Gut Dysfunction Research Articles

Prevention of colitis-induced liver oxidative stress and inflammation in a transgenic mouse model with increased omega-3 polyunsaturated fatty acids

Inflammatory bowel disease (IBD) is an immune-mediated gut dysfunction, which might also be associated with an inflammatory phenotype in the liver. It is known that the nutritional intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) is inversely correlated to the severity and occurrence of IBD. In order to investigate whether n-3 PUFA can also reduce liver inflammation and oxidative liver damage due to colon inflammation, we explored the dextran sulfate sodium (DSS)-induced colitis model in wild-type and fat-1 mice with endogenously increased n-3 PUFA tissue content. Besides confirming previous data of alleviated DSS-induced colitis in the fat-1 mouse model, the increase of n-3 PUFA also resulted in a significant reduction of liver inflammation and oxidative damage in colitis-affected fat-1 mice as compared to wild-type littermates. This was accompanied by a remarkable increase of established inflammation-dampening n-3 PUFA oxylipins, namely docosahexaenoic acid-derived 19,20-epoxydocosapentaenoic acid and eicosapentaenoic acid-derived 15-hydroxyeicosapentaenoic acid and 17,18-epoxyeicosatetraenoic acid. Taken together, these observations demonstrate a strong inverse correlation between the anti-inflammatory lipidome derived from n-3 PUFA and the colitis-triggered inflammatory changes in the liver by reducing oxidative liver stress.

Chronic early life stress alters the neuroimmune profile and functioning of the developing zebrafish gut

Chronic early life stress (ELS) potently impacts the developing central nervous and immune systems and is associated with the onset of gastrointestinal disease in humans. Though the gut-brain axis is appreciated to be a major target of the stress response, the underlying mechanisms linking ELS to gut dysfunction later in life is incompletely understood. Zebrafish are a powerful model validated for stress research and have emerged as an important tool in delineating neuroimmune mechanisms in the developing gut. Here, we developed a novel model of ELS and utilized a comparative transcriptomics approach to assess how chronic ELS modulated expression of neuroimmune genes in the developing gut and brain. Zebrafish exposed to ELS throughout larval development exhibited anxiety-like behavior and altered expression of neuroimmune genes in a time- and tissue-dependent manner. Further, the altered gut neuroimmune profile, which included increased expression of genes associated with neuronal modulation, correlated with a reduction in enteric neuronal density and delayed gut transit. Together, these findings provide insights into the mechanisms linking ELS with gastrointestinal dysfunction and highlight the zebrafish model organism as a valuable tool in uncovering how “the body keeps the score.”

Nutritional strategies during gastrointestinal dysfunction.

Gastrointestinal (GI) dysfunction is common among critically ill patients and is associated with poor outcomes. In particular, nutrient delivery can be impaired in patients with GI dysfunction and pose a significant challenge to clinicians in daily clinical practice. This review aims to summarize the impact of GI dysfunction on nutrition therapy during critical illness and provide an update on recent advances in nutritional strategies during gastrointestinal dysfunction. Although prognostic gastrointestinal dysfunction scoring systems exist, a lack of clear, uniform definitions of GI dysfunction limits diagnosis and subsequent adequate treatment. Recent studies have further investigated separate components of GI dysfunction in ICU patients, including the role of altered GI motility, nutrient digestion and absorption and the metabolic consequences of gut dysfunction. Various strategies to improve nutrient delivery are discussed. However, the evidence supporting their routine use is sometimes lacking. GI dysfunction frequently occurs during critical illness and negatively affects nutrition therapy. Strategies to improve nutrient delivery during GI dysfunction are available, though more research into the diagnosis and pathophysiology of GI dysfunction will likely further improve patient outcomes.

Revisiting the neuroinflammation hypothesis in Alzheimer's disease: a focus on the druggability of current targets.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease and disability in the elderly; it is estimated to account for 60%-70% of all cases of dementia worldwide. The most relevant mechanistic hypothesis to explain AD symptoms is neurotoxicity induced by aggregated amyloid-β peptide (Aβ) and misfolded tau protein. These molecular entities are seemingly insufficient to explain AD as a multifactorial disease characterized by synaptic dysfunction, cognitive decline, psychotic symptoms, chronic inflammatory environment within the central nervous system (CNS), activated microglial cells, and dysfunctional gut microbiota. The discovery that AD is a neuroinflammatory disease linked to innate immunity phenomena started in the early nineties by several authors, including the ICC´s group that described, in 2004, the role IL-6 in AD-type phosphorylation of tau protein in deregulating the cdk5/p35 pathway. The "Theory of Neuroimmunomodulation", published in 2008, proposed the onset and progression of degenerative diseases as a multi-component "damage signals" phenomena, suggesting the feasibility of "multitarget" therapies in AD. This theory explains in detail the cascade of molecular events stemming from microglial disorder through the overactivation of the Cdk5/p35 pathway. All these knowledge have led to the rational search for inflammatory druggable targets against AD. The accumulated evidence on increased levels of inflammatory markers in the cerebrospinal fluid (CSF) of AD patients, along with reports describing CNS alterations caused by senescent immune cells in neuro-degenerative diseases, set out a conceptual framework in which the neuroinflammation hypothesis is being challenged from different angles towards developing new therapies against AD. The current evidence points to controversial findings in the search for therapeutic candidates to treat neuroinflammation in AD. In this article, we discuss a neuroimmune-modulatory perspective for pharmacological exploration of molecular targets against AD, as well as potential deleterious effects of modifying neuroinflammation in the brain parenchyma. We specifically focus on the role of B and T cells, immuno-senescence, the brain lymphatic system (BLS), gut-brain axis alterations, and dysfunctional interactions between neurons, microglia and astrocytes. We also outline a rational framework for identifying "druggable" targets for multi-mechanistic small molecules with therapeutic potential against AD.

Vitamin E ameliorates oxidative stress in the stomach of l-arginine induced acute pancreatitis rat model

Gut dysfunction is a major outcome during acute pancreatitis (AP). Some studies have reported a positive association between acute pancreatitis and peptic ulcer. The major cause of peptic ulcer is due to ischaemia reperfusion leading to oxidative stress. This study assessed the oxidative status of the stomach during AP and the role of vitamin (Vit.) E administration. Twenty male Wistar rats were divided randomly into 4 groups; Control, Vit. E (500 mg/kg) only, AP and Vit. E + AP. Acute pancreatitis was induced by administering four doses of l-arginine (100 mg/100 g) intraperitoneally at 1-hour interval. The rats were sacrificed 72 hours later and stomach obtained for mucin content and biochemical assays (MDA, MPO, NO, CAT, GST, and GSH). Mucin content was depleted following AP induction while, vit. E significantly increase mucin content. AP resulted in significant reduction of antioxidant enzymes (GSH and GST) and increase in oxidative stress markers (MDA, MPO and NO). Vitamin E reverse these changes. In conclusion, the oxidative status of the stomach was greatly altered following AP induction with an increase in oxidative stress markers and decrease in antioxidants. Vitamin E was able to protect the stomach from the damaging effect of acute pancreatitis.

Podoplanin-positive dilated lymphatic vessels in duodenum associates with three-month mortality in patients with cirrhosis.

Dilated and dysfunctional gut lymphatic vessels (LVs) have been reported in experimental cirrhosis. Here, we studied LVs in duodenal (D2)-biopsies of liver cirrhosis patients and investigated the prognostic role of a LV marker, podoplanin (PDPN), in predicting the mortality of patients with cirrhosis. A prospective, single-center cohort study was performed in liver cirrhosis patients (n = 31) and matched healthy controls (n = 9). D2-biopsies were obtained during endoscopy procedure, immunostained with PDPN, and scored based on 1) intensity and 2) density of positively-stained LVs per high power field. Gut and systemic inflammation were estimated by quantifying duodenal CD3+ intraepithelial lymphocytes (IELs), CD68+ macrophages, and serum TNF-α and IL-6 levels, respectively. Gut permeability and inflammation as assessed by quantifying gene expression of TJP1, OCLN, TNF-α, and IL-6 in D2-biopsies. Gene expression of LV markers, PDPN (8-fold), and LYVE1 (3-fold) was enhanced in D2-biopsies of cirrhosis patients compared to control (p < 0.0001). The mean PDPN score in decompensated cirrhosis patients (6.91 ± 1.26, p < 0.0001) was significantly increased as compared to those with compensated (3.25 ± 1.60). PDPN score positively and significantly correlated with the number of IELs (r = 0.33), serum TNF-α (r = 0.35), and IL-6 (r = 0.48) levels, while inversely correlated with TJP1 expression (r = -0.46, p < 0.05 each). In Cox regression, the PDPN score was a significant and independent 3-month-mortality predictor in patients (HR: 5.61; 1.08-29.109; p = 0.04). The area under the curve for the PDPN score was 84.2, and cutoff value for predicting mortality was ≥6.5 with 100% sensitivity and 75% specificity. Collectively, dilated LVs with high PDPN expression in D2-biopsies is a characteristic feature of patients with decompensated cirrhosis. PDPN score correlates with enhanced gut and systemic inflammation and also associates with 3-month mortality in cirrhosis.

The Endotoxin Hypothesis of Parkinson's Disease.

The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Involvement of Immune Cells Between Ischemic Stroke and Gut Microbiota.

Ischemic stroke, a disease with high mortality and disability rate worldwide, currently has no effective treatment. The systemic inflammation response to the ischemic stroke, followed by immunosuppression in focal neurologic deficits and other inflammatory damage, reduces the circulating immune cell counts and multiorgan infectious complications such as intestinal and gut dysfunction dysbiosis. Evidence showed that microbiota dysbiosis plays a role in neuroinflammation and peripheral immune response after stroke, changing the lymphocyte populations. Multiple immune cells, including lymphocytes, engage in complex and dynamic immune responses in all stages of stroke and may be a pivotal moderator in the bidirectional immunomodulation between ischemic stroke and gut microbiota. This review discusses the role of lymphocytes and other immune cells, the immunological processes in the bidirectional immunomodulation between gut microbiota and ischemic stroke, and its potential as a therapeutic strategy for ischemic stroke.

How Toll-like receptors influence Parkinson's disease in the microbiome-gut-brain axis.

Recently, a large number of experimenters have found that the pathogenesis of Parkinson's disease may be related to the gut microbiome and proposed the microbiome-gut-brain axis. Studies have shown that Toll-like receptors, especially Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4), are key mediators of gut homeostasis. In addition to their established role in innate immunity throughout the body, research is increasingly showing that the Toll-like receptor 2 and Toll-like receptor 4 signaling pathways shape the development and function of the gut and enteric nervous system. Notably, Toll-like receptor 2 and Toll-like receptor 4 are dysregulated in Parkinson's disease patients and may therefore be identified as the core of early gut dysfunction in Parkinson's disease. To better understand the contribution of Toll-like receptor 2 and Toll-like receptor 4 dysfunction in the gut to early α-synuclein aggregation, we discussed the structural function of Toll-like receptor 2 and Toll-like receptor 4 and signal transduction of Toll-like receptor 2 and Toll-like receptor 4 in Parkinson's disease by reviewing clinical, animal models, and in vitro studies. We also present a conceptual model of the pathogenesis of Parkinson's disease, in which microbial dysbiosis alters the gut barrier as well as the Toll-like receptor 2 and Toll-like receptor 4 signaling pathways, ultimately leading to a positive feedback loop for chronic gut dysfunction, promoting α-synuclein aggregation in the gut and vagus nerve.

Microbes, metabolites and muscle: Metagenomic and metabolomic analyses in a mouse model of muscular dystrophy

Skeletal muscle is the largest metabolic organ. The metabolic and endocrine nature of skeletal muscle allows for long-range signaling and influence over the enteric environment and the resident microbiota. Commensal microbial signaling can influence the composition and development of skeletal muscle, forming a bidirectional gut-muscle axis.Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease characterised by skeletal muscle atrophy, fibrosis, and ultimately cardiorespiratory failure. The pathways involved in muscle atrophy can be influenced via gut microbial signaling; thus we sought to characterize metabolic signaling between the gut and the diaphragm in a mouse model of DMD ( mdx) to look for potential therapeutic targets.The study was divided into two arms and conducted following institutional ethical approval. The first arm investigated metabolomic signaling. 6-month-old male BL10 wildtype (WT; n = 12) and mdx (n = 12) mice were anaesthetized (induction by 5% isoflurane) and decapitated. Following collection of trunk blood, the diaphragm was excised, and colonic/cecal contents were collected. The samples were then processed by mass-spectrometry to isolate the metabolomic profiles of semi-polar, secondary bile acid, and short chain fatty acid (SCFA) targets in the gut, plasma and diaphragm of WT and mdx mice. The second arm of the study explores the gut microbial profile and diaphragm gene expression, structure and function. 6-month-old male WT (n = 15) and mdx (n = 15) were anesthetized (induction by 5% isoflurane) followed by cervical dislocation. The diaphragm was excised, and longitudinal strips were isolated for structural analysis (i.e., histological staining and immunohistochemistry for fibre type and size), PCR gene expression, and isometric force assessment ex vivo. Additionally, fecal pellets were collected and analyzed via shotgun metagenomic sequencing to assess microbial populations.Diaphragm twitch and tetanic force are profoundly decreased in mdx mice compared to WT. Our preliminary analysis suggests a substantially altered metabolic profile within skeletal muscle affecting glycolysis and oxidative metabolism. Interestingly, mdx diaphragms have lowered expression of the Olfr78 receptor, found within the vasculature of skeletal muscle, which transduces short-chain fatty acid signaling, primarily acetate and propionate. Our analysis of faecal metabolites showed a significant decrease in acetate (which also functions as a substrate in oxidative metabolism) in mdx mice. Activation of Olfr78 receptors contributes to vasodilation which suggests that blood supply to the mdx diaphragm may be compromised. Full analysis of metabolomic data and faecal metagenomic data is currently underway.A comprehensive characterisation of the gut-muscle axis in mdx mice may pave the way for novel microbiota-directed therapeutic strategies to ameliorate gut and muscle dysfunction in DMD. Funded by Science Foundation Ireland SFI/19/6628 INSPIRE DMD. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

24 Feed restriction as a model for disruption of gut homeostasis in horses: A pilot study

Involuntary feed restriction is commonly experienced by horses during transport, in preparation for or during competition, during illness or treatment for some diseases (eg, colic), and to facilitate weight loss in overweight individuals. Short-term reduction of feed intake is known to cause intestinal barrier dysfunction and precedes disease in multiple species. Using short-term feed restriction to induce gut dysfunction could provide a means to investigate meaningful interventions, as well as inform recommendations on routine management practices. The aim of this pilot study was to evaluate blood and gut inflammatory markers in response to short-term feed restriction (STFR). Feed restriction was imposed in 2-year-old Quarter Horses for 3 d (FR, n = 4) and compared with age- and time-matched control horses (CON, n = 4). The basal diet for all horses included concentrate (0.7% BW) and ad libitum grass hay and water. During the 3-d STFR period, intake for FR was reduced to 50% of daily DE requirements (50% of DE supplied by concentrate and 50% by hay) while CON horses remained on the basal diet. All horses were routinely housed in stalls during the day and in pasture at night but remained in stalls fulltime during the STFR period. Blood and fecal samples were taken immediately before (PRE) and at the conclusion of the 3-d STFR period (0 h), and at 9, 24, 33 and 48 h post-STFR. Serum amyloid A (SAA), serumcortisol, fecal immunoglobulins and fecal zonulin were measured by ELISA and data were compared using mixed model ANOVA with repeated measures. STFR resulted in greater (P < 0.01) loss of BW in FR horses (5.74 ± 0.51% of PRE BW) than CON horses (0.80 ± 0.38%) and, despite returning to their normal ration, FR horses retained a weight loss deficit 48 h post-STFR (P = 0.003). Serum cortisol did not differ between FR and CON but did fluctuate over time (P < 0.0001), likely related to the circadian rhythm. A time*treatment interaction was observed for SAA (P = 0.03), where it tended to be higher in FR than CON following STFR. However, SAA was highly variable between horses and the response to STFR was unimpressive. Fecal dry matter changed over time (P = 0.02), where it was elevated at 9 h post-STFR but had returned to the pre-STFR moisture level by h 33. A time*treatment interaction was also observed for fecal pH (P = 0.06) and tended to be higher (P = 0.08) in FR compared with CON following STFR. Evaluation of other inflammatory markers may be informative about the response to this STFR model. Additionally, measurements obtained during STFR (not just after) would help clarify when the most pronounced effects occur.

Role of the Microbiome in Gut-Heart-Kidney Cross Talk

Homeostasis is a prerequisite for health. When homeostasis becomes disrupted, dysfunction occurs. This is especially the case for the gut microbiota, which under normal conditions lives in symbiosis with the host. As there are as many microbial cells in and on our body as human cells, it is unlikely they would not contribute to health or disease. The gut bacterial metabolism generates numerous beneficial metabolites but also uremic toxins and their precursors, which are transported into the circulation. Barrier function in the intestine, the heart, and the kidneys regulates metabolite transport and concentration and plays a role in inter-organ and inter-organism communication via small molecules. This communication is analyzed from the perspective of the remote sensing and signaling theory, which emphasizes the role of a large network of multispecific, oligospecific, and monospecific transporters and enzymes in regulating small-molecule homeostasis. The theory provides a systems biology framework for understanding organ cross talk and microbe-host communication involving metabolites, signaling molecules, nutrients, antioxidants, and uremic toxins. This remote small-molecule communication is critical for maintenance of homeostasis along the gut-heart-kidney axis and for responding to homeostatic perturbations. Chronic kidney disease is characterized by gut dysbiosis and accumulation of toxic metabolites. This slowly impacts the body, affecting the cardiovascular system and contributing to the progression of kidney dysfunction, which in its turn influences the gut microbiota. Preserving gut homeostasis and barrier functions or restoring gut dysbiosis and dysfunction could be a minimally invasive way to improve patient outcomes and quality of life in many diseases, including cardiovascular and kidney disease.

Over-production of exopolysaccharide by Lacticaseibacillus rhamnosus CNCM I-3690 strain cutbacks its beneficial effect on the host

Most lactobacilli produce extracellular polysaccharides that are considered to contribute to the probiotic effect of many strains. Lacticaseibacillus rhamnosus CNCM I-3690 is an anti-inflammatory strain able to counterbalance gut barrier dysfunction. In this study ten spontaneous variants of CNCM I-3690 with different EPS-production were generated and characterized by their ropy phenotype, the quantification of the secreted EPS and genetic analysis. Amongst them, two were further analysed in vitro and in vivo: an EPS over-producer (7292) and a low-producer derivative of 7292 (7358, with similar EPS levels than the wild type (WT) strain). Our results showed that 7292 does not have anti-inflammatory profile in vitro, and lost the capacity to adhere to the colonic epithelial cells as well as the protective effect on the permeability. Finally, 7292 lost the protective effects of the WT strain in a murine model of gut dysfunction. Notably, strain 7292 was unable to stimulate goblet cell mucus production and colonic IL-10 production, all key features for the beneficial effect of the WT strain. Furthermore, transcriptome analysis of colonic samples from 7292-treated mice showed a down-regulation of anti-inflammatory genes. Altogether, our results point out that the increase of EPS production in CNCM I-3690 impairs its protective effects and highlight the importance of the correct EPS synthesis for the beneficial effects of this strain.

Antihypertensives and Antibiotics: Impact on Intestinal Dysfunction and Hypertension.

Gut dysfunction has emerged as a contributor to hypertension, the leading risk factor for disease globally, including stroke, heart failure, and kidney disease. This is underpinned by breakdown of the homeostatic relationship connecting intestinal epithelial function, the microbiota and immune responses. Antihypertensive medications have been shown to reverse intestinal dysfunction and gut dysbiosis. However, the mechanisms underlying this restoration of gut structure and function remain largely unknown. In this review, we examine current knowledge supporting a role for impaired intestinal epithelial permeability in hypertension, focusing on electrolyte movement, the renin-angiotensin-aldosterone system, and the restorative effects of orally administered antihypertensive medications and antibiotics. Further work is required to determine if the association between intestinal dysfunction and hypertension is causal. This is a rapidly evolving field, with intestinal dysfunction and dysbiosis representing an area that may be exploited to improve treatment of hypertension and cardiovascular disease.

Recent Trends on Mitigative Effect of Probiotics on Oxidative-Stress-Induced Gut Dysfunction in Broilers under Necrotic Enteritis Challenge: A Review.

Gut health includes normal intestinal physiology, complete intestinal epithelial barrier, efficient immune response, sustained inflammatory balance, healthy microbiota, high nutrient absorption efficiency, nutrient metabolism, and energy balance. One of the diseases that causes severe economic losses to farmers is necrotic enteritis, which occurs primarily in the gut and is associated with high mortality rate. Necrotic enteritis (NE) primarily damages the intestinal mucosa, thereby inducing intestinal inflammation and high immune response which diverts nutrients and energy needed for growth to response mediated effects. In the era of antibiotic ban, dietary interventions like microbial therapy (probiotics) to reduce inflammation, paracellular permeability, and promote gut homeostasis may be the best way to reduce broiler production losses. The current review highlights the severity effects of NE; intestinal inflammation, gut lesions, alteration of gut microbiota balance, cell apoptosis, reduced growth performance, and death. These negative effects are consequences of; disrupted intestinal barrier function and villi development, altered expression of tight junction proteins and protein structure, increased translocation of endotoxins and excessive stimulation of proinflammatory cytokines. We further explored the mechanisms by which probiotics mitigate NE challenge and restore the gut integrity of birds under disease stress; synthesis of metabolites and bacteriocins, competitive exclusion of pathogens, upregulation of tight junction proteins and adhesion molecules, increased secretion of intestinal secretory immunoglobulins and enzymes, reduction in pro-inflammatory cytokines and immune response and the increased production of anti-inflammatory cytokines and immune boost via the modulation of the TLR/NF-ĸ pathway. Furthermore, increased beneficial microbes in the gut microbiome improve nutrient utilization, host immunity, and energy metabolism. Probiotics along with biosecurity measures could mitigate the adverse effects of NE in broiler production.

Abstract 5544: Association of circulating markers of gut barrier damage and inflammation with colorectal neoplasia stage

Abstract A disturbance in the microbiome facilitated by gut barrier dysfunction and inflammation can influence the progression of colorectal neoplasia. One of the most studied indicators of gut barrier status is lipopolysaccharide (LPS). Increased permeability of the gut barrier leads to extensive translocation of microbes into the lamina propria, which is associated with higher circulating levels of LPS. Additionally, increased serum concentrations of inflammatory cytokines including IFNy, IL6, IL10, and TNFα have been associated with impaired gut integrity and its progressive dysfunction. We investigated the role of gut barrier permeability and inflammation in colorectal cancer (CRC) development by assessing markers of intestinal barrier dysfunction and inflammation in two different patient cohorts; Irish (discovery) and Czech (validation). ELISA assays were used to assess circulating concentrations of lipopolysaccharide binding protein (LBP) and C-reactive protein (CRP) in serum from patients with CRC (n=30), colorectal adenoma (n=40), and negative after colonoscopy/blood donor controls (n=35). Circulating levels of inflammatory cytokines and calprotectin were assessed using an MSD MultiSPOT platform and an MSD R-plex assay (Mesocale Discovery, Rockville, Md, United States), respectively. Differences between pathology groups were assessed using the Kruskal Wallis or Mann-Whitney U test. Receiver operating curve (ROC) analysis was implemented to identify single and combinations of biomarkers capable of discriminating between CRC patients and controls with maximum sensitivity (SE) and specificity (SP) (RStudio, PBC, Boston, MA URL http://www.rstudio.com/). In the discovery cohort, levels of LBP, TNFα, IL6, calprotectin and CRP were significantly higher in CRC patients than in controls after false discovery rate correction (p=0.02, p=0.03, p=0.006, p=0.01, p=0.006, respectively). The area under the ROC curve (AUC) was 0.76 (95% CI: 0.64-0.87, p = 0.003) for LBP, 0.69 (95% CI: 0.55-0.82, p = 0.007) for calprotectin and 0.87(95% CI: 0.74-1.00, p = 0.003) for CRP. The optimal biomarker combination for discriminating between CRC and controls was the combination of the three markers (SP= 0.75, SE = 0.75). In the validation cohort, levels of calprotectin and TNFα, were significantly higher in cancer compared to control (p=0.05, p=0.02, respectively). Furthermore, IFNγ and IL10 were also significantly elevated in cancer compared to control (p= 0.02, p=0.003, respectively). These results support the hypothesis that a dysfunctional gut barrier and attendant inflammation may influence CRC development and progression. Additionally, LBP, CRP and calprotectin may have potential as diagnostic biomarkers for CRC or for risk stratification. Gut bacterial and barrier wall modulation and stabilization has potential for preventing colorectal adenomas and hence colorectal cancer. Citation Format: Flavia Genua, Petr Holý, Pavel Souček, Václav Liška, David J. Hughes. Association of circulating markers of gut barrier damage and inflammation with colorectal neoplasia stage. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5544.

Vinpocetine prevents rotenone-induced Parkinson disease motor and non-motor symptoms through attenuation of oxidative stress, neuroinflammation and α-synuclein expressions in rats

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by motor and non-motor symptoms. Epidemiological reports showed a significant association between environmental toxicants-induced gut dysbiosis and PD. Neuroinflammation, mitochondrial dysfunction and decreased cerebral blood flow are hallmarks of PD. This study sought to evaluate the protective ability of vinpocetine (VIN), a neuroprotectant, on rotenone (ROT) (mitochondrial complex I inhibitor) induced PD in rats. Sixty male Sprague Dawley rats were randomly divided into six groups (n = 10) and treated orally as follows; group 1: vehicle (10 ml/kg); group 2: rotenone (10 mg/kg) + vehicle; group 3–5: vinpocetine (5, 10 or 20 mg/kg) + rotenone (10 mg/kg), respectively, or group 6: vinpocetine 20 mg/kg before behavioural assay for motor symptoms (fore-limb hanging test and open field test) and non-motor symptoms (working memory and learning capabilities in Y-maze/Morris water maze tasks, anxiety in hole board test and gut motility with intestinal transit time). Following treatment for 28 days, biochemical assays and immunostaining was performed. We examined the effect of vinpocetine on rotenone-induced oxidative stress and inflammatory markers. The pretreatment of rats with vinpocetine reversed rotenone-induced locomotor deficit, motor incoordination, cognition deficits and gut dysfunction. In addition, rotenone-induced a significant increase in the level of interleukin-6 and tumor necrotic factor-α, oxidative stress markers, cholinergic signalling, gut dysfunction and haematologic dysfunctions which were attenuated by vinpocetine administration. Immunostainings showed that rotenone-induced dopamine neuron loss, microglia reactivity, astrocytes activation, toll-like receptor 4 (TLR4) and α-synuclein (SNCA) expressions which were attenuated by vinpocetine administration. Findings from this study revealed a neuroprotective effect of vinpocetine on rotenone-induced PD through anti-neuroinflammatory and antioxidant mechanisms.

Eucommia Polysaccharides Ameliorate Aging-Associated Gut Dysbiosis: A Potential Mechanism for Life Extension in Drosophila.

The gut microbiota is increasingly considered to play a key role in human immunity and health. The aging process alters the microbiota composition, which is associated with inflammation, reactive oxygen species (ROS), decreased tissue function, and increased susceptibility to age-related diseases. It has been demonstrated that plant polysaccharides have beneficial effects on the gut microbiota, particularly in reducing pathogenic bacteria abundance and increasing beneficial bacteria populations. However, there is limited evidence of the effect of plant polysaccharides on age-related gut microbiota dysbiosis and ROS accumulation during the aging process. To explore the effect of Eucommiae polysaccharides (EPs) on age-related gut microbiota dysbiosis and ROS accumulation during the aging process of Drosophila, a series of behavioral and life span assays of Drosophila with the same genetic background in standard medium and a medium supplemented with EPs were performed. Next, the gut microbiota composition and protein composition of Drosophila in standard medium and the medium supplemented with EPs were detected using 16S rRNA gene sequencing analysis and quantitative proteomic analysis. Here, we show that supplementation of Eucommiae polysaccharides (EPs) during development leads to the life span extension of Drosophila. Furthermore, EPs decreased age-related ROS accumulation and suppressed Gluconobacter, Providencia, and Enterobacteriaceae in aged Drosophila. Increased Gluconobacter, Providencia, and Enterobacteriaceae in the indigenous microbiota might induce age-related gut dysfunction in Drosophila and shortens their life span. Our study demonstrates that EPs can be used as prebiotic agents to prevent aging-associated gut dysbiosis and reactive oxidative stress.

Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe?

Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe?

Alterations in gut immunological barrier in SARS-CoV-2 infection and their prognostic potential.

Although coronavirus disease 2019 (COVID-19) is primarily associated with mild respiratory symptoms, a subset of patients may develop more complicated disease with systemic complications and multiple organ injury. The gastrointestinal tract may be directly infected by SARS-CoV-2 or secondarily affected by viremia and the release of inflammatory mediators that cause viral entry from the respiratory epithelium. Impaired intestinal barrier function in SARS-CoV-2 infection is a key factor leading to excessive microbial and endotoxin translocation, which triggers a strong systemic immune response and leads to the development of viral sepsis syndrome with severe sequelae. Multiple components of the gut immune system are affected, resulting in a diminished or dysfunctional gut immunological barrier. Antiviral peptides, inflammatory mediators, immune cell chemotaxis, and secretory immunoglobulins are important parameters that are negatively affected in SARS-CoV-2 infection. Mucosal CD4+ and CD8+ T cells, Th17 cells, neutrophils, dendritic cells, and macrophages are activated, and the number of regulatory T cells decreases, promoting an overactivated immune response with increased expression of type I and III interferons and other proinflammatory cytokines. The changes in the immunologic barrier could be promoted in part by a dysbiotic gut microbiota, through commensal-derived signals and metabolites. On the other hand, the proinflammatory intestinal environment could further compromise the integrity of the intestinal epithelium by promoting enterocyte apoptosis and disruption of tight junctions. This review summarizes the changes in the gut immunological barrier during SARS-CoV-2 infection and their prognostic potential.