important treatment option for preventing infectious complications and modulating immunity. Further basic and clinical research is needed to promote intestinal therapies for critically ill patients.

Comparative short-term and long-term outcomes between internal and external intestinal plication in the management of small bowel obstruction

Background Small bowel obstruction (SBO) is common and usually requires surgical intervention. Intestinal plication is a traditional but critical strategy for SBO in certain scenarios. This study is to compare the short-term and long-term outcome between internal and external plications in the management of SBO. Methods All patients receiving intestinal plication in our hospital were retrospectively collected. Short-term outcome including postoperative complications, reoperation, postoperative ICU stay, starting day of liquid diet and postoperative hospitalization, as well as long-term outcome including recurrence of obstruction, readmission, reoperation and death were compared between groups. Gut function at annual follow-up visits was evaluated as well. Results Nine internal and 11 external candidates were recruited into each group. The major causes of plication were adhesive obstruction, abdominal cocoon, volvulus and intussusception. Lower incidence of postoperative complication (p = 0.043) and shorter postoperative hospitalization (p = 0.049) was observed in internal group. One patient receiving external plication died from anastomosis leakage. During the 5-year follow-up period, the readmission rate was low in both groups (22.2 % vs. 9.1 %), and none of patients required reoperation or deceased. None of patients exhibited gut dysfunction, and all patients restored normal gut function after 4 years. Patients in external group demonstrated accelerated recovery of gut function after surgery. Conclusions This study compares short-term and long-term outcome of patients receiving internal or external intestinal plication. We suggest a conservative attitude toward external plication strategy. Surgical indication for intestinal plication is critical and awaits future investigations.

Non-invasive, vagus nerve stimulation to reduce ileus after colorectal surgery: protocol for a feasibility trial with nested mechanistic studies

IntroductionIleus is a common and distressing condition characterised by gut dysfunction after surgery. While a number of interventions have aimed to curtail its impact on patients and healthcare systems, ileus is still an unmet challenge. Electrical stimulation of the vagus nerve is a promising new treatment due to its role in modulating the neuro-immune axis through a novel anti-inflammatory reflex. The protocol for a feasibility study of non-invasive vagus nerve stimulation (nVNS), and a programme of mechanistic and qualitative studies, is described.Methods and analysisThis is a participant-blinded, parallel-group, randomised, sham-controlled feasibility trial (IDEAL Stage 2b) of self-administered nVNS. One hundred forty patients planned for elective, minimally invasive, colorectal surgery will be randomised to four schedules of nVNS before and after surgery. Feasibility outcomes include assessments of recruitment and attrition, adequacy of blinding and compliance to the intervention. Clinical outcomes include bowel function and length of hospital stay. A series of mechanistic substudies exploring the impact of nVNS on inflammation and bowel motility will inform the design of the final stimulation schedule. Semistructured interviews with participants will explore experiences and perceptions of the intervention, while interviews with patients who decline participation will explore barriers to recruitment.Ethics and disseminationThe protocol has been approved by the Tyne and Wear South National Health Service (NHS) Research Ethics Committee (19/NE/0217) on 2 July 2019. Feasibility, mechanistic and qualitative findings will be disseminated to national and international partners through peer-reviewed publications, academic conferences, social media channels and stakeholder engagement activities. The findings will build a case for or against progression to a definitive randomised assessment as well as informing key elements of study design.Trial registration numberISRCTN62033341.

Gut microbiota in COVID-19 treatment

A novel coronavirus (severe acute respiratory syndrome coronavirus [SARS-CoV-2]), has been causing a COVID-19 pandemic of acute respiratory syndrome in humans since December 2019. It appears to be similar in structure to the virus that caused the SARS-CoV outbreak of 18 years ago. However, in addition to the respiratory disorders, the COVID-19 patients might suffer extra-pulmonary disorders, including gut dysfunction or liver dysfunction complications, which show as gut–lung crosstalk. Fecal specimens should be considered as a source of detection of SARS-CoV-2 as one of the routine diagnostic tests in order to guide hospital’s liberation and release of quarantine of patients.