Gastrointestinal Immune System Research Articles

Post-marketing safety concerns with rimegepant based on a pharmacovigilance study

PurposeThis study aimed to comprehensively assess the safety of rimegepant administration in real-world clinical settings.MethodsData from the Food and Drug Administration Adverse Event Reporting System (FAERS) spanning the second quarter of 2020 through the first quarter of 2023 were retrospectively analyzed in this pharmacovigilance investigation. This study focuses on employing subgroup analysis to monitor rimegepant drug safety. Descriptive analysis was employed to examine clinical characteristics and concomitant medication of adverse event reports associated with rimegepant, including report season, reporter country, sex, age, weight, dose, and frequency, onset time, et al. Correlation analysis, including techniques such as violin plots, was utilized to explore relationships between clinical characteristics in greater detail. Additionally, four disproportionality analysis methods were applied to assess adverse event signals associated with rimegepant.ResultsA total of 5,416,969 adverse event reports extracted from the FAERS database, 10, 194 adverse events were identified as the “primary suspect” (PS) drug attributed to rimegepant. Rimegepant-associated adverse events involved 27 System Organ Classes (SOCs), and the significant SOC meeting all four detection criteria was “general disorders and administration site conditions” (SOC: 10018065). Additionally, new significant adverse events were discovered, including “vomiting projectile” (PT: 10047708), “eructation” (PT: 10015137), “motion sickness” (PT: 10027990), “feeling drunk” (PT: 10016330), “reaction to food additive” (PT: 10037977), etc. Descriptive analysis indicated that the majority of reporters were consumers (88.1%), with most reports involving female patients. Significant differences were observed between female and male patients across age categories, and the concomitant use of rimegepant with other medications was complex.ConclusionThis study has preliminarily identified potential new adverse events associated with rimegepant, such as those involving the gastrointestinal system, nervous system, and immune system, which warrant further research to determine their exact mechanisms and risk factors. Additionally, significant differences in rimegepant-related adverse events were observed across different age groups and sexes, and the complexity of concomitant medication use should be given special attention in clinical practice.

Properties of methylmercury and its physiological effect on the human body

With the development of Chemistry industry, more and more organic mercury compounds are now found in environment and the level of their exposure is increasing, polluting and harming the environment. Humans may be exposed to organic forms of mercury through inhalation, oral routes. Among them, the most common phenomenon is by eating fish and shellfish contaminated by methylmercury. Many methods are used in detecting the existence of mercury in the tissue of samples or the concentration of mercury in sediments of Minamata Bay, which is the origin of Minamata disease, such as using ammonium sulfide and hydrogen sulfate through the observation of brownish back granules. Generally, the effects of exposure to organic mercury are primarily on the nervous system, while many other organ systems may also be affected, including the gastrointestinal tract, respiratory system, liver, immune system, skin, and kidneys. The study investigates the physiological effect of the organic mercury and how to detect the existence of the organic mercury in the environment.

Seasonal variation of melatonin secretion across various segments of the gastrointestinal tract in rats

ObjectiveTo investigate whether melatonin (MT) secretion in different parts of the gastrointestinal tract (GIT) exhibits seasonal variations and its correlation with immune regulation. MethodsSixty Sprague-Dawley rats were divided into control and model groups, and the pineal gland was removed in the model group. Stomach, jejunum, ileum, and colon tissues were obtained during the spring equinox, summer solstice, beginning of autumn, autumn equinox, and winter solstice. The levels of MT, MT receptors (MR), arylalkylamine N-acetyltransferase (AANAT), hydroxyindole-O-methyltransferase (HIOMT), interleukin-2 (IL-2), and interleukin-10 (IL-10) in the GIT were measured using enzyme-linked immunosorbent assay. ResultsExcept for the stomach, the jejunum, ileum, and the colon showed seasonal tendencies in MT secretion. In the control group, MT secretion in the jejunum and ileum was the highest in the long summer, and colonic MT secretion was the highest in winter. In the model group, MT levels in the colon were highest in the summer. The seasonal rhythms of the MR, AANAT, HIOMT, IL-2, and IL-10 in the colon were roughly similar to those of MT, and changed accordingly after pinealectomy. ConclusionsGastrointestinal MT secretion is related to seasonal changes, and MT secretion in each intestinal segment is influenced by different seasons. The biological effects of MT in the gut are inextricably linked to the mediation of MR, and a hormone-receptor linkage exists between MT and MR. The effect of seasonal changes on the gastrointestinal immune system may be mediated through the regulation of seasonal secretion of MT.

Effect of Lactobacillus casei FNCC 0090 to improve gastrointestinal bacterial abundance, immune system and water quality in catfish farming

Abstract. ‘Aini N, Bachruddin M, Fatimah, Andriyono S, Wahyuningsih SPA. 2024. Effect of Lactobacillus casei FNCC 0090 to improve gastrointestinal bacterial abundance, immune system and water quality in catfish farming. Biodiversitas 25: 2130-2138. Catfish is the most widely cultivated type of fish. However, along with the increase in catfish production as an effort to fulfill the fishery stock, there is an obstacle to the emergence of disease infection caused by Aeromonas hydrophila. For this reason, good fisheries management is required. One of the efforts to deal with this is by giving probiotics Lactobacillus casei FNCC 00990. Lactobacillus casei FNCC 0090 is expected to improve the immune system of catfish through improving the blood profile of fish and increasing the number of lactic acid bacteria in the gastrointestinal tract of catfish. This research aims to determine the effect of administering the probiotic L. casei FNCC 0090 on the abundance of microbes in the fish digestive tract, immune system, and water quality in cultivating catfish infected with A. hydrophila. The research design was a completely randomized design with five treatments and five replications. The treatments were A (administering 5% probiotics and infected with 0.1 mL x 108 CFU/mL), B (10% probiotics and infected), C (15% probiotics and infected), KP (positive control with 0% probiotics and infected with pathogens), KN (negative control, without probiotics and pathogen infection). Fish are kept for 42 days; on the 35th day, the fish were infected with A. hydrophila by intramuscular injection. Probiotics were mixed with feed with a total of 108 CFU/mL. Data in the form of BAL counts and total bacterial counts of fish digestive tracts, blood profiles, and water quality were analyzed using Statistical Package for the Social Sciences (SPSS) software version 23.0 (IBM SPSS Statistics). The results showed

Effects of different lipid sources with or without a probiotic on gastrointestinal tract, immune system and blood parameters of chickens: An animal model.

The objective of this study was to determine the effects of different lipid sources, with or without a probiotic, on the gastrointestinal tract, immune system and blood parameters of Ross 308 male chickens. In this study, 360 one-day-old chickens were randomly allotted to six treatments with six replicates. Experimental diets were: (1) control (CTL); (2) a diet containing 30 g/kg lipid from tallow (CTL+TLW); (3) a diet containing 30 g/kg lipid from soybean oil (CTL+SO); (4) the basal diet plus a probiotic (CTL+PRO), (5) a diet containing 30 g/kg tallow plus probiotic (TLW+PRO); and (6) a diet containing 30 g/kg soybean oil plus probiotic (SO+PRO). The percentage of liver and jejunum in the treatments that used tallow alone or tallow with probiotics had a significant increase as compared to the control. The villus height and crypt depth of the ileum and villus height/crypt depth in the treatments that used soybean oil and probiotic alone had a significant increase compared to the control. The weight of the spleen, bursa of Fabricius, and thymus in the treatments that used probiotics had a significant increase compared to the control. The amount of alkaline phosphatase and alanine aminotransferase as well as triacylglycerol in the treatment containing probiotic and its mixture with soybean oil had the least significant difference with the control. The results showed that the use of soybean oil, probiotics, and their mixture can improve intestinal morphology, strengthen the immune system, and reduce liver enzymes in chickens.

Efficient enzyme-free method to assess the development and maturation of the innate and adaptive immune systems in the mouse colon

Researchers who aim to globally analyze the gastrointestinal immune system via flow cytometry have many protocol options to choose from, with specifics generally tied to gut wall layers of interest. To get a clearer idea of the approach we should use on full-thickness colon samples from mice, we first undertook a systematic comparison of three tissue dissociation techniques: two based on enzymatic cocktails and the other one based on manual crushing. Using flow cytometry panels of general markers of lymphoid and myeloid cells, we found that the presence of cell-surface markers and relative cell population frequencies were more stable with the mechanical method. Both enzymatic approaches were associated with a marked decrease of several cell-surface markers. Using mechanical dissociation, we then developed two minimally overlapping panels, consisting of a total of 26 antibodies, for serial profiling of lymphoid and myeloid lineages from the mouse colon in greater detail. Here, we highlight how we accurately delineate these populations by manual gating, as well as the reproducibility of our panels on mouse spleen and whole blood. As a proof-of-principle of the usefulness of our general approach, we also report segment- and life stage-specific patterns of immune cell profiles in the colon. Overall, our data indicate that mechanical dissociation is more suitable and efficient than enzymatic methods for recovering immune cells from all colon layers at once. Additionally, our panels will provide researchers with a relatively simple tool for detailed immune cell profiling in the murine gastrointestinal tract, regardless of life stage or experimental conditions.

Neonatal Gut and Immune Responses to β-Casein Enriched Formula in Piglets

Backgroundβ-casein is the main casein constituent in human milk (HM) and a source of bioactive peptides for the developing gastrointestinal tract and immune system. Infant formulas contain less β-casein than HM, but whether different concentrations of β-casein affect tolerability and gut and immune maturation in newborns is unknown. ObjectivesUsing near-term piglets as a model for newborn infants, we investigated whether increasing the β-casein fraction in bovine-based formula is clinically safe and may improve gut and immune maturation. MethodsThree groups of near-term pigs (96% gestation) were fed formula with bovine casein and whey protein (ratio 40:60): 1) standard skim milk casein (BCN-standard, 35% β-casein of total casein, n = 18); 2) β-casein enrichment to HM concentrations (BCN-medium, 65%, n = 19); and 3) high β-casein enrichment (BCN-high, 91%, n = 19). A reference group was fed 100% whey protein concentrate (WPC) as protein (WPC, n = 18). Intestinal and immune parameters were assessed before and after euthanasia on day 5. ResultsClinical variables (mortality, activity, body growth, and diarrhea) were similar among the groups, and no differences in intestinal or biochemical parameters were observed between BCN-standard and BCN-medium pigs. However, pigs receiving high amounts of β-casein (BCN-high) had lower small intestine weight and tended to have more intestinal complications (highest gut pathology score, permeability, and interleukin-8) than the other groups, particularly those receiving no casein (WPC pigs). Blood lymphocyte, thrombocyte, and reticulocyte counts were increased with higher β-casein, whereas eosinophil counts were reduced. In vitro blood immune cell responses were similar among groups. Conclusionsβ-casein enrichment of bovine-based formula to HM concentrations is clinically safe, as judged from newborn, near-term pigs, whereas no additional benefits to gut maturation were observed. However, excessive β-casein supplementation, beyond concentrations in HM, may potentially induce gut inflammation together with increased blood cell populations relative to natural β-casein concentrations or pure whey-based formula.

Structural characterization and therapeutic effect of Alhagi honey oligosaccharide on liver fibrosis in mice

Alhagi honey is derived from the secretory granules of Alhagi pseudoalhagi Desv., a leguminous plant commonly known as camelthorn. Modern medical research has demonstrated that the extract of Alhagi honey possesses regulatory properties for the gastrointestinal tract and immune system, as well as exerts anti-tumor, anti-oxidative, anti-inflammatory, anti-bacterial, and hepatoprotective effects. The aim of this study was to isolate and purify oligosaccharide monomers (referred to as Mel) from camelthorn and elucidate their structural characteristics. Subsequently, the impact of Mel on liver injury induced by carbon tetrachloride (CCl4) in mice was investigated. The analysis identified the isolated oligosaccharide monomer (α-D-Glcp-(1 → 3)-β-D-Fruf-(2 → 1)-α-D-Glcp), with the molecular formula C18H32O16. In a mouse model of CCl4-induced liver fibrosis, Mel demonstrated significant therapeutic effects by attenuating the development of fibrosis. Moreover, it enhanced anti-oxidant enzyme activity (glutathione peroxidase and superoxide dismutase) in liver tissues, thereby reducing oxidative stress markers (malondialdehyde and reactive oxygen species). Mel also improved serum albumin levels, lowered liver enzyme activities (aspartate aminotransferase and alanine aminotransferase), and decreased inflammatory factors (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6). Immunohistochemistry, immunofluorescence, and western blotting analyses confirmed the ability of Mel to downregulate hepatic stellate cell-specific markers (collagen type I alpha 1 chain, alpha-smooth muscle actin, transforming growth factor-beta 1. Non-targeted metabolomics analysis revealed the influence of Mel on metabolic pathways related to glutathione, niacin, pyrimidine, butyric acid, and amino acids. In conclusion, the results of our study highlight the promising potential of Mel, derived from Alhagi honey, as a viable candidate drug for treating liver fibrosis. This discovery offers a potentially advantageous option for individuals seeking natural and effective means to promote liver health.

Dissecting the respective roles of microbiota and host genetics in the susceptibility of Card9−/− mice to colitis

BackgroundThe etiology of inflammatory bowel disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown.ResultsCard9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3β and Reg3γ independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that 5 weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups’ own genotype.ConclusionsThese results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or “healthy” microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders.-8ZHpF322gum1G2x3b5GvyVideo

P077 The Immunometabolic Bimodal Mechanism of NLRX1 Agonist NX-13 in a Pig Model of Ulcerative Colitis

Abstract Background In mouse models, NX-13 is an orally active, gut-restricted NLRX1 agonist that has been shown to reduce severity of disease in multiple UC models through a novel immunometabolic, bimodal mechanism. Most preclinical UC studies rely upon rodent models, the human gastrointestinal physiology, microbiome, and immune system bear a greater similarity to that of pigs. Therefore, we sought to expand and validate our preclinical NX-13 results in mice using the dextran sulfate sodium (DSS) pig model of colitis. Here, we describe the disease severity, cellular, and biomarker results, and confirm the immunometabolic MOA observed in other species. Methods Pigs were randomized by weight (n=6 per group) and were administered tablets of excipient alone (placebo), NX-13 10 mg, NX-13 50 mg, or NX-13 100mg once daily. Pigs were challenged with 1% DSS in drinking water for 6 days and monitored daily for weight gain (loss). Composite disease activity score (0-12) was taken based on the sum of three subscores (0-4) for rectal bleeding, stool consistency and overall health/activity. Necropsy was conducted on day 7. Feces were collected for fecal calprotectin (FCP) quantification. Colonic tissue was macroscopically scored and collected for analysis by flow cytometry, histopathology and gene expression. Results Oral NX-13 treatment protected against weight loss and reduced colitis development with differences as early as day 2, becoming significant between days 4 and 6 as disease worsens in placebo treated pigs (Fig1A). NX-13 yielded a dose-dependent improvement in macroscopic lesion severity and microscopic immune cell infiltration (Fig1B). Specifically, Th1 cells (Fig1C) and TNF producing myeloid cells in the colonic lamina propria were reduced by NX-13, as well as FCP levels in stool (Fig1D) and mRNA expression in the colon (Fig1E). Oral NX-13 treatment reduced inflammatory markers including TNF, monocyte and neutrophil chemo attractants, IL-6, and IL-23 (Fig3F). Additionally, NX-13 treatment affected markers specific to the bimodal immunometabolic MOA of NLRX1 activation, namely upregulation of NLRX1 and mitochondrial metabolism gene COX3 (Fig1G), and reduction of NFkB and NLRP3 (Fig1H). Conclusion NX-13 demonstrated fast and clinically meaningful improvement in disease activity, and significantly impacted on key inflammatory markers in a DSS colitis model in pigs. These results align with previous murine results and observations in the phase 1b clinical program. Therefore, they can be used to generate additional mechanistic hypotheses for translational studies in the ongoing NEXUS phase 2 trial in moderate to severe UC.

Periodontitis and risk of cancer: Mechanistic evidence

AbstractThis review aims to critically analyze the pathways of interaction and the pathogenic mechanisms linking periodontitis and oral bacteria with the initiation/progression of cancer at different body compartments. A higher risk of head and neck cancer has been consistently associated with periodontitis. This relationship has been explained by the local promotion of dysbiosis, chronic inflammation, immune evasion, and direct (epi)genetic damage to epithelial cells by periodontal pathobionts and their toxins. Epidemiological reports have also studied a possible link between periodontitis and the incidence of other malignancies at distant sites, such as lung, breast, prostate, and digestive tract cancers. Mechanistically, different pathways have been involved, including the induction of a chronic systemic inflammatory state and the spreading of oral pathobionts with carcinogenic potential. Indeed, periodontitis may promote low‐grade systemic inflammation and phenotypic changes in the mononuclear cells, leading to the release of free radicals and cytokines, as well as extracellular matrix degradation, which are all mechanisms involved in carcinogenic and metastatic processes. Moreover, the transient hematogenous spill out or micro‐aspiration/swallowing of periodontal bacteria and their virulence factors (i.e., lipopolysaccharides, fimbriae), may lead to non‐indigenous bacterial colonization of multiple microenvironments. These events may in turn replenish the tumor‐associated microbiome and thus influence the molecular hallmarks of cancer. Particularly, specific strains of oral pathobionts (e.g., Porphyromonas gingivalis and Fusobacterium nucleatum) may translocate through the hematogenous and enteral routes, being implicated in esophageal, gastric, pancreatic, and colorectal tumorigenesis through the modulation of the gastrointestinal antitumor immune system (i.e., tumor‐infiltrating T cells) and the increased expression of pro‐inflammatory/oncogenic genes. Ultimately, the potential influence of common risk factors, relevant comorbidities, and upstream drivers, such as gerovulnerability to multiple diseases, in explaining the relationship cannot be disregarded. The evidence analyzed here emphasizes the possible relevance of periodontitis in cancer initiation/progression and stimulates future research endeavors.

Analysis of the influence of the microbial load of poultry facilities on the development of keel “mins” in turkeys

The balanced composition of the microflora in the poultry's environment is one factor that ensures the normal functioning of the gastrointestinal tract, immune, and other systems and supports the body's homeostasis. Instead, an imbalance can lead to the development of specific pathologies in the bird. Currently, in the conditions of industrial poultry farming, studying the influence of the microbial environment of poultry houses on the health and development of birds is a relevant and important topic of scientific research. The obtained results make it possible to solve the critical tasks of the industry, aimed at creating conditions that will provide the opportunity to achieve maximum indicators of poultry productivity and the quality of the obtained products. The work aimed to investigate the dynamics of the quantitative and qualitative composition of the microflora in individual facilities of poultry houses (air, walls and litter) throughout the entire cycle of growing turkeys and to further determine the role of isolated microorganisms in the etiology of keel “mins”. As a result of the research, it was established that the microbial load of the air in the poultry houses of the experimental farms during the growing turkeys was, on average, in the range from 5.13 ± 0.11 to 5.19 ± 0.88 log CFU/m3. The smallest amount of microflora in the air was determined in the period up to 30 days after the landing of the poultry; it was from 4.76 ± 1.23 to 4.95 ± 1.07 lg CFU/m3. The maximum values of the microbial load were from 60 to 90 days when 1 m3 contained from 5.35 ± 1.20 to 5.41 ± 0.17 lg CFU. From the 91st day until the end of the production cycle, a decrease in the microbial load of poultry houses' air was noted, from 2.5 to 3.9 %. The load of the walls and litter with microorganisms was also the lowest at the initial stage and was, respectively, from 4.12 ± 0.62 to 4.34 ± 0.46 lg CFU/cm3 of wash and from 5.15 ± 0.73 to 6.17 ± 0.96 CFU/h. However, unlike air, their load with microorganisms increased throughout the entire production cycle, reached maximum values at the final stage, and ranged from 5.23 ± 0.51 to 5.26 ± 0.65 lg CFU/cm3 of washing and from 9.16 ± 0.53 to 11.74 ± 1.12 CFU/g. During the entire production cycle, the microbial load of the walls of the poultry houses of the experimental farms and their litter was in the range from 4.80 ± 0.20 to 4.95 ± 0.26 lg CFU/cm3 of washing and from 7.06 ± 0.73 to 8. 93 ± 1.02 CFU/g. 13 types of microorganisms represented the microbial landscape of the studied objects. Its prominent representatives in the air were E. coli, Staphylococsus spp., Streptococcus spp., Proteus sрp. and Clostridium sрp., their share was 39.1, respectively; 18.5; 16.9; 16.6 and 5.4 %. E. coli was 43.6 and 43.4 % on the walls and litter, and Staphylococsus spp. – 17.1 and 16.9 %. Unlike air, Proteus sрp. (15.9 and 16.9 %), followed by Streptococcus spp. (15.3 and 12.8 %) and Clostridium sрp. (4.6 and 7.2 %). The number of other isolated microorganisms, including Aspergillus spp., Campilobacter sрp., Penicillium spp., P. aerugenosae, Enterobacter sрp., Yersinia sрp., Mucor spp. and Klebsiella sрp. Did not exceed 1 % for all the studied objects.

The Potential Therapeutic Role of Lactobacillaceae rhamnosus for Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a heterogeneous group of diseases associated with chronic inflammation of the intestinal tract, and is highly prevalent worldwide. Although its origin is not yet fully understood, new evidence emphasizes that environmental factors, especially dietary factors and intestinal microbiota disorders are key triggers of IBD. Probiotics, such as Lactobacillaceae spp., play an essential role in human health as they exert beneficial effects on the composition of the human gastrointestinal microbial community and immune system. Probiotic-based therapies have been shown to be effective in alleviating IBD. Among these, Lactobacillaceae rhamnosus is one of the most widely used strains. L. rhamnosus is widely present in the intestines of healthy individuals; it regulates the intestinal immune system and reduces inflammation through a variety of mechanisms. The purpose of this study was to identify scientific evidence related to L. rhamnosus and IBD, review and summarize the results, and discuss the possible mechanisms of action as a starting point for future research on IBD treatment.

Food Protein-induced Enterocolitis Syndrome.

Food protein-induced enterocolitis syndrome (FPIES) is a type of non-IgE-mediated gastrointestinal food allergy. FPIES is characterized by repetitive vomiting without classic IgE-mediated allergic skin or respiratory symptoms 1-4 h after causative food ingestion. The condition may be classified as acute or chronic, typical or atypical, and liquid or solid according to the course of symptoms, presence of IgE antibodies, and causative food, respectively. Since the development of international consensus guidelines in 2017, epidemiological studies have been conducted in many countries. FPIES is a relatively rare disease, with a prevalence of 0.015%-0.7%. However, the number of patients has been increasing in recent years. Most patients develop the disease in infancy. The natural history of FPIES is generally favorable, with most FPIES cases resolving before school age. FPIES is diagnosed using symptoms such as vomiting or diarrhea, or via an oral food challenge (OFC). Currently, no validated biomarker is available for diagnosis, and the mechanisms related to gastrointestinal manifestations and immune system involved in the development of FPIES have not yet been elucidated. Treatment with intravenous fluids and ondansetron is recommended in the acute phase. Long-term management consists of complete causative food elimination and periodic OFC to confirm tolerance. Given that many diagnoses are delayed because of a lack of awareness of the condition, FPIES must be widely recognized by healthcare providers. In the future, it is expected that FPIES pathogenesis will be further clarified, and more objective diagnostic criteria will be developed.

Through the Looking-Glass: Psychoneuroimmunology and the Microbiome-Gut-Brain Axis in the Modern Antiretroviral Therapy Era.

ABSTRACTObjectiveDepression, substance use disorders, and other neuropsychiatric comorbidities are common in people with HIV (PWH), but the underlying mechanisms are not sufficiently understood. HIV-induced damage to the gastrointestinal tract potentiates residual immune dysregulation in PWH receiving effective antiretroviral therapy. However, few studies among PWH have examined the relevance of microbiome-gut-brain axis: bidirectional crosstalk between the gastrointestinal tract, immune system, and central nervous system.MethodsA narrative review was conducted to integrate findings from 159 articles relevant to psychoneuroimmunology (PNI) and microbiome-gut-brain axis research in PWH.ResultsEarly PNI studies demonstrated that neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis and autonomic nervous system could partially account for the associations of psychological factors with clinical HIV progression. This review highlights the need for PNI studies examining the mechanistic relevance of the gut microbiota for residual immune dysregulation, tryptophan catabolism, and oxytocin release as key biological determinants of neuropsychiatric comorbidities in PWH (i.e., body-to-mind pathways). It also underscores the continued relevance of neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and oxytocin release in modifying microbiome-gut-brain axis functioning (i.e., mind-to-body pathways).ConclusionsAdvancing our understanding of PNI and microbiome-gut-brain axis pathways relevant to depression, substance use disorders, and other neuropsychiatric comorbidities in PWH can guide the development of novel biobehavioral interventions to optimize health outcomes. Recommendations are provided for biobehavioral and neurobehavioral research investigating bidirectional PNI and microbiome-gut-brain axis pathways among PWH in the modern antiretroviral therapy era.

Melatonin shapes bacterial clearance function of porcine macrophages during enterotoxigenic Escherichia coli infection.

Due to the immature gastrointestinal immune system, weaning piglets are highly susceptible to pathogens, e.g., enterotoxigenic Escherichia coli (ETEC). Generally, pathogens activate the immune cells (e.g., macrophages) and shape intracellular metabolism (including amino acid metabolism); nevertheless, the metabolic cues of tryptophan (especially melatonin pathway) in directing porcine macrophage function during ETEC infection remain unclear. Therefore, this study aimed to investigate the changes in the serotonin pathway of porcine macrophages during ETEC infection and the effect of melatonin on porcine macrophage functions. Porcine macrophages (3D4/21 cells) were infected with ETEC, and the change of serotonin pathway was analysed by reverse transcription PCR and metabolomic analysis. The effect of melatonin on porcine macrophage function was also studied with proteomic analysis. In order to investigate the effect of melatonin on bacterial clearance function of porcine macrophages during ETEC infection, methods such as bacterial counting, reverse transcription PCR and western blotting were used to detect the corresponding indicators. The results showed that ETEC infection blocked melatonin production in porcine macrophages (P < 0.05) which is largely associated with the heat-stable enterotoxin b (STb) of ETEC (P < 0.05). Interestingly, melatonin altered porcine macrophage functions, including bacteriostatic and bactericidal activities based on proteomic analysis. In addition, melatonin pre-treatment significantly reduced extracellular lactate dehydrogenase (LDH) activity (P < 0.05), indicating that melatonin also attenuated ETEC-triggered macrophage death. Moreover, melatonin pre-treatment resulted in the decrease of viable ETEC in 3D4/21 cells (P < 0.05), suggesting that melatonin enhances bacterial clearance of porcine macrophages. These results suggest that melatonin is particularly important in shaping porcine macrophage function during ETEC infection.

Differential Nutrition-Health Properties of Ocimum basilicum Leaf and Stem Extracts.

(1) Background: Ocimum basilicum L. is an aromatic medicinal plant of the Lamiaceae family known as sweet basil. It is used in traditional medicine for its beneficial effects on gastrointestinal disorders, inflammation, immune system, pyrexia or cancer among others. Ocimum basilicum (OB) leaf extracts contain many phytochemicals bearing the plant health effects but no reports is available on the potential bioactivity of stem extracts. Our investigation aimed at assessing the differential biological activity between basil leaf and stem to promote this co-product valorization. (2) Method: For this purpose we explored phytochemical composition of both parts of the plant. Antioxidant activity was evaluated through total polyphenol content measure, DPPH and ORAC tests. Anti-inflammatory markers on stimulated macrophages, including NO (nitric oxide), TNFa (tumor necrosis factor alpha), IL-6 (interleukin 6), MCP1 (monocyte attractant protein 1) and PGE-2 (prostaglandin E2), were evaluated. In addition, we investigated OB effects on jejunum smooth muscle contractility. (3) Results: OB extracts from leaves and stems demonstrated a different biological activity profile at the level of both antioxidant, anti-inflammatory and smooth muscle relaxation effects. (4) Conclusion: Taken together our results suggest that Ocimum basilicum extracts from co-product stems, in addition to leaves, may be of interest at the nutrition-health level with specific therapeutic potential.

NOD2 signaling in CD11c + cells is critical for humoral immune responses during oral vaccination and maintaining the gut microbiome

Nucleotide-binding oligomerization domain containing 2 (NOD2) is a critical regulator of immune responses within the gastrointestinal tract. This innate immune receptor is expressed by several cell types, including both hematopoietic and nonhematopoietic cells within the gastrointestinal tract. Vaccination targeting the gastrointestinal mucosal immune system is especially difficult due to both physical and mechanistic barriers to reaching inductive sites. The use of lactic acid bacteria is appealing due to their ability to persist within harsh conditions, expression of selected adjuvants, and manufacturing advantages. Recombinant Lactobacillus acidophilus (rLA) has shown great promise in activating the mucosal immune response with minimal impacts on the resident microbiome. To better classify the kinetics of mucosal vaccination with rLA, we utilized mice harboring knockouts of NOD2 expression specifically within CD11c + cells. The results presented here show that NOD2 signaling in CD11c + cells is necessary for mounting a humoral immune response against exogenous antigens expressed by rLA. Additionally, disruption of NOD2 signaling in these cells results in an altered bacterial microbiome profile in both control mice and mice receiving L. acidophilus strain NCK1895 and vaccine strain LaOVA.

A study on the effect of symbiotic fermented milk products on human gastrointestinal health: Double-blind randomized controlled clinical trial.

Several studies have claimed that the consumption of fermented dairy products can improve human gastrointestinal (GI) health. However, the numbers of systematic clinic trials are limited. In this study, a yogurt containing both probiotics and prebiotics was developed and a double‐blind randomized controlled clinical trial was carried out to evaluate the effect of the product on human gastrointestinal health in three different aspects: (1) the effect on functional constipation (FC) and functional diarrhea (FD); (2) the effect on gastrointestinal (GI) tract immune system; and (3) the changes in GI tract microbiota. Participants who suffered FC or FD were randomized into three groups (n = 66 each group): the first group was treated with fermented milk with Lactobacillus plantarum ST‐III (7 mg/kg) and inulin (1.5%), the second group was treated with L. plantarum ST‐III (7 mg/kg) and inulin (1.0%), and the third group (control group) was treated without probiotics and prebiotics. Half of the participants stopped the treatment after 14 days and the rest of the group continued the trial to the full 28 days. The fecal samples of participants were analyzed regarding their short‐chain fatty acids (SCFAs), secretory immunoglobulin A (sIgA), and microbiota. A survey on GI tract health was conducted and the Bristol stool scale was recorded. The results showed that the consumption of the symbiotic yogurt for 14 days and 28 days can both improve the digestive system, with the continual consumption of product containing L. plantarum ST‐III (7 mg/kg) and inulin (1.5%) for 28 days showing the most significance. The consumption of this product may be used as a potential functional food.

Morphological, immuno- and lectinohistochemical evaluation of the lymphoid apparatus of the human fetal appendix

Aim. To identify the morphological and functional features of the human appendix lymphoid formations in the late period of prenatal ontogenesis. Materials and methods. The vermiform appendices from 42 human fetuses of both sexes without anomalies, diseases of the gastrointestinal tract, immune system and hematopoiesis were examined. Histological, lectinohistochemical (PNA+, SBA+), immunohistochemical (expression of markers CD3+, CD4+, CD8+, CD20+, CD34+, CD68+, Ki-67, caspase 3+), morphometric methods of examination were used with statistical analysis of the obtained results. Results. Single lymphocytes are seen near venules in the mucous membrane of the human fetal vermiform appendix at 16–18 weeks’ gestation; the lymphocytes are aggregated to form the lymphoid follicles at the 25th week. The lymphoid follicles are populated by small- and medium-sized lymphocytes, macrophages, cells at the stages of apoptosis (Caspase 3+) and proliferation (Ki-67+), reticular cells. From the 28th week of the prenatal period, lymphoepithelial nodules are detected compositionally resembling perivascular ones. In the subepithelial and peripheral zones of the nodules, there are lymphocytes expressing CD3 and PNA receptors, in the central zone – CD20 and SBA receptors, macrophages (CD68+/PNA+/SBA+), cells at the stage of proliferation (Ki-67+) and apoptosis (caspase 3+). By the end of the fetal period, the lymphoid follicles of the human appendix contain fewer T-lymphocytes (CD3+) and an increased number of B-lymphocytes (CD20+) and macrophages (CD68+), which are localized mainly in the central zone, however, the germinal centers are not yet formed. Conclusions. In the developmental process of the vermiform appendix lymphoid tissue during the prenatal period of ontogenesis, the following critical periods were noted: the 16th–18th weeks – the appearance of lymphocytes in the lamina propria, the 25th week – the formation of perivascular lymphoid follicles near venules, the 28th week – the appearance of lymphoepithelial nodules. The number of T-lymphocytes (CD3+) was decreased in the lymphoid follicles, while the number of B-lymphocytes (CD20+) and macrophages (CD68+) was increased with age.