Article

Tyramine-induced gastrointestinal dysregulation is attenuated via estradiol associated mechanisms in a zebrafish larval model

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Development of targeted therapeutics to alleviate gastrointestinal (GI) inflammation and its debilitating consequences are required. In this context, the trace aminergic system may link together sex, diet and inflammation. Utilising a zebrafish larval model of GI inflammation, the current study aimed to investigate mechanisms by which excess amounts of trace amines (TAs) may influence GI health. In addition, we probed the potential role of 17β-estradiol (E2) and its receptors, given the known female-predominance of many GI disorders. To assess GI functionality and integrity, live imaging techniques (neutral red staining) and post-mortem immunofluorescent staining of tight junction proteins (occludin and ZO-1) were analyzed respectively. In addition, behavioural assays, as an indication of overall wellbeing, as well as whole body H2O2 and prostaglandin E2 assays were performed to inform on oxidative and inflammatory status. Excess β-phenethylamine (PEA), tryptamine (TRP) and ρ-tyramine (TYR) resulted in adverse GI and systemic effects. In this regard, clear beneficial effects of E2 to modulate the effects of PEA, TRP and TYR was evident. Moreover, agmatine displayed potential protective effects on GI epithelium and whole body oxidative status, however, potential to induce systemic inflammation suggests the importance of dosage and administration optimisation. Taken together, TYR seems like the most prominent TA to have damaging GI effects, feasibly exacerbating GI inflammation. In this context, the relative lack of E2 may provide mechanistic insights into the reported female-predominance of GI disorders. Moreover, an effective therapeutic in this context may be required to maintain GI TA load despite fluctuating E2 levels.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... These overlap with the neurological adverse events reported by people living with HIV after treatment with DTG. Furthermore, in the context of gastrointestinal health, differential roles for different trace amines have been reported in the context of irritable bowel syndrome [12][13][14] and other gastrointestinal disorders [15], again pointing to adverse outcomes in the face of a dysregulated trace amine profile. Of further interest to the HIV context, our group recently demonstrated oestrogen can affect the trace amine secretion profile of gut commensals and probiotic microbes [16], which is in line with women reporting relatively more adverse effects of DTG [17,18]. ...
... This potentially suggests that tight regulation of AGM concentrations (to prevent accumulation) could promote metabolite (PUT, SPD and SPM) formation. This notion is supported by previous data from our group, which linked disruption of tight junction protein expression and distribution profile to accumulation (lack of metabolism) of AGM after its experimental addition to (HT-29) human gut epithelial cells in culture [16], while the same effect was not observed in larval zebrafish, where AGM metabolism would be intact [14]. In this model, AGM seemed to protect from intestinal inflammation, likely due to the action of its anti-inflammatory metabolites (metabolites of AGM [PUT, SPD and SPM] have been demonstrated to accelerate epithelial cell renewal and to increase the abundance of anti-inflammatory macrophages [39]). ...
... For example, higher abundance of Enterococci and Lactobacilli genera (both prominent contributors to TYR synthesis) was recently reported in a comprehensive study on pro-inflammatory dysbiosis of microorganisms and their metabolites in HIV [19]. Although TYR and its metabolites were not specifically reported, the current data showing reduced TYR in response to DTG suggest that DTG may in fact normalise an HIV-associated increase in TYR abundance, which has been linked to poorer outcome in the context of intestinal inflammation [14]. Similarly, the same HIV study also reported higher fecal levels of l-tryptophan (precursor to TRP), as well as higher levels of CAD, PUT, SPD and PEA, in HIV+ patients versus controls. ...
Article
Full-text available
Dolutegravir (DTG), an integrase strand inhibitor, is currently used as the first-line treatment for HIV. Despite relatively poor tissue penetration, the risk of adverse effects in metabolic and excretory systems should be considered. The trace aminergic system and trace amines are emerging as relevant role players in many chronic diseases that are commonly diagnosed but poorly understood. Trace amines are biogenic amines that are endogenously produced and can also be ingested by the intake of trace amine-rich food. Trace amines are known to differentially regulate inflammatory and neurological outcome. This study investigated the effects of DTG on the trace amine profile in a wistar rat model. A total of 24 healthy wistar rats were randomly divided into four experimental groups: male and female controls and male and female DTG-treated. Blood and tissue samples were collected following a 12-week DTG administration study. Liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was used to determine trace amine concentrations in urine, plasma, brain, and gastrointestinal tissue. Current data illustrate that polyamines differ significantly (p < 0.05) between males and females in various matrices. DTG significantly (p < 0.05) reduced jejunal tyramine and urinary synephrine levels. Data do not raise major concerns about DTG in the context of the trace amine profile. However, given the importance of the dysregulated trace amine profile in various diseased states, including HIV, current data warrant clinical investigation to further evaluate the significance of DTG-associated effects on the trace amine profile.
... This approach also allows for evaluation of potential drug-hormone interaction, which may play an important role in eliminating the male-bias in research which predominated until very recently (Holdcroft 2007). For example, oestradiol enrichment was recently applied in the larval zebrafish model of trinitrobenzene sulphonic acid (TNBS)-induced intestinal inflammation (a recognised model of IBD in both zebrafish and rodents) (Pretorius and Smith 2023a). In this study, the addition of oestradiol at doses equivalent to human (female) gut oestradiol levels, illustrated interactive effects between oestradiol and constituents of the gut microbial secretome products, which affected gut epithelial dysregulation, suggesting the requirement for different dosing strategiesor even mechanisms of action-for IBD-aimed drugs in males vs females. ...
... dominated by Firmicutes and Bacteroides) (Zhong et al. 2022;Xia et al. 2022). In the context of IBD, several trace amines (as microbial secretome constituents) have been successfully screened for their role in disease outcome, with some illustrated to exacerbate disease, while others may alleviate inflammatory outcome (Pretorius and Smith 2023a). ...
Article
Full-text available
Immune-mediated inflammatory disease (IMID) prevalence is estimated at 3–7% for Westernised populations, with annual incidence reported at almost 1 in 100 people globally. More recently, drug discovery approaches have been evolving towards more targeted therapies with an improved long-term safety profile, while the requirement for individualisation of medicine in complex conditions such as IMIDs, is acknowledged. However, existing preclinical models—such as cellular and in vivo mammalian models—are not ideal for modern drug discovery model requirements, such as real-time in vivo visualisation of drug effects, logistically feasible safety assessment over the course of a lifetime, or dynamic assessment of physiological changes during disease development. Zebrafish share high homology with humans in terms of proteins and disease-causing genes, with high conservation of physiological processes at organ, tissue, cellular and molecular level. These and other unique attributes, such as high fecundity, relative transparency and ease of genetic manipulation, positions zebrafish as the next major role player in IMID drug discovery. This review provides a brief overview of the suitability of this organism as model for human inflammatory disease and summarises the range of approaches used in zebrafish-based drug discovery research. Strengths and limitations of zebrafish as model organism, as well as important considerations in research study design, are discussed. Finally, under-utilised avenues for investigation in the IMID context are highlighted.
... A wholemount immunofluorescent staining protocol with subsequent JB-4 resin embedding and sectioning to visualise mid-intestinal tight junction proteins as indicators of epithelial barrier integrity, was performed as previously described (Pretorius and Smith, 2023). Briefly larvae were euthanised, fixed (4% PFA overnight at 4 • C) and permeabilized (ice cold acetone) before being immersed in a blocking buffer for 3 h at room temperature. ...
... The current study demonstrated several gut health promoting activities of an aqueous GR extract. In an in vivo model of mild gastrointestinal inflammation commonly used to model aspects of irritable bowel syndrome and inflammatory bowel disease (Fenero et al., 2021;Oehlers et al., 2011;Padovani et al., 2022;Pretorius and Smith, 2023), the current data suggests that the GR supplementation fared as well or in some cases better than the standard treatment control, prednisolone, to improve tight junction protein expressionvisually preserving intestinal epithelial morphologyas well as whole body redox and inflammatory status. Moreover, this GR intervention seems to beneficially modulate gastrointestinal motility in the presence of chemical mediators which both increase and decrease gastrointestinal transit time. ...
... Elevated levels of tyramine not only induce intestinal inflammation but also impair the expression of tight junction proteins in the gut barrier, exacerbating inflammation and barrier damage that lead to systemic health issues, such as renal inflammation [44]. PI responses. ...
... This interpretation is supported by literature from other preclinical models, confirming the antioxidant effect of estrogen, 19,22 as well as by previous work from our own group in larval zebrafish. 23 Although the lipid peroxidation data was slightly variable at the 1-h time point, it is perhaps relevant to note that increased TEAC was paralleled by decreased lipid peroxidation. This suggests that the magnitude of antioxidant outcome after estradiol treatment was indeed likely sufficient to achieve improved energy levels and thus activity in the LDTT. ...
Article
Full-text available
Anxiety disorders are the most prevalent psychiatric disorders, exhibiting strong female bias. Clinical studies implicate declining estradiol levels in the exacerbation of anxiety symptoms in the premenstrual phase of the menstrual cycle. This study aimed to simulate estradiol fluctuation-linked anxiety behavior in larval zebrafish, using an estradiol treatment withdrawal model. Contrary to model aims, estradiol treatment withdrawal decreased both basal activity and anxiety-like hyperlocomotion (ANOVA main effect of dose, P < 0.0001 and P < 0.01, respectively) in the light/dark transition test. The accuracy of the estradiol washout model was not improved by longer durations of treatment or withdrawal. Basal activity was slightly altered by supraphysiological concentrations of WAY-200070 in the absence of added estradiol. Estrogen receptor (ER) β expression was not upregulated in larvae exposed to physiologically relevant, low concentrations of estradiol. Longer exposure to low concentrations of estradiol increased antioxidant capacity (P < 0.01). In addition, acute exposure to low concentrations of estradiol increased basal activity. Data suggest that in the current models, estradiol-associated altered activity levels were linked to more favorable redox status, rather than reflecting altered anxiety levels. As such, it is recommended that zebrafish larval behavioral analysis be conducted in parallel with mechanistic studies such as redox indicators, for investigations focused on ER signaling.
... E2 also had a regulatory effect on the secretion of tyrosine substances by microorganisms. The mechanisms might be related to the reduction of tyrosine in 2# [44]. The phosphorylation of tyrosine was conducive to the stability of estrogen binding. ...
Article
Full-text available
A large amount of estrogen is introduced into the feed to improve livestock growth, excessive residual estrogen would exist in the excrements. The accumulation of estrogen can cause the water and soil pollution around the farm, further inhibit growth and induce caner for organisms and human. Anaerobic digestion (AD) could effectively remove estrogen in livestock manure while the mechanism is still unclear. In this study, the mechanism of estrogen removal by AD was explored during AD process of pig manure. Estrone (E1), estradiol (E2) estriol (E3) and ethinylestradiol (EE2) were selected as research subjects. The removal rates of E1, E2, E3 and EE2 were 19.14, 28.62, 25.83 and 11.81%. Dissolved organic matters (DOM), especially humic acid, play an important role in reducing bioavailability of estrogen. Estrogen will be absorbed by DOM through structures such as aromatic ring and amides. Estrogen may also promote the growth of microorganisms which could degrade estrogen, such as Rhodococcus, Sphingomonas and Pseudomonas. The amount of these microorganisms and dissolved microbial metabolites did not change obviously. This study would give a new explanation for the removal of estrogen and can provide theoretical support for harmless treatment of pig manure. Graphical Abstract
Article
The adrenergic system plays a central role in human physiology. However, it can also affect commensal bacteria via adrenergic hormones. Bacteria use adrenergic hormones as xenosiderophore for iron supply, modulators of biofilm formation, quorum sensing autoinducers regulating virulence factors and pathogenicity, and for interaction with other commensals influencing the microbiome profiles. Bacteria also produce biogenic amines through aromatic amino acid decarboxylation which is widely expressed in human commensals. These biogenic amines are capable of interacting with adrenergic receptors, leading to a variety of different effects on the human body. Phenylacetyl acid is another compound produced by bacteria found in the gut that acts as a precursor of phenylacetylglutamine, a compound that has been linked to cardiac diseases due to its ablitiy to induce thrombosis by activating adrenergic receptors present in platelets.
Article
Full-text available
Up to 50% of systemic lupus erythematosus (SLE) patients world-wide develop lupus nephritis (LN). In low to middle income countries and in particular in sub-Saharan Africa, where SLE is prevalent with a more aggressive course, LN and end stage renal disease is a major cause of mortality. While developed countries have the funding to invest in SLE and LN research, patients of African descent are often underrepresented in clinical trials. Thus, the complex influence of ethnicity and genetic background on outcome of LN and SLE as a whole, is not fully understood. Several pathophysiological mechanisms including major role players driving LN have been identified. A large body of literature suggest that prevention of fibrosis—which contributes to chronicity of LN—may significantly improve long-term prognosis. Bone morphogenetic protein-7 (BMP-7) was first identified as a therapeutic option in this context decades ago and evidence of its benefit in various conditions, including LN, is ever-increasing. Despite these facts, BMP-7 is not being implemented as therapy in the context of renal disease. With this review, we briefly summarise current understanding of LN pathology and discuss the evidence in support of therapeutic potential of BMP-7 in this context. Lastly, we address the obstacles that need to be overcome, before BMP-7 may become available as LN treatment.
Article
Full-text available
In order to promote gastrointestinal health, significant increases in the prevalence of gastrointestinal disorders should be paralleled by similar surges in therapeutics research. Nutraceutical interventions may play a significant role in patient management. The current study aimed to determine the potential of Aspalathus linearis (rooibos) to prevent gastrointestinal dysregulation resulting from high-dose trace-amine (TA) exposure. Considering the substantial female bias in functional gastrointestinal disorders, and the suggested phytoestrogenicity of rooibos, the study design allowed for a comparison between the effects of an ethanol extract of green rooibos and 17β-estradiol (E2). High levels of ρ-tyramine (TYR) and agmatine (AGM), but not β-phenethylamine (PEA) or tryptamine (TRP), resulted in prostaglandin E2 (PGE2) hypersecretion, increased tight-junction protein (TJP; occludin and ZO-1) secretion and (dissimilarly) disrupted the TJP cellular distribution profile. Modulating benefits of rooibos and E2 were TA-specific. Rooibos pre-treatment generally reduced IL-8 secretion across all TA conditions and prevented PGE2 hypersecretion after exposure to both TYR and AGM, but was only able to normalise TJP levels and the distribution profile in AGM-exposed cells. In contrast, E2 pre-treatment prevented only TYR-associated PGE2 hypersecretion and TJP dysregulation. Together, the data suggest that the antioxidant and anti-inflammatory effects of rooibos, rather than phytoestrogenicity, affect benefits illustrated for rooibos.
Article
Full-text available
Introduction Irritable bowel syndrome (IBS) is a female predominant functional gastrointestinal disorder, underpinned by microbial dysbiosis and microinflammation. We suggest that changes in trace amine (TA) load and metabolism may link together diet, inflammation and sex in this context. Methods The effect of E2 treatment on microbial growth and TA generation was assessed using liquid chromatography and tandem mass spectrometry methodology. To investigate the effects of TAs on the gut, WST-1, prostaglandin E2 and tight junction protein dynamics were investigated in TA treated (HT-29) colon epithelial monolayer cultures. Results Differential E2-dependent alterations of the TA production capabilities of microbes were observed. Significantly, E2 treatment resulted in a 50% increase in tryptamine secretion from a probiotic microbe (p < 0.0001). Moreover, in vitro experiments indicated that TA treatment exerted type-specific effects in the gut, e.g., reducing mitochondrial functionality, even at low doses of tryptamine (p < 0.0001) and ρ-tyramine (p < 0.001). Additionally, prostaglandin E2 levels were significantly increased following ρ-tyramine and agmatine treatment (p < 0.05). In terms of functionality, all investigated TAs resulted in occludin redistribution and loss of zona occludens-1 and occludin co-localization. Conclusion Increases in the gastrointestinal TA load may contribute to a relatively pro-inflammatory outcome in the intestine, along with tight junction protein disruption. Additionally, fluctuating levels of endogenous E2 may modulate microbially-derived TA levels, potentially explaining exaggerating gastrointestinal symptomology in females during low E2 phases. Thus, current data warrants subsequent investigations in appropriate in vivo models to fully elucidate the role of the trace aminergic system in the sex bias observed in IBS.
Article
Full-text available
Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, Escherichia coli in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine.
Article
Full-text available
Recent studies emphasize the role of microbial metabolites in regulating gastrointestinal (GI) physiology through activation of host receptors, highlighting the potential for inter-kingdom signaling in treating GI disorders. In this study, we show that tryptamine, a tryptophan-derived bacterial metabolite, stimulates mucus release from goblet cells via activation of G-protein-coupled receptor (GPCR) 5-HT4R. Germ-free mice colonized with engineered Bacteroides thetaiotaomicron optimized to produce tryptamine (Trp D+) exhibit decreased weight loss and increased mucus release following dextran sodium sulfate treatment when compared with mice colonized with control B. thetaiotaomicron (Trp D-). Additional beneficial effects in preventing barrier disruption and lower disease activity index were seen only in female mice, highlighting sex-specific effects of the bacterial metabolite. This study demonstrates potential for the precise modulation of mucus release by microbially produced 5-HT4 GPCR agonist as a therapeutic strategy to treat inflammatory conditions of the GI tract.
Article
Full-text available
Since the Great Oxidation Event, about 2.4 billion years ago, the Earth is immersed in an oxidizing atmosphere. Thus, it has been proposed that excess oxygen, originally a waste product of photosynthetic cyanobacteria, induced oxidative stress and the production of reactive oxygen species (ROS), which have since acted as fundamental drivers of biologic evolution and eukaryogenesis. Indeed, throughout an organism’s lifespan, ROS affect directly (as mutagens) or indirectly (as messengers and regulators) all structural and functional components of cells, and many aspects of cell biology. Whether left unchecked by protective antioxidant systems, excess ROS not only cause genomic mutations but also induce irreversible oxidative modification of proteins (protein oxidation and peroxidation), lipids and glycans (advanced lipoxidation and glycation end products), impairing their function and promoting disease or cell death. Conversely, low-level local ROS play an important role both as redox-signaling molecules in a wide spectrum of pathways involved in the maintenance of cellular homeostasis (MAPK/ERK, PTK/PTP, PI3K-AKT-mTOR), and regulating key transcription factors (NFκB/IκB, Nrf2/KEAP1, AP-1, p53, HIF-1). Consequently, ROS can shape a variety of cellular functions, including proliferation, differentiation, migration and apoptosis. In this review, we will give a brief overview of the relevance of ROS in both physiological and pathological processes, particularly inflammation and aging. In-depth knowledge of the molecular mechanisms of ROS actuation and their influence under steady-state and stressful conditions will pave the way for the development of novel therapeutic interventions. This will mitigate the harmful outcomes of ROS in the onset and progression of a variety of chronic inflammatory and age-related diseases.
Article
Full-text available
Due to a lack of specific or sensitive biomarkers, drug discovery advances have been limited for individuals suffering from irritable bowel syndrome (IBS). While current therapies provide symptomatic relief, inflammation itself is relatively neglected, despite the presence of chronic immune activation and innate immune system dysfunction. Moreover, considering the microgenderome concept, gender is a significant aetiological risk factor. We believe that we have pinpointed a "missing link" that connects gender, dysbiosis, diet, and inflammation in the context of IBS, which may be manipulated as therapeutic target. The trace aminergic system is conveniently positioned at the interface of the gut microbiome, dietary nutrients and by-products, and mucosal immunity. Almost all leukocyte populations express trace amine associated receptors and significant amounts of trace amines originate from both food and the gut microbiota. Additionally, although IBS-specific data are sparse, existing data supports an interpretation in favour of a gender dependence in trace aminergic signalling. As such, trace aminergic signalling may be altered by fluctuations of especially female reproductive hormones. Utilizing a multidisciplinary approach, this review discusses potential mechanisms of actions, which include hyperreactivity of the immune system and aberrant serotonin signalling, and links outcomes to the symptomology clinically prevalent in IBS. Taken together, it is feasible that the additional level of regulation by the trace aminergic system in IBS has been overlooked, until now. As such, we suggest that components of the trace aminergic system be considered targets for future therapeutic action, with the specific focus of reducing oxidative stress and inflammation.
Article
Full-text available
Background & Aims Although functional gastrointestinal disorders (FGIDs), now called disorders of gut–brain interaction, have major economic effects on healthcare systems and adversely affect quality of life, little is known about their global prevalence and distribution. We investigated the prevalence of and factors associated with 22 FGIDs, in 33 countries on 6 continents. Methods Data were collected via the internet in 24 countries, personal interviews in 7 countries, and both in 2 countries, using the Rome IV diagnostic questionnaire, Rome III irritable bowel syndrome questions, and 80 items to identify variables associated with FGIDs. Data collection methods differed for internet and household groups, so data analyses were conducted and reported separately. Results Among the 73,076 adult respondents (49.5% women), diagnostic criteria were met for at least 1 FGID by 40.7% persons who completed the internet surveys (95% CI, 40.2–41.1) and 20.9% of persons who completed the household surveys. FGIDs were more prevalent among women than men, based on responses to the internet survey (odds ratio, 1.7; 95% CI, 1.6–1.7) and household survey (odds ratio, 1.4; 95% CI, 1.3–1.5). FGIDs were associated with lower quality of life and more frequent doctor visits. Proportions of subjects with irritable bowel syndrome were lower when the Rome IV criteria were used, compared with the Rome III criteria, in the internet survey (4.1% vs 10.1%) and household survey (1.5% vs 3.5%). Conclusions In a large-scale multi-national study, we found that more than 40% of persons worldwide have FGIDs, which affect quality of life and healthcare use. Although the absolute prevalence was higher among internet respondents, similar trends and relative distributions were found in people who completed internet vs personal interviews.
Article
Full-text available
Trace amines and their primary receptor, Trace Amine-Associated Receptor-1 (TAAR1) are widely studied for their involvement in the pathogenesis of neuropsychiatric disorders despite being found in the gastrointestinal tract at physiological levels. With the emergence of the “brain-gut-microbiome axis,” we take the opportunity to review what is known about trace amines in the brain, the defined sources of trace amines in the gut, and emerging understandings on the levels of trace amines in various gastrointestinal disorders. Similarly, we discuss localization of TAAR1 expression in the gut, novel findings that TAAR1 may be implicated in inflammatory bowel diseases, and the reported comorbidities of neuropsychiatric disorders and gastrointestinal disorders. With the emergence of TAAR1 specific compounds as next-generation therapeutics for schizophrenia (Roche) and Parkinson’s related psychoses (Sunovion), we hypothesize a therapeutic benefit of these compounds in clinical trials in the brain-gut-microbiome axis, as well as a potential for thoughtful manipulation of the brain-gut-microbiome axis to modulate symptoms of neuropsychiatric disease.
Article
Full-text available
Agmatine (AGM) produces a dual effect on the mitochondrial permeability transition (MPT) mechanism in rat liver mitochondria: at low concentrations, it induces the phenomenon, at high ones, inhibits it. The prevention at high concentrations is evidenced by the significant inhibition of mitochondrial swelling induced by Ca²⁺ and phosphate; in this condition, AGM both prevents the release of Apoptosis Inducing Factor (AIF) and enhances the release of other pro-apoptotic factors, such as cytochrome c (cyt c) and Smac/DIABLO. As these factors are released without MPT induction, the involvement of mitochondrial outer membrane permeabilization (MOMP) could be hypothesized. Cyclosporin A (CsA), a powerful inhibitor of MPT, enhanced the AGM-mediated inhibition of swelling, and surprisingly, prevented the release of cyt c and Smac/DIABLO. In the presence of Ca²⁺, AGM also activated the Bcl-2 family protein Bax, a key factor in inducing MOMP, which is inactivated by CsA. Together with the voltage-dependent anion channel (VDAC), Bax forms channels in the outer membrane further supporting the involvement of MOMP in the release of pro-apoptotic factors. In view of the fact that VDAC was inactivated by ruthenium red, which in turn inhibited the release of cyt c, it can be hypothesized that, on the one hand, AGM inhibits MPT induction and, on the other, it selectively permeabilizes the outer membrane via MOMP induction.
Article
Full-text available
Background: The burden of inflammatory bowel disease (IBD) is rising globally, with substantial variation in levels and trends of disease in different countries and regions. Understanding these geographical differences is crucial for formulating effective strategies for preventing and treating IBD. We report the prevalence, mortality, and overall burden of IBD in 195 countries and territories between 1990 and 2017, based on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Methods: We modelled mortality due to IBD using a standard Cause of Death Ensemble model including data mainly from vital registrations. To estimate the non-fatal burden, we used data presented in primary studies, hospital discharges, and claims data, and used DisMod-MR 2.1, a Bayesian meta-regression tool, to ensure consistency between measures. Mortality, prevalence, years of life lost (YLLs) due to premature death, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) were estimated. All of the estimates were reported as numbers and rates per 100 000 population, with 95% uncertainty intervals (UI). Findings: In 2017, there were 6·8 million (95% UI 6·4-7·3) cases of IBD globally. The age-standardised prevalence rate increased from 79·5 (75·9-83·5) per 100 000 population in 1990 to 84·3 (79·2-89·9) per 100 000 population in 2017. The age-standardised death rate decreased from 0·61 (0·55-0·69) per 100 000 population in 1990 to 0·51 (0·42-0·54) per 100 000 population in 2017. At the GBD regional level, the highest age-standardised prevalence rate in 2017 occurred in high-income North America (422·0 [398·7-446·1] per 100 000) and the lowest age-standardised prevalence rates were observed in the Caribbean (6·7 [6·3-7·2] per 100 000 population). High Socio-demographic Index (SDI) locations had the highest age-standardised prevalence rate, while low SDI regions had the lowest age-standardised prevalence rate. At the national level, the USA had the highest age-standardised prevalence rate (464·5 [438·6-490·9] per 100 000 population), followed by the UK (449·6 [420·6-481·6] per 100 000). Vanuatu had the highest age-standardised death rate in 2017 (1·8 [0·8-3·2] per 100 000 population) and Singapore had the lowest (0·08 [0·06-0·14] per 100 000 population). The total YLDs attributed to IBD almost doubled over the study period, from 0·56 million (0·39-0·77) in 1990 to 1·02 million (0·71-1·38) in 2017. The age-standardised rate of DALYs decreased from 26·5 (21·0-33·0) per 100 000 population in 1990 to 23·2 (19·1-27·8) per 100 000 population in 2017. Interpretation: The prevalence of IBD increased substantially in many regions from 1990 to 2017, which might pose a substantial social and economic burden on governments and health systems in the coming years. Our findings can be useful for policy makers developing strategies to tackle IBD, including the education of specialised personnel to address the burden of this complex disease. Funding: Bill & Melinda Gates Foundation.
Article
Full-text available
Genome-wide association studies have identified over 200 genomic loci associated with inflammatory bowel disease (IBD). High-effect risk alleles define key roles for genes involved in bacterial response and innate defense. More high-throughput in vivo systems are required to rapidly evaluate therapeutic agents. We visualize, in zebrafish, the effects on epithelial barrier function and intestinal autophagy of one-course and repetitive injury. Repetitive injury induces increased mortality, impaired recovery of intestinal barrier function, failure to contain bacteria within the intestine and impaired autophagy. Prostaglandin E2 (PGE2) administration protected against injury by enhancing epithelial barrier function and limiting systemic infection. Effects of IBD therapeutic agents were defined: mesalamine showed protective features during injury, whereas 6-mercaptopurine displayed marked induction of autophagy during recovery. Given the highly conserved nature of innate defense in zebrafish, it represents an ideal model system with which to test established and new IBD therapies targeted to the epithelial barrier. This article has an associated First Person interview with the first author of the paper.
Article
Full-text available
Background Irritable Bowel Syndrome (IBS) is a chronic gastrointestinal disorder characterised by recurrent abdominal pain and disturbed bowel habits and unclear aetiology. IBS is also associated with psychosocial factors, impaired quality of life and lost work productivity. This study sought to determine whether the association between IBS and lost work productivity might be accounted for by poor coping strategies and loss of confidence in the healthcare system. Methods Case–control design was employed sampling IBS and non-gastrointestinal (non-GI) primary healthcare seekers in a defined region in Sweden. Non-GI patients were of similar age and sex distribution to the IBS patients. Questionnaires applied in this study included instruments designed to measure confidence in the social security system and in the community, as well as questions about whether gastrointestinal problems might affect working life and Sense of coherence (SOC) questionnaire. The study’s primary hypothesis was evaluated via an a priori path model. Results Statistically significant differences were found between IBS cases (n = 305) and controls (n = 369) concerning abdominal pain or discomfort affecting everyday performance at work (p < 0.0001). IBS cases also showed significantly lower (p = 0.001) confidence in public healthcare. The study’s hypothesis was supported with the finding of a statistically significant indirect association via poor coping strategies, although the indirect associations were lesser in magnitude than the direct association. Conclusions This study found a clear association between clinically diagnosed IBS status and interference in work by gastrointestinal symptoms in which sense of coherence might be of importance.
Article
Full-text available
Abstract The human gut microbiome is a critical component of digestion, breaking down complex carbohydrates, proteins, and to a lesser extent fats that reach the lower gastrointestinal tract. This process results in a multitude of microbial metabolites that can act both locally and systemically (after being absorbed into the bloodstream). The impact of these biochemicals on human health is complex, as both potentially beneficial and potentially toxic metabolites can be yielded from such microbial pathways, and in some cases, these effects are dependent upon the metabolite concentration or organ locality. The aim of this review is to summarize our current knowledge of how macronutrient metabolism by the gut microbiome influences human health. Metabolites to be discussed include short-chain fatty acids and alcohols (mainly yielded from monosaccharides); ammonia, branched-chain fatty acids, amines, sulfur compounds, phenols, and indoles (derived from amino acids); glycerol and choline derivatives (obtained from the breakdown of lipids); and tertiary cycling of carbon dioxide and hydrogen. Key microbial taxa and related disease states will be referred to in each case, and knowledge gaps that could contribute to our understanding of overall human wellness will be identified.
Article
Full-text available
Background: Irritable bowel syndrome (IBS) is a common and potential disabling functional gastrointestinal disorder. Studies have revealed a possible association between IBS and psychological problems, such as anxiety and depression. Existing systematic reviews have addressed only the levels of anxiety or depression in patients with IBS. Aim: To investigate systematically the prevalence of anxiety or depression in IBS patients Methods: A literature search was conducted using the related keywords from the bibliographic databases of Embase, PubMed, Scopus, Web of Science and POPLINE published until 1 January 2019 with no language restriction. Studies reporting the prevalence of anxiety/depressive symptoms/disorders in adult (≥15 years) IBS patients were evaluated. The pooled prevalence, odds ratio (OR) and 95% CI were calculated using stata software. Results: A total of 14 926 articles were initially screened, and finally 73 papers were included. The prevalence rates of anxiety symptoms and disorders in IBS patients were 39.1% (95% CI: 32.4‐45.8) and 23% (95% CI: 17.2‐28.8) respectively. The ORs for anxiety symptoms and disorders in IBS patients compared with healthy subjects were 3.11 (95% CI: 2.43‐3.98) and 2.52 (95% CI: 1.99‐3.20) respectively. The prevalence estimates of depressive symptoms and disorders in IBS patients were 28.8% (95% CI: 23.6‐34) and 23.3% (95% CI: 17.2‐29.4) respectively. The ORs for depressive symptoms and disorders in IBS patients compared to healthy subjects were 3.04 (95% CI: 2.37‐3.91) and 2.72 (95% CI: 2.45‐3.02) respectively. Conclusion: Patients with IBS have a three‐fold increased odds of either anxiety or depression, compared to healthy subjects.
Article
Full-text available
Lactic acid bacteria (LAB) are considered as the main biogenic amine (BA) producers in fermented foods. These compounds derive from amino acid decarboxylation through microbial activities and can cause toxic effects on humans, with symptoms (headache, heart palpitations, vomiting, diarrhea) depending also on individual sensitivity. Many studies have focused on the aminobiogenic potential of LAB associated with fermented foods, taking into consideration the conditions affecting BA accumulation and enzymes/genes involved in the biosynthetic mechanisms. This review describes in detail the different LAB (used as starter cultures to improve technological and sensorial properties, as well as those naturally occurring during ripening or in spontaneous fermentations) able to produce BAs in model or in real systems. The groups considered were enterococci, lactobacilli, streptococci, lactococci, pediococci, oenococci and, as minor producers, LAB belonging to Leuconostoc and Weissella genus. A deeper knowledge of this issue is important because decarboxylase activities are often related to strains rather than to species or genera. Moreover, this information can help to improve the selection of strains for further applications as starter or bioprotective cultures, in order to obtain high quality foods with reduced BA content.
Article
Full-text available
Abstract Tyramine, histamine and putrescine are the most commonly detected and most abundant biogenic amines (BA) in food. The consumption of food with high concentrations of these BA is discouraged by the main food safety agencies, but legal limits have only been set for histamine. The present work reports a transcriptomic investigation of the oncogenic potential of the above-mentioned BA, as assessed in the HT29 human intestinal epithelial cell line. Tyramine had a greater effect on the expression of genes involved in tumorigenesis than did histamine or putrescine. Since some of the genes that showed altered expression in tyramine-exposed cells are involved in DNA damage and repair, the effect of this BA on the expression of other genes involved in the DNA damage response was investigated. The results suggest that tyramine might be genotoxic for intestinal cells at concentrations easily found in BA-rich food. Moreover, a role in promoting intestinal cancer cannot be excluded.
Article
Full-text available
Because of the sex-gender differences that are shown in a diversity of physiological and psychological factors, it can be speculated that the clinical presentation of symptoms as well as treatment strategies in women and men with irritable bowel syndrome (IBS) may differ. Studies have revealed that IBS is more common in women than men. As for the IBS subtype, IBS with constipation is significantly more prevalent among women than men. Sex hormones and gender differences may play important roles in the pathophysiology of IBS. However, its pathophysiologic mechanisms still remain largely unknown, and therapeutic implications are limited. Moreover, women IBS patients have been reported to feel more fatigue, depression, anxiety, and lower quality of life than men IBS patients. Furthermore, there has been evidence of differences in the appropriate treatment efficacy to IBS in men and women, although relatively few men are enrolled in most relevant clinical trials. A more sex-gender-oriented approach in the medical care setting could improve understanding of heterogeneous patients suffering from IBS. An individualized and multicomponent approach including sex and gender issues might help improve the treatment of IBS.
Article
Full-text available
Polyamines (PAs) are indispensable polycations ubiquitous to all living cells. Among their many critical functions, PAs contribute to the oxidative balance of the cell. Beginning with studies by the Tabor laboratory in bacteria and yeast, the requirement for PAs as protectors against oxygen radical-mediated damage has been well established in many organisms, including mammals. However, PAs also serve as substrates for oxidation reactions that produce hydrogen peroxide (H2O2) both intra- and extracellularly. As intracellular concentrations of PAs can reach millimolar concentrations, the H2O2 amounts produced through their catabolism, coupled with a reduction in protective PAs, is sufficient to cause the oxidative damage associated with many pathologies, including cancer. Thus, the maintenance of intracellular polyamine homeostasis may ultimately contribute to the maintenance of oxidative homeostasis. Again, pioneering studies by Tabor and colleagues led the way in first identifying spermine oxidase in Saccharomyces cerevisiae They also first purified the extracellular bovine serum amine oxidase and elucidated the products of its oxidation of primary amine groups of PAs when included in culture medium. These investigations formed the foundation for many polyamine-related studies and experimental procedures still performed today. The following review will summarize key innovative studies regarding PAs and oxidative damage, starting with those from the Tabor laboratory and including the most recent advances, with a focus on mammalian systems.
Article
Full-text available
Trace amines and their receptors (trace amine-associated receptors; TAARs) are an emerging pharmacological target for the treatment of human disorders. While most studies have focused on their therapeutic potential for neurologic and psychiatric disorders, TAARs are also expressed throughout the periphery, including prominent expression in human leukocytes. Furthermore, recent independent, unbiased metabolomic studies have consistently identified one or more TAAR ligands as potential etiologic factors in inflammatory bowel disease (IBD). The putative role of TAARs in diseases such as IBD that are associated with hyperactive immune responses has not, however, previously been systematically addressed. Here, we review the current state of the knowledge of the effects of TAARs on leukocyte function, in particular in the context of mucosal epithelial cells that interface with the environment; developing a model whereby TAARs may be considered as a novel therapeutic target for disorders associated with dysregulated immune responses to environmental factors. In this model, we hypothesize that altered trace amine homeostasis results in hyperactivity of the immune system. Such loss of homeostasis can occur through many different mechanisms including TAAR polymorphisms and altered trace amine load due to changes in host synthesis and/or degradative enzymes, diet, or microbial dysbiosis. The resulting alterations in TAAR functioning can then lead to a loss of homeostasis of leukocyte chemotaxis, differentiation, and activation, as well as an altered ability of members of the microbiota to adhere to and penetrate the epithelial cell layers. Such changes would generate a pro-inflammatory state at mucosal epithelial barrier layers that can manifest as clinical symptomatology such as that seen in IBD. These alterations may also have the potential to induce systemic effects, which could possibly contribute to immunomodulatory disorders in other systems, including neurological diseases.
Article
Full-text available
Irritable bowel syndrome (IBS) is a functional bowel disorder associated with abdominal pain and alterations in bowel habits. The presence of IBS greatly impairs patients' quality of life and imposes a high economic burden on the community; thus, there is intense pressure to reveal its elusive pathogenesis. Many etiological mechanisms have been implicated, but the pathophysiology of the syndrome remains unclear. As a result, novel drug development has been slow and no pharmacological intervention is universally accepted. A growing evidence implicates the role of low-grade inflammation and innate immune system dysfunction, although contradictory results have frequently been presented. Mast cells (MC), eosinophils and other key immune cells together with their mediators seem to play an important role, at least in subgroups of IBS patients. Cytokine imbalance in the systematic circulation and in the intestinal mucosa may also characterize IBS presentation. Toll-like receptors and their emerging role in pathogen recognition have also been highlighted recently, as dysregulation has been reported to occur in patients with IBS. This review summarizes the current knowledge regarding the involvement of any immunological alteration in the development of IBS. There is substantial evidence to support innate immune system dysfunction in several IBS phenotypes, but additional studies are required to better clarify the underlying pathogenetic pathways. IBS heterogeneity could potentially be attributed to multiple causes that lead to different disease phenotypes, thus explaining the variability found between study results.
Article
Full-text available
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Article
Full-text available
In humans, acid–base balance is crucial to cell homeostasis. Acidosis is observed in numerous inflammatory processes, primarily acute conditions such as sepsis, trauma, or acute respiratory distress where females tend to exhibit better prognosis compared with males. The mechanisms underlying these gender-dependent differences are multiple, probably involving hormonal and genetic factors, particularly the X chromosome. Although pH influences multiple immunological functions, gender differences in acid–base balance have been poorly investigated. In this review, we provide an update on gender differences in human susceptibility to inflammatory diseases. We additionally discuss the potential impact of acid–base balance on the gender bias of the inflammatory response in view of our recent observation that girls present higher neutrophilic inflammation and lower pH with a trend toward better prognosis in severe sepsis. We also highlight the potent role played by endothelial cells in gender differences of inflammation through activation of proton-sensing G protein-coupled receptors.
Article
Full-text available
Irritable bowel syndrome (IBS) is a functional bowel disorder associated with abdominal pain and alterations in bowel habits. The presence of IBS greatly impairs patients’ quality of life and imposes a high economic burden on the community; thus, there is intense pressure to reveal its elusive pathogenesis. Many etiological mechanisms have been implicated, but the pathophysiology of the syndrome remains unclear. As a result, novel drug development has been slow and no pharmacological intervention is universally accepted. A growing evidence implicates the role of low-grade inflammation and innate immune system dysfunction, although contradictory results have frequently been presented. Mast cells (MC), eosinophils and other key immune cells together with their mediators seem to play an important role, at least in subgroups of IBS patients. Cytokine imbalance in the systematic circulation and in the intestinal mucosa may also characterize IBS presentation. Toll-like receptors and their emerging role in pathogen recognition have also been highlighted recently, as dysregulation has been reported to occur in patients with IBS. This review summarizes the current knowledge regarding the involvement of any immunological alteration in the development of IBS. There is substantial evidence to support innate immune system dysfunction in several IBS phenotypes, but additional studies are required to better clarify the underlying pathogenetic pathways. IBS heterogeneity could potentially be attributed to multiple causes that lead to different disease phenotypes, thus explaining the variability found between study results.
Article
Full-text available
A subgroup of biogenic amines, the so-called trace amines (TAs), are produced by mammals and bacteria and can act as neuromodulators. In the genus Staphylococcus, certain species are capable of producing TAs through the activity of staphylococcal aromatic amino acid decarboxylase (SadA). SadA decarboxylates aromatic amino acids to produce TAs, as well as dihydroxy phenylalanine and 5-hydroxytryptophan to thus produce the neurotransmitters dopamine and serotonin. SadA-expressing staphylococci were prevalent in the gut of most probands, where they are part of the human intestinal microflora. Furthermore, sadA-expressing staphylococci showed increased adherence to HT-29 cells and 2- to 3-fold increased internalization. Internalization and adherence was also increased in a sadA mutant in the presence of tryptamine. The α2-adrenergic receptor is required for enhanced adherence and internalization. Thus, staphylococci in the gut might contribute to gut activity and intestinal colonization.
Article
Full-text available
Background: Biogenic amines (BAs) are metabolites produced by the decarboxylation of amino acids with significant physiological functions in eukaryotic and prokaryotic cells. BAs can be produced by bacteria in fermented foods, but little is known concerning the potential for microbes within the human gut microbiota to produce or degrade BAs. Objective: To isolate and identify BA-producing and BA-degrading microbes from the human gastrointestinal tract. Design: Fecal samples from human volunteers were screened on multiple growth media, under multiple growth conditions. Bacterial species were identified using 16S rRNA sequencing and BA production or degradation was assessed using ultra-performance liquid chromatography. Results: In total, 74 BA-producing or BA-degrading strains were isolated from the human gut. These isolates belong to the genera Bifidobacterium, Clostridium, Enterococcus, Lactobacillus, Pediococcus, Streptococcus, Enterobacter, Escherichia, Klebsiella, Morganella and Proteus. While differences in production or degradation of specific BAs were observed at the strain level, our results suggest that these metabolic activities are widely spread across different taxa present within the human gut microbiota. Conclusions: The isolation and identification of microbes from the human gut with BA-producing and BA-degrading metabolic activity is an important first step in developing a better understanding of how these metabolites influence health and disease.
Article
Full-text available
Zebrafish are a powerful model system to assess the molecular and cellular effects of exposure to toxic chemicals during embryonic development. To study the effects of environmental endocrine disruptors, embryos and larvae are commonly exposed to supraphysiologic concentrations of these compounds in the water, but their bioavailability in zebrafish is largely unknown. One hypothesis is that supraphysiologic concentrations of estrogens in the water are required to achieve physiologic levels in vivo, however this has not been directly tested. To test this hypothesis, we developed an assay using radiolabeled estradiol ([3H]E2) to measure uptake from water at multiple concentrations and exposure durations in developing zebrafish from 0-5 days post fertilization (dpf). We found that [3H]E2 uptake increased with increasing concentration, duration, and developmental stage. Percent uptake from the total volume of treatment solution increased with increasing exposure duration and developmental stage, but remained constant with increasing concentration. We also found that the chorion, an acellular envelope surrounding embryos through 3 dpf, did not substantially affect [3H]E2 uptake. Finally, we found that at 1 dpf, estradiol was preferentially taken up by the yolk at multiple exposure durations, while at 2 dpf estradiol was preferentially taken up into the embryonic body. Our results support the hypothesis that exposing zebrafish embryos and larvae to supraphysiologic concentrations of estrogens is required to achieve physiologically-relevant doses in vivo. The isotopic assay reported here will provide a foundation for determining the uptake of other compounds for teratogenicity, toxicology, and drug discovery studies.
Article
Full-text available
Inflammatory bowel disease (IBD) is a chronic, recurrent, and remitting inflammatory disease with unclear etiology. As a clinically frequent disease, it can affect individuals throughout their lives, with multiple complications. Unfortunately, traditional murine models are not efficient for the further study of IBD. Thus, effective and convenient animal models are needed. Zebrafish have been used as model organisms to investigate IBD because of their suggested highly genetic similarity to humans and their superiority as laboratory models. The zebrafish model has been used to study the composition of intestinal microbiota, novel genes, and therapeutic approaches. The pathogenesis of IBD is still unclear and many risk factors remain unidentified. In this review, we compare traditional murine models and zebrafish models in terms of advantages, pathogenesis, and drug discovery screening for IBD. We also review the progress and deficiencies of the zebrafish model for scientific applications.
Article
Full-text available
Background Due to the sex differences in physiological and psychological factors, it can be speculated that clinical presentation of symptoms in male and female patients with irritable bowel syndrome (IBS) might be different. AimTo evaluate sex-related differences in clinical symptoms, quality of life, and biochemical factors in IBS. Methods Ninety IBS patients (29 men, 61 women (45 premenopausal, 16 postmenopausal)) were recruited from the outpatient clinic of the University Hospital. All the patients met the Rome III Diagnostic Criteria. The IBS severity score system (IBS-SSS), gastrointestinal (GI) symptoms, IBS specific quality of life (IBS-QoL), and biochemical factors (IL-17, IL-10, TNFα, malondialdehyde (MDA), total antioxidant capacity (TAC)) were assessed. ResultsDiarrhea predominant IBS (IBS-D) was more common in men (44.8%), whereas constipation-predominant IBS (IBS-C) and alternating bowel habits IBS (IBS-A) were more common in women (39.3, 42.6%, respectively). The women had a greater severity of abdominal distention, rumbling, flatulence, and dissatisfaction with bowel habits as compared with men. The scores of IBS-QoL in women were significantly (P < 0.05) lower than those in men. Moreover, pro-inflammatory cytokines (IL-17, TNFα) increased, and anti-inflammatory cytokine (IL-10) decreased in women versus men. In addition, there was no significant difference (P > 0.05) between pre- and postmenopausal women in the severity of symptoms. All of the GI symptoms and IBS-SSS have a significant negative correlation with IBS-QoL in both men and women. Conclusions Female with IBS reports a greater severity of IBS symptoms, increased inflammatory cytokines, and has an impaired quality of life compared with male.
Article
Full-text available
Background Irritable bowel syndrome (IBS) affects 10–15% of adults in the US, and is associated with significant impairment in health-related quality of life (HRQoL); however, information specific to the diarrhea subtype (IBS-D) is lacking. We assessed the impact of IBS-D on HRQoL, work productivity, and daily activities, and the associated indirect costs, among a sample of the US population. Methods Respondents (≥18 years) from the 2012 US National Health and Wellness Survey who reported an IBS-D diagnosis by a physician or symptoms consistent with Rome II criteria for IBS-D were identified as having IBS-D. Controls included respondents without IBS-D or inflammatory bowel disease. HRQoL was assessed via the Short Form 36 Health Survey version 2 questionnaire and summarized into Mental and Physical Component Summary (MCS; PCS) scores and a Short Form-6 dimension (SF-6D) utility score. Work and activity impairment were assessed via the Work Productivity and Activity Impairment Questionnaire: General Health version (WPAI:GH), which measures absenteeism, presenteeism, overall work productivity loss, and daily activity impairment. Indirect costs were calculated using unit cost data from the Bureau of Labor Statistics and variables from the WPAI:GH. Generalized linear models were used to examine differences in health outcomes between respondents with IBS-D and controls, controlling for demographic and health characteristics. ResultsIn total, 66,491 respondents (1102 IBS-D; 65,389 controls) were analyzed. Mean age was 48.7 years; 50% were female. Compared with controls, the IBS-D cohort reported significantly lower HRQoL (mean MCS: 45.16 vs. 49.48; p < 0.001; mean PCS: 47.29 vs. 50.67; p < 0.001; mean SF-6D: 0.677 vs. 0.741; p < 0.001) and greater absenteeism (5.1% vs. 2.9%; p = 0.004), presenteeism (17.9% vs. 11.3%; p < 0.001), overall work productivity loss (20.7% vs. 13.2%; p < 0.001), and activity impairment (29.6% vs. 18.9%; p < 0.001). Respondents with IBS-D also incurred an estimated $2486 more in indirect costs ($7008 vs. $4522; p < 0.001). Conclusions Compared with controls, IBS-D is associated with significantly lower HRQoL, greater impairments in work and daily activities, and higher indirect costs, imposing a substantial burden on patients and employers. These findings suggest a significant unmet need exists for effective IBS-D treatments.
Article
Full-text available
Background & Aims Microbes may increase susceptibility to inflammatory bowel disease (IBD) by producing bioactive metabolites that affect immune activity and epithelial function. We undertook a family based study to identify microbial and metabolic features of IBD that may represent a predisease risk state when found in healthy first-degree relatives. Methods Twenty-one families with pediatric IBD were recruited, comprising 26 Crohn’s disease patients in clinical remission, 10 ulcerative colitis patients in clinical remission, and 54 healthy siblings/parents. Fecal samples were collected for 16S ribosomal RNA gene sequencing, untargeted liquid chromatography–mass spectrometry metabolomics, and calprotectin measurement. Individuals were grouped into microbial and metabolomics states using Dirichlet multinomial models. Multivariate models were used to identify microbes and metabolites associated with these states. Results Individuals were classified into 2 microbial community types. One was associated with IBD but irrespective of disease status, had lower microbial diversity, and characteristic shifts in microbial composition including increased Enterobacteriaceae, consistent with dysbiosis. This microbial community type was associated similarly with IBD and reduced microbial diversity in an independent pediatric cohort. Individuals also clustered bioinformatically into 2 subsets with shared fecal metabolomics signatures. One metabotype was associated with IBD and was characterized by increased bile acids, taurine, and tryptophan. The IBD-associated microbial and metabolomics states were highly correlated, suggesting that they represented an integrated ecosystem. Healthy relatives with the IBD-associated microbial community type had an increased incidence of elevated fecal calprotectin. Conclusions Healthy first-degree relatives can have dysbiosis associated with an altered intestinal metabolome that may signify a predisease microbial susceptibility state or subclinical inflammation. Longitudinal prospective studies are required to determine whether these individuals have a clinically significant increased risk for developing IBD.
Article
Full-text available
Starting out as a model for developmental biology, during the last decade, zebrafish have also gained the attention of the immunologists and oncologists. Due to its small size, high fecundity and full annotation of its genome, the zebrafish is an attractive model system. The fact that fish are transparent early in life combined with the growing list of immune cell reporter fish, enables in vivo tracking of immune responses in a complete organism. Since zebrafish develop ex utero from a fertilized egg, immune development can be monitored from the start of life. Given that several gut functions and immune genes are conserved between zebrafish and mammals, the zebrafish is an interesting model organism to investigate fundamental processes underlying intestinal inflammation and injury. This review will first provide some background on zebrafish intestinal development, bacterial colonization and immunity, showing the similarities and differences compared to mammals. This will be followed by an overview of the existing models for intestinal disease, and concluded by future perspectives in light of the newest technologies and insights.
Article
Full-text available
Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of "microgenderome" related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.
Article
Ethnopharmacology relevance Aspalathus linearis (Burm.f.) R. Dahlgren (rooibos) tea is anecdotally renowned for its calming effect in the context of gastrointestinal discomfort, but little scientific support is available to elucidate potential mechanisms of action. Enhancement of dietary polyphenol content to improve gut health via prebiotic-like modulation of the gut microbiota has gained significant research interest. Given the known high polyphenol content of rooibos, rooibos tea may potentially exert a prebiotic effect in the gut to facilitate an improvement in chronic inflammatory gastrointestinal conditions. Aim of the study: This study aimed to determine the prebiotic or health-modulating potential of rooibos tea in terms of its effect on gut microbial growth and secretome trace amine composition, as well as to determine how differential rooibos processing alters this activity. Methods Three rooibos preparations (green and fermented leave aqueous extracts, as well as a green leaf ethanol extract) were compared in terms of their phenolic composition (qTOF-LC/MS). Moreover, the effect of rooibos exposure on growth and secretome trace amine levels of probiotic and commensal microbes were assessed (LC/MS). In addition, given the known female bias prevalent for many gastrointestinal disorders, experiments were conducted in the absence and presence of estradiol. Results Polyphenolic composition of rooibos was drastically reduced by fermentation. Aqueous extracts of both green and fermented rooibos improved microbial growth, although fermented rooibos had the most pronounced effect (p < 0.01). In terms of secretome trace amine profile, both aqueous extracts of rooibos seemed to facilitate increased putrescine secretion (p < 0.0001) and decreased tryptamine production (p < 0.0001). Estradiol seemed to suppress trace amine secretion by bacteria (Lactobacillus plantarum, Lactobacillus reuteri and Enterococcus mundtii) but increased it in yeast (Saccharomyces boulardii). Conclusion Rooibos altered gut probiotic and commensal microbial growth and secretome trace amine profiles in vitro, suggesting it has potential to modulate gut microbial composition and functionality as a prebiotic. Current data suggest that these effects are highly dependent on raw material processing. Finally, rooibos may be able to prevent estradiol-associated alterations in trace amine profile, which may have important implications for patient management in female-predominant gastrointestinal disorders.
Article
Background Inflammatory bowel disease (IBD) is a lifelong condition with no cure. Patients with IBD might experience symptoms of common mental disorders such as anxiety and depression because of bidirectional communication via the gut–brain axis and chronicity of symptoms, and because of impaired quality of life and reduced social functioning. However, uncertainties remain about the magnitude of this problem. We aimed to assess prevalence of symptoms of anxiety or depression in adult patients with IBD. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, Embase Classic, and PsycINFO for papers published from inception to Sept 30, 2020, reporting observational studies that recruited at least 100 adult patients with IBD and that reported prevalence of symptoms of anxiety or depression according to validated screening instruments. We excluded studies that only used a structured interview to assess for these symptoms and studies that did not provide extractable data. We extracted data from published study reports and calculated pooled prevalences of symptoms of anxiety and depression, odds ratios (OR), and 95% CIs. Findings Of 5544 studies identified, 77 fulfilled the eligibility criteria, including 30 118 patients in total. Overall, pooled prevalence of anxiety symptoms was 32·1% (95% CI 28·3–36·0) in 58 studies (I²=96·9%) and pooled prevalence of depression symptoms was 25·2% (22·0–28·5) in 75 studies (I²=97·6%). In studies that reported prevalence of anxiety or depression in patients with Crohn's disease and ulcerative colitis within the same study population, patients with Crohn's disease had higher odds of anxiety symptoms (OR 1·2, 95% CI 1·1–1·4) and depression symptoms (1·2, 1·1–1·4) than patients with ulcerative colitis. Overall, women with IBD were more likely to have symptoms of anxiety than were men with IBD (pooled prevalence 33·8% [95% CI 26·5–41·5] for women vs 22·8% [18·7–27·2] for men; OR 1·7 [95% CI 1·2–2·3]). They were also more likely to have symptoms of depression than men were (pooled prevalence 21·2% [95% CI 15·4–27·6] for women vs 16·2% [12·6–20·3] for men; OR 1·3 [95% CI 1·0–1·8]). The prevalence of symptoms of anxiety (57·6% [95% CI 38·6–75·4]) or depression (38·9% [26·2–52·3]) was higher in patients with active IBD than in patients with inactive disease (38·1% [30·9–45·7] for anxiety symptoms and 24·2% [14·7–35·3] for depression symptoms; ORs 2·5 [95% CI 1·5–4·1] for anxiety and 3·1 [1·9–4·9] for depression). Interpretation There is a high prevalence of symptoms of anxiety and depression in patients with IBD, with up to a third of patients affected by anxiety symptoms and a quarter affected by depression symptoms. Prevalence was also increased in patients with active disease: half of these patients met criteria for anxiety symptoms and a third met criteria for depression symptoms. Encouraging gastroenterologists to screen for and treat these disorders might improve outcomes for patients with IBD. Funding None.
Article
Eukaryotic cells take up macromolecules and particles from the surrounding milieu and also internalize membrane proteins via a precise process of endocytosis. The role of endocytosis in diverse physiological processes such as cell adhesion, cell signaling, tissue remodeling, and healing is well recognized. The epithelial tight junctions (TJs), present at the apical lateral membrane, play a key role in cell adhesion and regulation of paracellular pathway. These vital functions of the TJ are achieved through the dynamic regulation of the presence of pore and barrier-forming proteins within the TJ complex on the plasma membrane. In response to various intracellular and extracellular clues, the TJ complexes are actively regulated by intracellular trafficking. The intracellular trafficking consists of endocytosis and recycling cargos to the plasma membrane or targeting them to the lysosomes for degradation. Increased intestinal TJ permeability is a pathological factor in inflammatory bowel disease (IBD), and the TJ permeability could be increased due to the altered endocytosis or recycling of TJ proteins. This review discusses the current information on endocytosis of intestinal epithelial TJ proteins. The knowledge of the endocytic regulation of the epithelial TJ barrier will provide further understanding of pathogenesis and potential targets for IBD and a wide variety of human disease conditions.
Article
Immune-mediated diseases typically show a female preponderance. Looking at all autoimmune diseases combined, 8 of 10 patients are females. Although not as prominent, gender differences in inflammatory bowel disease (IBD) have been reported for epidemiology, disease presentation, disease course and complications, medical and surgical therapies, adherence, psychosocial functioning, and psychiatric co-disorders. While for some factors evidence is rather good, for others data are conflicting. Gastroenterologists dealing with IBD patients in daily clinical practice should be aware of gender-specific issues for the following reasons: (1) misperception of disease presentation potentially delays IBD diagnosis, which has been shown to have deleterious effects, and (2) awareness of gender-specific symptoms and disease severity allows initiation of early and adequately tailored treatment. This might prevent development of complications. And (3) insights into gender-specific differences in terms of treatment and adherence to treatment can improve disease management and foster a more individualized treatment approach. In this review, we summarize current knowledge about gender-specific differences in IBD and highlight the most clinically relevant aspects.
Article
The zebrafish (Danio rerio) has become a widely used vertebrate model for bacterial, fungal, viral, and protozoan infections. Due to its genetic tractability, large clutch sizes, ease of manipulation, and optical transparency during early life stages, it is a particularly useful model to address questions about the cellular microbiology of host‐microbe interactions. Although its use as a model for systemic infections, as well as infections localized to the hindbrain and swimbladder have been thoroughly reviewed, studies focusing on host‐microbe interactions in the zebrafish gastrointestinal tract have been neglected. Here, we summarize recent findings regarding the developmental and immune biology of the gastrointestinal tract, drawing parallels to mammalian systems. We discuss the use of adult and larval zebrafish as models for gastrointestinal infections, and more generally, for studies of host‐microbe interactions in the gut. This article is protected by copyright. All rights reserved.
Article
In a previous study we showed a clear relationship between immune system and behavior in zebrafish and we hypothesized that the immune system is capable of inducing behavioral changes. To further investigate this subject and to address our main question, here we induced an inflammatory response in one group of fish by the inoculation of formalin-inactivated Aeromonoas hydrophila bacterin and compared their social and exploratory behavior with control groups. After the behavioral tests, we also analyzed the expression of cytokines genes and markers of neuronal activity in fish brain. In the bacterin-inoculated fish, the locomotor activity, social preference and exploratory behavior towards a new object were reduced compared to the control fish while the expression of proinflammatory cytokines in the brain was upregulated. With this study we demonstrated for the first time that the immune system is capable of causing behavioral changes that are consistent with the sickness behavior observed in mammals.
Article
Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the physiologic effect of tryptamine in the gastrointestinal (GI) tract remains unknown. Here, we show that the biological effects of tryptamine are mediated through the 5-HT4 receptor (5-HT4R), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium. Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, consistent with increased intestinal secretion. The secretory effect of tryptamine is dependent on 5-HT4R activation and is blocked by 5-HT4R antagonist and absent in 5-HT4R-/- mice. GF mice colonized by Bacteroides thetaiotaomicron engineered to produce tryptamine exhibit accelerated GI transit. Our study demonstrates an aspect of host physiology under control of a bacterial metabolite that can be exploited as a therapeutic modality. VIDEO ABSTRACT.
Article
The exposure of cells, tissues and extracellular matrix to harmful reactive species causes a cascade of reactions and induces activation of multiple internal defence mechanisms (enzymatic or non-enzymatic) that provide removal of reactive species and their derivatives. The non-enzymatic antioxidants are represented by molecules characterized by the ability to rapidly inactivate radicals and oxidants. This paper focuses on the major intrinsic non-enzymatic antioxidants, including metal binding proteins (MBPs), glutathione (GSH), uric acid (UA), melatonin (MEL), bilirubin (BIL) and polyamines (PAs).
Article
A growing body of evidence suggests a possible role for low-grade inflammation in the pathogenesis of irritable bowel syndrome (IBS). The objectives of this study were to measure serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-17, interleukin (IL)-10, malondialdehyde (MDA) and total antioxidant capacity (TAC) in IBS patients and healthy controls (HCs), and to evaluate possible correlations of such markers with gastrointestinal (GI) symptoms and quality of life (QoL). Ninety Rome III positive IBS patients and 90 sex and age matched HCs were recruited. GI symptoms, IBS-QoL, IBS severity score system (IBSSS), and the serum levels of inflammatory cytokines and oxidative stress biomarkers were evaluated. In IBS patients, TNFα, IL-17 and MDA cytokines were significantly (P < 0.05) higher, and IL-10 cytokine and TAC were significantly (P < 0.05) lower vs. HCs. When comparing IBS subtypes, TNFα and IL-17 were significantly (P < 0.05) higher, and IL-10 was significantly (P < 0.05) lower in diarrhea predominant IBS (IBS-D) compared to HCs, whereas the inflammatory cytokine profile of other subtypes more closely resembled that of HCs. The serum levels of MDA and TAC were significantly different (P < 0.05) in all the subtypes vs. HCs. All the inflammatory cytokines had significant (P < 0.05) correlations with GI symptoms, IBSSS and IBS-QoL, whereas no significant association was found between oxidative stress biomarkers and these symptoms. IBS-D patients display increased pro-inflammatory cytokines and decreased anti-inflammatory cytokines. Present study demonstrated a correlation between inflammatory cytokines and both IBS symptoms and QoL.
Article
Ulcerative colitis is the typical progression of chronic inflammatory bowel disease. Amino acids, particularly tryptophan, have been reported to exert a protective effect against colitis induced by dextran sodium sulfate (DSS), but the precise underlying mechanisms remain incompletely clarified. Tryptophan metabolites are recognized to function as endogenous ligands for aryl hydrocarbon receptor (Ahr), which is a critical regulator of inflammation and immunity. Thus, we conducted this study to investigate whether dietary tryptophan supplementation protects against DSS-induced colitis by acting through Ahr. Female wild-type (WT) and Ahr-deficient (knockout; KO) mice (10–12 weeks old) were divided into 4 groups and fed either a control or 0.5% tryptophan diet. The tryptophan diet ameliorated DSS-induced colitis symptoms and severity in WT mice but not in KO mice, and the diet reduced the mRNA expression of Il-6, Tnfα, Il-1β, and the chemokines Ccl2, Cxcl1, and Cxcl2 in the WT groups. Furthermore, Il-22 and Stat3 mRNA expression in the colon was elevated in WT mice fed with the tryptophan diet, which mainly protected epithelial layer integrity, and Ahr also modulated immune homeostasis by regulating Foxp3 and Il-17 mRNA expression. These data suggest that tryptophan-containing diet might ameliorate DSS-induced acute colitis and regulate epithelial homeostasis through Ahr. Thus, tryptophan could serve as a promising preventive agent in the treatment of ulcerative colitis.
Article
The microbiota-the collection of microorganisms that live within and on all mammals-provides crucial signals for the development and function of the immune system. Increased availability of technologies that profile microbial communities is facilitating the entry of many immunologists into the evolving field of host-microbiota studies. The microbial communities, their metabolites and components are not only necessary for immune homeostasis, they also influence the susceptibility of the host to many immune-mediated diseases and disorders. In this Review, we discuss technological and computational approaches for investigating the microbiome, as well as recent advances in our understanding of host immunity and microbial mutualism with a focus on specific microbial metabolites, bacterial components and the immune system.
Article
Background: Mononuclear phagocytes, such as monocytes, macrophages, and dendritic cells, are important cellular components of the innate immune system that contribute to the pathogenesis of many intestinal inflammatory diseases. Summary: While mononuclear phagocytes play a key role in the induction of inflammation in many different tissues through production of pro-inflammatory cytokines and chemokines (such as IL-1, TNF, IL-6, IL-8 and MCP-1), free oxygen radicals (also termed 'oxidative burst'), proteases (such as cathepsins) and tissue-degrading enzymes (such as metalloproteinases), resident macrophages as well as dendritic cells in the intestine display an anergic and 'tolerogenic' phenotype mediating tolerance to commensal bacteria. In recent years many single nucleotide polymorphisms (SNPs) in genes mainly expressed in the above-mentioned cell types have been identified to convey an increased risk of autoimmune diseases. SNPs in the NOD2, ATG16L1 and TNFSF15 genes, which are involved in the function of the innate immune cells, are identified as risk factors for Crohn's disease (CD). Of note, these genes are involved in the different functions in the innate immune cells. For example, while NOD2 is required for intracellular recognition of microbial components, ATG16L1 is involved in autophagy responses against intracellular microbes. Likewise, TNFSF15 contributes to the induction of inflammatory responses by innate immune cells. Furthermore, the frequency of mutations in these genes differs by ethnicity. Genetic variations in the NOD2 and ATG16L1 genes are associated with CD in Caucasians but much less in Eastern Asian populations, whereas SNPs in TNFSF15 are dominated in Asian populations. Thus, different genetic risks may eventually lead to similar impairments in innate immune cells, thereby developing the same disease in Western and Asian patients with CD. Key messages: Despite differences in risk genes, similar mechanisms associated with the innate immune system may trigger autoimmune and chronic inflammatory intestinal diseases in East and West.
Article
Healthy women at reproductive age experience a cyclical alteration of gastrointestinal (GI) symptomatology during the menstrual cycle. Additionally, the majority of healthy women also complain of worsening of GI symptoms either during the premenstrual or menstrual phase. Despite conflicting evidence, studies suggest that sex hormones may increase GI transit time during the luteal phase. Similar phenomenon is also observed in women with underlying inflammatory bowel disease (IBD). The mechanism underlying this complex pathophysiology is still not completely understood. However, a possible influence of sex hormones on the brain-gut-microbiota axis is hypothesized. The diagnosis of IBD is associated with a delay in menarche as well as menstrual function irregularities including alterations in cycle length and duration of flow. There are little data on the effect of menopause on IBD disease activity and there were conflicting data on the effect of IBD diagnosis on the onset of menopause. The role of contraceptives and hormone replacement therapies on the development or disease activity of IBD has not been established. Moreover, IBD patients with concomitant dysmenorrhea report heightened pain during menses. The effect of non-steroidal anti-inflammatory drugs in treating primary dysmenorrhea on the disease course of IBD is unclear. In addition, the effect of IBD medications including immunomodulators and biologics on menstrual function remains unclear. Also, the role of IBD surgery on menstrual irregularities needs to be fully elucidated. Hence, the understanding the influence of menstrual function on IBD disease activity and vice versa and maintenance of a normal menstrual function in those patients is important in improving overall reproductive health and fertility. This article is protected by copyright. All rights reserved.
Article
The gastrointestinal (GI) tract contains much of the body's serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here, we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes. Copyright © 2015 Elsevier Inc. All rights reserved.
Article
Background and purpose: BBB disruption after acute ischemic stroke and subsequent permeability increase may be enhanced by reperfusion. Agmatine has been reported to attenuate BBB disruption. Our aim was to evaluate the effects of agmatine on BBB stabilization in a rat model of transient cerebral ischemia by using permeability dynamic contrast-enhanced MR imaging at early stages and subsequently to demonstrate the feasibility of dynamic contrast-enhanced MR imaging for the investigation of new therapies. Materials and methods: Thirty-four male Sprague-Dawley rats were subjected to transient MCA occlusion for 90 minutes. Immediately after reperfusion, agmatine (100 mg/kg) or normal saline was injected intraperitoneally into the agmatine-treated group (n = 17) or the control group, respectively. MR imaging was performed after reperfusion. For quantitative analysis, regions of interest were defined within the infarct area, and values for volume transfer constant, rate transfer coefficient, volume fraction of extravascular extracellular space, and volume fraction of blood plasma were obtained. Infarct volume, infarct growth, quantitative imaging parameters, and numbers of factor VIII-positive cells after immunohistochemical staining were compared between control and agmatine-treated groups. Results: Among the permeability parameters, volume transfer constant and volume fraction of extravascular extracellular space were significantly lower in the agmatine-treated group compared with the control group (0.05 ± 0.02 minutes(-1) versus 0.08 ± 0.03 minute(-1), P = .012, for volume transfer constant and 0.12 ± 0.06 versus 0.22 ± 0.15, P = .02 for volume fraction of extravascular extracellular space). Other permeability parameters were not significantly different between the groups. The number of factor VIII-positive cells was less in the agmatine-treated group than in the control group (3-fold versus 4-fold, P = .037). Conclusions: In ischemic stroke, agmatine protects the BBB, which can be monitored in vivo by quantification of permeability by using dynamic contrast-enhanced MR imaging. Therefore, dynamic contrast-enhanced MR imaging may serve as a potential imaging biomarker for assessing the BBB stabilization properties of pharmacologic agents.
Article
Several recent studies describe the influence of the gut microbiota on host brain and behavior. However, the mechanisms responsible for microbiota-nervous system interactions are largely unknown. Using a combination of genetics, biochemistry, and crystallography, we identify and characterize two phylogenetically distinct enzymes found in the human microbiome that decarboxylate tryptophan to form the β-arylamine neurotransmitter tryptamine. Although this enzymatic activity is exceedingly rare among bacteria more broadly, analysis of the Human Microbiome Project data demonstrate that at least 10% of the human population harbors at least one bacterium encoding a tryptophan decarboxylase in their gut community. Our results uncover a previously unrecognized enzymatic activity that can give rise to host-modulatory compounds and suggests a potential direct mechanism by which gut microbiota can influence host physiology, including behavior.
Article
Reactive oxygen species are key signaling molecules which play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear leukocytes (PMNs) at the site of inflammation cause endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells help in clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress mediated signaling mechanisms involved in inflammation and tissue injury.