No file available
To read the file of this research,
you can request a copy directly from the authors.
Isomalto/Malto-Polysaccharides Exert Immune-Stimulating Effects Via Toll-Like Receptor 2 and 4: Proof-of-Principle in Preventing Antibiotic-Induced Cytokine Reduction
Preprints and early-stage research may not have been peer reviewed yet.
ResearchGate has not been able to resolve any citations for this publication.
Tol-like receptor (TLR) agonists, as potent adjuvants, have gained attention in vaccine research for their ability to enhance immune responses. This study focuses on their application in improving vaccine efficacy against key viral infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), SARS-CoV-2, influenza virus, and flaviviruses, including West Nile virus, dengue virus, and chikungunya virus. Vaccines are crucial in preventing microbial infections, including viruses, and adjuvants play a vital role in modulating immune responses. However, there are still many diseases for which effective vaccines are lacking or have limited immune response, posing significant threats to human health. The use of TLR agonists as adjuvants in viral vaccine formulations holds promise in improving vaccine effectiveness. By tailoring adjuvants to specific pathogens, such as HBV, HCV, HIV, SARS-CoV-2, influenza virus, and flavivirus, protective immunity against chronic and emerging infectious disease can be elicited.
Food ingredients that can activate and improve immunological defense, against e.g., pathogens, have become a major field of research. Resistant starches (RSs) can resist enzymes in the upper gastrointestinal (GI) tract and induce health benefits. RS-3 physicochemical characteristics such as chain length (DP), A- or B-type crystal, and polydispersity index (PI) might be crucial for immunomodulation by activating human toll-like receptors (hTLRs). We hypothesize that crystal type, DP and PI, alone or in combination, impact the recognition of RS-3 preparations by hTLRs leading to different RS-3 immunomodulatory effects. We studied the activation of hTLR2, hTLR4, and hTLR5 by 0.5, 1 and 2 mg/mL of RS-3. We found strong activation of hTLR2-dependent NF-kB activation with PI <1.25, DP 18 as an A- or B-type crystal. At different doses, NF-kB activation was increased from 6.8 to 7.1 and 10-fold with A-type and 6.2 to 10.2 and 14.4-fold with B-type. This also resulted in higher cytokine production in monocytes. Molecular docking, using amylose-A and single bondB, demonstrated that B-crystals bind hTLR2 promoting hTLR2-1 dimerization, supporting the stronger effects of B-type crystals. Immunomodulatory effects of RS-3 are predominantly hTLR2-dependent, and activation can be tailored by managing crystallinity, chain length, and PI.
Background Doxycycline post-exposure prophylaxis (DoxyPEP) has demonstrated efficacy for prevention of bacterial sexually transmitted infections. To inform policy decisions on the use of DoxyPEP for gonorrhea prevention, we used a mathematical model to investigate its impact on resistance dynamics and the burden of infection in men who have sex with men (MSM).
Methods and Findings Using a deterministic compartmental model of gonorrhea transmission in an MSM population, we introduced DoxyPEP at various uptake levels (10-75%) and compared 20-year prevalence and resistance dynamics relative to those at baseline (i.e., no DoxyPEP introduction). Uptake of DoxyPEP resulted in initial drops in the prevalence and incidence of gonorrhea infection, but also accelerated the spread of doxycycline resistance, with increasing DoxyPEP use driving steeper initial declines followed by faster spread of resistance. This resulted in the total loss of DoxyPEP's clinical efficacy within 1-2 decades in almost all scenarios explored. The magnitude by which DoxyPEP initially reduced the prevalence of infection was constrained by the extent of pre-existing doxycycline resistant strains in the population. De novo emergence of doxycycline resistance did not influence these dynamics. Additionally, the implementation of DoxyPEP had minimal impact on extending the clinically useful lifespan of ceftriaxone monotherapy.
Conclusions Model findings suggest DoxyPEP can be an effective but short-term solution for reducing the burden of gonorrhea infection, as its selection for doxycycline-resistant strains results in loss of its prophylaxis benefit. Increasing levels of DoxyPEP uptake and higher starting prevalence of doxycycline resistance resulted in faster loss of its efficacy and had little change on extending the clinical lifespan of ceftriaxone for treatment of N. gonorrhoeae infections.
Staphylococcus aureus (S. aureus) causes a broad range of infections. TLR2 senses the S. aureus lipoproteins in S. aureus infections. Aging raises the risk of infection. Our aim was to understand how aging and TLR2 impact the clinical outcomes of S. aureus bacteremia. Four groups of mice (Wild type/young, Wild type/old, TLR2-/-/young, and TLR2-/-/old) were intravenously infected with S. aureus, and the infection course was followed. Both TLR2 deficiency and aging enhanced the susceptibility to disease. Increased age was the main contributing factor to mortality and changes in spleen weight, whereas other clinical parameters such as weight loss and kidney abscess formation were more TLR2 dependent. Importantly, aging increased mortality without relying on TLR2. In vitro, both aging and TLR2 deficiency downregulated cytokine/chemokine production of immune cells with distinct patterns. In summary, we demonstrate that aging and TLR2 deficiency impair the immune response to S. aureus bacteremia in distinct ways.
Background
Reducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential to identify the greatest threats to public health. To our knowledge, this is the first study to present global comprehensive estimates of deaths associated with 33 bacterial pathogens across 11 major infectious syndromes.
Methods
We estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2·5th and 97·5th percentiles across 1000 posterior draws for each quantity of interest.
Findings
From an estimated 13·7 million (95% UI 10·9–17·1) infection-related deaths in 2019, there were 7·7 million deaths (5·7–10·2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13·6% (10·2–18·1) of all global deaths and 56·2% (52·1–60·1) of all sepsis-related deaths in 2019. Five leading pathogens—Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa—were responsible for 54·9% (52·9–56·9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185–285) per 100 000 population, and lowest in the high-income super-region, with 52·2 deaths (37·4–71·5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths.
Interpretation
The 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development.
Funding
Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care, using UK aid funding managed by the Fleming Fund.
Background
Antibiotics are used to treat bacterial infections but also impact immunity. This is usually attributed to antibiotic-induced dysbiosis of the microbiota, but antibiotics may have a direct effect on immune cells and immunity-associated receptors, such as Toll-like receptors (TLRs).
Objectives
To investigate whether antibiotics alter TLR2/1, TLR2/6 and TLR4 activity in immune cells.
Methods
We evaluated the effects of amoxicillin, ciprofloxacin, doxycycline and erythromycin on TLR2/1-, TLR2/6- and TLR4-induced NF-κB activation in THP1-XBlue™-MD2-CD14 cells. Furthermore, we studied TNF-α and IL-6 levels in THP-1-derived macrophages after exposure to these antibiotics and TLR ligands.
Results
Amoxicillin had no effect on any of the TLRs studied. However, ciprofloxacin reduced TLR2/1, TLR2/6 and TLR4 activity in THP1-XBlue™-MD2-CD14 cells and decreased TLR2/1-induced TNF-α and IL-6 in macrophages. Doxycycline reduced TLR2/6 and TLR4 activity in THP1-XBlue™-MD2-CD14 cells and TNF-α and IL-6 levels in response to TLR2/6 stimulation in macrophages. Erythromycin decreased TLR2/1 and TLR4 activity in THP1-XBlue™-MD2-CD14 cells without changes in TNF-α and IL-6 levels in macrophages. In addition, ciprofloxacin decreased the expression of TLR2 mRNA.
Conclusions
These results suggest that some antibiotics may attenuate TLR-dependent monocyte/macrophage responses and likely reduce bacterial clearance. The latter is particularly important in infections with AMR bacteria, where misprescribed antibiotics not only fail in control of AMR infections but might also weaken host defence mechanisms by limiting innate immune responses. Our data suggest that efforts should be made to prevent the deterioration of the immune response during and after antibiotic treatment.
Respiratory virus infections initiate in the upper respiratory tract (URT). Innate immunity is critical for initial control of infection at this site, particularly in the absence of mucosal virus-neutralising antibodies. If the innate immune response is inadequate, infection can spread to the lower respiratory tract (LRT) causing community-acquired pneumonia (as exemplified by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/coronavirus disease 2019). Vaccines for respiratory viruses (influenza and SARS-CoV-2) leverage systemic adaptive immunity to protect from severe lung disease. However, the URT remains vulnerable to infection, enabling viral transmission and posing an ongoing risk of severe disease in populations that lack effective adaptive immunity.
Innate immunity is triggered by host cell recognition of viral pathogen-associated molecular patterns via molecular sensors such as Toll-like receptors (TLRs). Here we review the role of TLRs in respiratory viral infections and the potential of TLR-targeted treatments to enhance airway antiviral immunity to limit progression to severe LRT disease and reduce person-to-person viral transmission. By considering cellular localisation and antiviral mechanisms of action and treatment route/timing, we propose that cell surface TLR agonist therapies are a viable strategy for preventing respiratory viral diseases by providing immediate, durable pan-viral protection within the URT.
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host’s defense against infectious diseases, autoimmune diseases, and cancer.
While antibiotics are clearly important treatments for infection, antibiotic-induced modulation of the immune system can have detrimental effects on pathogen clearance and immune functionality, increasing the risk of secondary infection. These injurious consequences may be mediated, at least in part, through effects on the mitochondria, the functioning of which is already compromised by the underlying septic process. Here, we review the complex interactions between antibiotic administration, immune cell and mitochondrial dysfunction.
Agonists of TLRs are potential adjuvant candidates for mucosal vaccination. We demonstrated that the TLR-mediated inflammatory and antibody responses in the URT of SPF mice exposed to extracellular TLR agonists were substantially restricted.
Toll-like receptors (TLRs) are the important mediators of inflammatory pathways in the gut which play a major role in mediating the immune responses towards a wide variety of pathogen-derived ligands and link adaptive immunity with the innate immunity. Numerous studies in different populations across the continents have reported on the significant roles of TLR gene polymorphisms in modulating the risk of colorectal cancer (CRC). CRC is one of the major malignancies affecting the worldwide population and is currently ranking the third most common cancer in the world. In this review, we have attempted to discuss the structure, functions, and signaling of TLRs in comprehensive detail together with the role played by various TLR gene SNPs in CRC susceptibility.
Commensal gut microbiota protects the immune defense of extra-intestinal organs. Gut microbiota depletion by antibiotics can impair host antiviral immune responses and alter hepatitis B virus (HBV) infection outcomes. However, how gut microbiota modulates antiviral immune response in the liver remains unclear. Here, mice were treated with broad-spectrum antibiotics to deplete gut microbiota. Gut integrity was evaluated, and translocation of live commensal gut bacteria and their components into the liver was investigated. An HBV infection model was established to evaluate impairment of antiviral immune response in the liver after gut microbiota depletion. We found that gut microbiota depletion was associated with impairment of colon epithelial integrity, and live commensal gut microbiota could translocate to the liver. Further, T cell antiviral function in the liver was impaired, partially relying on enhanced PD-1 expression, and HBV immune clearance was hampered. In conclusion, gut microbiota depletion by antibiotics can impair gut barrier function and suppress T cell antiviral immune response in the liver.
Previously, we have identified and characterized 4,6-α-glucanotransferase enzymes of Glycosyl Hydrolase (GH) family 70 (GH70) that cleave (α1→4)-linkages in amylose and introduce (α1→6)-linkages in linear chains. The 4,6-α-glucanotransferase of Lactobacillus reuteri 121, for instance, converts amylose into an Isomalto/Malto-Polysaccharide (IMMP) with 90% (α1→6)-linkages. Over the years, also branching sucrase enzymes belonging to the GH70 family have been characterized. These enzymes use sucrose as donor substrate to glucosylate dextran as acceptor substrate, introducing single -(1→2,6)-α-D-Glcp-(1→6)- (Leuconostoc citreum enzyme) or -(1→3,6)-α-D-Glcp-(1→6)-branches (Leuconostoc citreum, Leuconostoc fallax, Lactobacillus kunkeei enzymes). In this work we observed that the catalytic domain 2 of the L. kunkeei branching sucrase not only used dextran but also IMMP as acceptor substrate, introducing -(1→3,6)-α-D-Glcp-(1→6)-branches. The products obtained have been structurally characterized in detail, revealing the addition of single (α1→3)-linked glucose units to IMMP (resulting in a comb-like structure). The in vitro digestibility of the various α-glucans was estimated with the Glucose Generation Rate (GGR) assay that uses rat intestinal acetone powder to simulate the digestive enzymes in the upper intestine. Raw wheat starch is known to be a slowly digestible carbohydrate in mammals and was used as a benchmark control. Compared to raw wheat starch, IMMP and dextran showed reduced digestibility, with partially digestible and indigestible portions. Interestingly, the digestibility of the branching sucrase modified IMMP and dextran products considerably decreased with increasing percentages of (α1→3)-linkages present. Treatment of amylose with 4,6-α-glucanotransferase and branching sucrase/sucrose thus allowed synthesis of amylose/starch derived α-glucans with markedly reduced digestibility. These starch derived α-glucans may find applications in the food industry.
The term “megalo-saccharide” is used for saccharides with ten or more saccharide units, whereas the term “oligo-saccharide” is used for saccharides containing fewer than ten monosaccharide units. Megalo-type α-1,6-glucosaccharide (M-IM) is a non-digestible saccharide and not utilized by intestinal bacteria, suggesting that ingested M-IM may encounter ileum Peyer’s patches that contains immune cells such as macrophages. Macrophages are responsible for antigen incorporation and presentation during the initial step of immune responses. We investigated whether M-IMs modulate macrophage functions such as cytokine production, nitric oxide production, cell viability, and phagocytosis. Primary macrophages collected from the rats were cultured with the existence of M-IM or lipopolysaccharides (LPS). M-IM and LPS induced the production of tumor necrosis factor α (TNFα), interleukin 6 (IL6), and nitric oxide in the primary macrophages. The gene expression profile of inflammatory factors including TNFα, IL6, and ILlβ in M-IM-stimulated cells was similar to that of LPS-stimulated cells. The M-IM did not affect phagocytosis in the primary macrophages. The M-IM-induced TNFα production was suppressed in the cells treated with a tolllike receptor 4 (TLR4) inhibitor called TAK-242. In conclusion, the M-IM modulates cytokine expression via TLR4 signaling and may play a role in the modulation of immune responses.
Toll-like receptors (TLRs) are crucial components of innate immunity that specifically recognize diverse pathogen-associated molecular patterns from pathogens. The continuous hydrogen-bond network (asparagine ladder) formed among the asparagine residues on the concave surfaces of neighboring leucine-rich repeat modules assists in stabilizing the overall shape of TLR ectodomains responsible for ligand recognition. Analysis of 28 types of vertebrate TLRs showed that their ectodomains possessed three types of architectures: a single-domain architecture with an intact asparagine ladder, a three-domain architecture with the ladder interrupted in the middle, and a trans-three-domain architecture with the ladder broken in both termini. Based on a phylogenetic analysis, the three vertebrate TLR architectures arose during early evolution. The 1428 vertebrate TLRs can be divided into eight families based on sequence and structural differences. TLRs ligand specificities are affected by their ectodomain architectures. Three-domain TLRs bind hydrophobic ligands, whereas single-domain and trans-three-domain TLRs mainly recognize hydrophilic ligands. Analysis of 39 vertebrate genomes suggested that the number of single-domain TLR genes in terrestrial vertebrate genomes decreased by half compared to aquatic vertebrate genomes. Single-domain TLR genes underwent stronger purifying selective pressures than three-domain TLR genes in mammals. Overall, ectodomain architecture influences the sequence and functional evolution of vertebrate TLRs.
The nuclear factor kappa B ( NFκB ) family of transcription factors is a key regulator of immune development, immune responses, inflammation, and cancer. The NFκB signaling system (defined by the interactions between NFκB dimers, IκB regulators, and IKK complexes) is responsive to a number of stimuli, and upon ligand–receptor engagement, distinct cellular outcomes, appropriate to the specific signal received, are set into motion. After almost three decades of study, many signaling mechanisms are well understood, rendering them amenable to mathematical modeling, which can reveal deeper insights about the regulatory design principles. While other reviews have focused on upstream, receptor proximal signaling (Hayden MS, Ghosh S. Signaling to NF‐κB. Genes Dev 2004, 18:2195–2224; Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R. TLR‐4, IL‐1R and TNF‐R signaling to NF‐κB: variations on a common theme. Cell Mol Life Sci 2008, 65:2964–2978), and advances through computational modeling (Basak S, Behar M, Hoffmann A. Lessons from mathematically modeling the NF‐κB pathway. Immunol Rev 2012, 246:221–238; Williams R, Timmis J, Qwarnstrom E. Computational models of the NF‐KB signalling pathway. Computation 2014, 2:131), in this review we aim to summarize the current understanding of the NFκB signaling system itself, the molecular mechanisms, and systems properties that are key to its diverse biological functions, and we discuss remaining questions in the field. WIREs Syst Biol Med 2016, 8:227–241. doi: 10.1002/wsbm.1331
This article is categorized under: Biological Mechanisms > Cell Signaling
Models of Systems Properties and Processes > Mechanistic Models
Physiology > Organismal Responses to Environment
The evolution of macrophages has made them primordial for both development and immunity. Their functions range from the shaping of body plans to the ingestion and elimination of apoptotic cells and pathogens. Cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. A portfolio of cytokines is central to the role of macrophages as sentries of the innate immune system that mediate the transition from innate to adaptive immunity. In concert with other mediators, cytokines bias the fate of macrophages into a spectrum of inflammation-promoting “classically activated,” to anti-inflammatory or “alternatively activated” macrophages. Deregulated cytokine secretion is implicated in several disease states ranging from chronic inflammation to allergy. Macrophages release cytokines via a series of beautifully orchestrated pathways that are spatiotemporally regulated. At the molecular level, these exocytic cytokine secretion pathways are coordinated by multi-protein complexes that guide cytokines from their point of synthesis to their ports of exit into the extracellular milieu. These trafficking proteins, many of which were discovered in yeast and commemorated in the 2013 Nobel Prize in Physiology or Medicine, coordinate the organelle fusion steps that are responsible for cytokine release. This review discusses the functions of cytokines secreted by macrophages, and summarizes what is known about their release mechanisms. This information will be used to delve into how selected pathogens subvert cytokine release for their own survival.
Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.
The intestinal mucosa is constantly facing a high load of antigens including bacterial antigens derived from the microbiota and food. Despite this, the immune cells present in the gastrointestinal tract do not initiate a pro-inflammatory immune response. Toll-like receptors (TLRs) are pattern recognition receptors expressed by various cells in the gastrointestinal tract, including intestinal epithelial cells (IEC) and resident immune cells in the lamina propria. Many diseases, including chronic intestinal inflammation (e.g., inflammatory bowel disease), irritable bowel syndrome (IBS), allergic gastroenteritis (e.g., eosinophilic gastroenteritis and allergic IBS), and infections are nowadays associated with a deregulated microbiota. The microbiota may directly interact with TLR. In addition, differences in intestinal TLR expression in health and disease may suggest that TLRs play an essential role in disease pathogenesis and may be novel targets for therapy. TLR signaling in the gut is involved in either maintaining intestinal homeostasis or the induction of an inflammatory response. This mini review provides an overview of the current knowledge regarding the contribution of intestinal epithelial TLR signaling in both tolerance induction or promoting intestinal inflammation, with a focus on food allergy. We will also highlight a potential role of the microbiota in regulating gut immune responses, especially through TLR activation.
Background
The Avogadro project has developed an advanced molecule editor and visualizer designed for cross-platform use in computational chemistry, molecular modeling, bioinformatics, materials science, and related areas. It offers flexible, high quality rendering, and a powerful plugin architecture. Typical uses include building molecular structures, formatting input files, and analyzing output of a wide variety of computational chemistry packages. By using the CML file format as its native document type, Avogadro seeks to enhance the semantic accessibility of chemical data types.
Results
The work presented here details the Avogadro library, which is a framework providing a code library and application programming interface (API) with three-dimensional visualization capabilities; and has direct applications to research and education in the fields of chemistry, physics, materials science, and biology. The Avogadro application provides a rich graphical interface using dynamically loaded plugins through the library itself. The application and library can each be extended by implementing a plugin module in C++ or Python to explore different visualization techniques, build/manipulate molecular structures, and interact with other programs. We describe some example extensions, one which uses a genetic algorithm to find stable crystal structures, and one which interfaces with the PackMol program to create packed, solvated structures for molecular dynamics simulations. The 1.0 release series of Avogadro is the main focus of the results discussed here.
Conclusions
Avogadro offers a semantic chemical builder and platform for visualization and analysis. For users, it offers an easy-to-use builder, integrated support for downloading from common databases such as PubChem and the Protein Data Bank, extracting chemical data from a wide variety of formats, including computational chemistry output, and native, semantic support for the CML file format. For developers, it can be easily extended via a powerful plugin mechanism to support new features in organic chemistry, inorganic complexes, drug design, materials, biomolecules, and simulations. Avogadro is freely available under an open-source license from
http://avogadro.openmolecules.net.
A large body of literature suggests that certain polysaccharides affect immune system function. Much of this literature, however, consists of in vitro studies or studies in which polysaccharides were injected. Their immunologic effects following oral administration is less clear. The purpose of this systematic review was to consolidate and evaluate the available data regarding the specific immunologic effects of dietary polysaccharides.
Studies were identified by conducting PubMed and Google Scholar electronic searches and through reviews of polysaccharide article bibliographies. Only articles published in English were included in this review. Two researchers reviewed data on study design, control, sample size, results, and nature of outcome measures. Subsequent searches were conducted to gather information about polysaccharide safety, structure and composition, and disposition.
We found 62 publications reporting statistically significant effects of orally ingested glucans, pectins, heteroglycans, glucomannans, fucoidans, galactomannans, arabinogalactans and mixed polysaccharide products in rodents. Fifteen controlled human studies reported that oral glucans, arabinogalactans, heteroglycans, and fucoidans exerted significant effects. Although some studies investigated anti-inflammatory effects, most studies investigated the ability of oral polysaccharides to stimulate the immune system. These studies, as well as safety and toxicity studies, suggest that these polysaccharide products appear to be largely well-tolerated.
Taken as a whole, the oral polysaccharide literature is highly heterogenous and is not sufficient to support broad product structure/function generalizations. Numerous dietary polysaccharides, particularly glucans, appear to elicit diverse immunomodulatory effects in numerous animal tissues, including the blood, GI tract and spleen. Glucan extracts from the Trametes versicolor mushroom improved survival and immune function in human RCTs of cancer patients; glucans, arabinogalactans and fucoidans elicited immunomodulatory effects in controlled studies of healthy adults and patients with canker sores and seasonal allergies. This review provides a foundation that can serve to guide future research on immune modulation by well-characterized polysaccharide compounds.
Macrophages in the gastrointestinal mucosa represent the largest pool of tissue macrophages in the body. In order to maintain mucosal homeostasis, resident intestinal macrophages uniquely do not express the lipopolysaccharide (LPS) co-receptor CD14 or the IgA (CD89) and IgG (CD16, 32, and 64) receptors, yet prominently display Toll-like receptors (TLRs) 3-9. Remarkably, intestinal macrophages also do not produce proinflammatory cytokines in response to TLR ligands, likely because of extracellular matrix (stromal) transforming growth factor-β (TGF-β) dysregulation of nuclear factor (NF)-κB signal proteins and, via Smad signaling, expression of IκBα, thereby inhibiting NF-κB-mediated activities. Thus, in noninflamed mucosa, resident macrophages are inflammation anergic but retain avid scavenger and host defense function, an ideal profile for macrophages in close proximity to gut microbiota. In the event of impaired epithelial integrity during intestinal infection or inflammation, however, blood monocytes also accumulate in the lamina propria and actively pursue invading microorganisms through uptake and degradation of the organism and release of inflammatory mediators. Consequently, resident intestinal macrophages are inflammation adverse, but when the need arises, they receive assistance from newly recruited circulating monocytes.
Doxycycline is a member of the tetracycline class of antibiotics and has been used clinically for more than 40 years. It is a well-tolerated drug that is bacteriostatic and acts via the inhibition of bacterial ribosomes. It is generally given at a dose of 100-mg daily or twice daily. It is well absorbed and has generally good tissue penetration. The serum half-life is 18–22 hours and dosage does not need to be adjusted in the presence of renal or hepatic impairment. Major side effects are gastro-intestinal and dermatological and it is generally contra-indicated in pregnancy or childhood because of concerns about discolouration of developing teeth and potential effects on growing bones. Drug interactions are not common although can occur with the concomitant use of methotrexate and the oral contraceptive pill, and its absorption can be reduced by the co-administration with some antacids and iron preparations. It has activity against many organisms, including Gram-positives, Gram-negatives and atypical bacteria. In addition, it appears to have some potentially clinically useful anti-inflammatory properties.
The importance of a properly functioning and well-balanced immune system for maintaining health has become strikingly evident over the past decades. Roughly since World War II, there has been an apparent decrease in the prevalence of "traditional" infectious diseases, with a concomitant increase in immune-related disorders, such as allergies. Causally, a relationship with changes in life-style-related factors such as the increasing use of hygienic practices seems likely. Diet and nutrition can affect the functioning of various immune parameters. This concept can be utilised in attempts to prevent or mitigate allergic reactions via the development of targeted food products or ingredients. This review describes recent findings with respect to food products and ingredients that show potential in this respect, with special emphasis on pro- and prebiotics, beta-glucans and fungal immunomodulatory proteins. What all of these approaches have in common is that they appear to strengthen Th1-mediated immunity, thus possibly restoring defective immune maturation due to overly hygienic living conditions: a little bit of dirt does not seem bad!
Pattern recognition receptors are a key component of the first line host defense against infection, recognizing specific microbial products. We hypothesize that monocyte hyporesponsiveness in human sepsis is associated with a downregulation of the pattern recognition receptors Toll-like receptor (TLR)-2 and TLR4.
Protein expression of CD14, TLR2 and TLR4 on blood monocytes was examined using flow cytometry from 29 patients with sepsis and 14 healthy controls. In addition LPS stimulated TNF-α and IL-10 production was studied in a 24 hour whole blood assay.
We found an increased expression of CD14, TLR2 and TLR4 in patients with sepsis compared to controls (p < 0.01). In patients with sepsis, death was associated with significant lower CD14 and TLR2 expression at admission (CD14: 25.7 +- 19.1 vs 39.1 +- 17.3 mean fluorescence intensity [MFI], p = 0.02; TLR2: 21.8 +- 9.4 vs. 30.9 +- 9.6, p = 0.01). At 72 hours the TLR2 expression on monocytes was associated with the IL-10 inducibility after LPS stimulation (r = 0.52, p = 0.02) and the CD14 expression with the IL-6, IL-10 and TNF inducibility.
We conclude that septic patients are characterized by an increased expression of CD14, TLR2 and TLR4 on monocytes compared to controls. Death is associated with downregulation of TLR2 and CD14 expression on monocytes correlating with reduced cytokine inducibility. We suggest that CD14 and TLR2 are a key factor in monocyte hyporesponsibility during severe sepsis.
The lipopolysaccharide (LPS) of Gram negative bacteria is a well-known inducer of the innate immune response. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules. To understand the ligand specificity and receptor activation mechanism of the TLR4-MD-2-LPS complex we determined its crystal structure. LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically. LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2, forming a hydrophobic interaction with the conserved phenylalanines of TLR4. The F126 loop of MD-2 undergoes localized structural change and supports this core hydrophobic interface by making hydrophilic interactions with TLR4. Comparison with the structures of tetra-acylated antagonists bound to MD-2 indicates that two other lipid chains in LPS displace the phosphorylated glucosamine backbone by approximately 5 A towards the solvent area. This structural shift allows phosphate groups of LPS to contribute to receptor multimerization by forming ionic interactions with a cluster of positively charged residues in TLR4 and MD-2. The TLR4-MD-2-LPS structure illustrates the remarkable versatility of the ligand recognition mechanisms employed by the TLR family, which is essential for defence against diverse microbial infection.
Dysregulation of innate and adaptive intestinal immune responses to bacterial microbiota is supposed to be involved in pathogenetic mechanisms of inflammatory bowel diseases (IBDs). We investigated expression of Toll-like receptor 2 (TLR2), TLR4, and their transmembrane coreceptor CD14 in biopsy samples from patients with IBD and in non-inflamed gut mucosa from controls. Small intestine and colon samples were obtained by colonoscopy from patients with Crohn's disease (CD), ulcerative colitis (UC), and controls. Immunohistochemical analysis of cryostat sections using polyclonal and monoclonal antibodies specific for TLR2, TLR4, and CD14 showed a significant increase in TLR2 expression in the terminal ileum of patients with inactive and active UC against controls. Significant upregulation of TLR4 expression relative to controls was found in the terminal ileum and rectum of UC patients in remission and in the terminal ileum of CD patients with active disease. CD14 expression was upregulated in the terminal ileum of CD patients in remission and with active disease, in the cecum of UC patients in remission and with active disease, and in rectum of UC patients with active disease. Hence, dysregulation of TLR2, TLR4, and CD14 expression in different parts of the intestinal mucosa may be crucial in IBD pathogenesis.
Over the past two decades, cases of sexually transmitted infections (STIs) due to syphilis, gonorrhea, and chlamydia have been rising in the United States, disproportionately among gay, bisexual, and other men who have sex with men (MSM), as well as racial and ethnic minorities of all genders. In this review, we address updates about the evidence on doxycycline post-exposure prophylaxis (doxy-PEP) for prevention of bacterial STIs, including efficacy, safety, antimicrobial resistance (AMR), acceptability, modeling population impact, and evolving guidelines for use. Equitable implementation of doxy-PEP will require evaluation of who is offered and initiates it, understanding patterns of use and longer-term STI incidence and AMR, provider training, and tailored community education.
Starch-based isomalto/malto-polysaccharides (IMMPs) are soluble dietary fibres produced by the incubation of α-(1 → 4) linked glucans with the 4,6-α-glucanotransferase (GTFB) enzyme. In this study, we investigated the reaction dynamics of the GTFB enzyme by using isoamylase debranched starches as simplified linear substrates. Modification of α-glucans by GTFB was investigated over time and analysed with ¹H NMR, HPSEC, HPAEC combined with glucose release measurements. We demonstrate that GTFB modification of linear substrates followed a substrate/acceptor model, in which α-(1 → 4) linked glucans DP ≥ 6 functioned as donor substrate, and α-(1 → 4) linked malto-oligomers DP < 6 functioned as acceptor. The presence of α-(1 → 4) linked malto-oligomers DP < 6 resulted in higher GTFB transferase activity, while their absence resulted in higher GTFB hydrolytic activity. The information obtained in this study provides a better insight into GTFB reaction dynamics and will be useful for α-glucan selection for the targeted synthesis of IMMPs in the future.
The oral antibiotic therapies administered widely to people and animals can cause gut dysbiosis and barrier disruption inevitably. Increasing attention has been directed toward antibiotic-induced gut dysbiosis, which involves a loss of diversity, changes in the abundances of certain taxa and consequent effects on their metabolic capacity, and the spread of antibiotic-resistant bacterial strains. Treatment with beta-lactam, glycopeptide, and macrolide antibiotics is associated with the depletion of beneficial commensal bacteria in the genera Bifidobacterium and Lactobacillus. The gut microbiota is a reservoir for antibiotic resistance genes, the prevalence of which increases sharply after antibiotic ingestion. The intestinal barrier, which comprises secretory, physical, and immunological barriers, is also a target of antibiotics. Antibiotic induced changes in the gut microbiota composition could induce weakening of the gut barrier through changes in mucin, cytokine, and antimicrobial peptide production by intestinal epithelial cells. Reports have indicated that dietary interventions involving prebiotics, probiotics, omega-3 fatty acids, and butyrate supplementation, as well as fecal microbiota transplantation, can alleviate antibiotic-induced gut dysbiosis and barrier injuries. This review summarizes the characteristics of antibiotic-associated gut dysbiosis and barrier disruption, as well as the strategies for alleviating this condition. This information is intended to provide a foundation for the exploration of safer, more efficient, and affordable strategies to prevent or relieve antibiotic-induced gut injuries.
Infectious diseases remain a threat to critically ill patients, particularly with the rise of antibiotic-resistant bacteria. Septic shock carries a mortality of up to ∼40% with no compelling evidence of promising therapy to reduce morbidity or mortality. Septic shock survivors are also prone to nosocomial infections. Treatment with toll-like receptor 4 (TLR4) agonists have demonstrated significant protection against common nosocomial pathogens in various clinically relevant models of infection and septic shock. TLR4 agonists are derived from a bacteria cell wall or synthesized de novo, and more recently novel small molecule TLR4 agonists have also been developed. TLR4 agonists augment innate immune functions including expansion and recruitment of innate leukocytes to the site of infection. Recent studies demonstrate TLR4-induced leukocyte metabolic reprogramming of cellular metabolism to improve antimicrobial function. Metabolic changes include sustained augmentation of macrophage glycolysis, mitochondrial function, and tricarboxylic acid cycle flux. These findings set the stage for the use of TLR4 agonists as standalone therapeutic agents or antimicrobial adjuncts in patient populations vulnerable to nosocomial infections.
Parallel β-sheet-containing repeat proteins often display a structural motif in which conserved asparagines form a continuous ladder buried within the hydrophobic core. In such "asparagine ladders", the asparagine side-chain amides form a repetitive pattern of hydrogen bonds with neighboring main-chain NH and CO groups. Although asparagine ladders have been thought to be important for stability, there is little experimental evidence to support such speculation. Here we test the contribution of a minimal asparagine ladder from the leucine-rich repeat protein pp32 to stability and investigate lattice rigidity and hydrogen bond character using solution nuclear magnetic resonance (NMR) spectroscopy. Point substitutions of the two ladder asparagines of pp32 are strongly destabilizing and decrease the cooperativity of unfolding. The chemical shifts of the ladder side-chain H
Z
protons are shifted significantly downfield in the NMR spectrum and have low temperature coefficients, indicative of strong hydrogen bonding. In contrast, the H
E
protons are shifted upfield and have temperature coefficients close to zero, suggesting an asymmetry in hydrogen bond strength along the ladder. Ladder NH2 groups have weak 1H-15N cross-peak intensities; 1H-15N nuclear Overhauser effect and 15N CPMG experiments show this to be the result of high rigidity. Hydrogen exchange measurements demonstrate that the ladder NH2 groups exchange very slowly, with rates approaching the global exchange limit. Overall, these results show that the asparagine side chains are held in a very rigid, nondynamic structure, making a significant contribution to the overall stability. In this regard, buried asparagine ladders can be considered "second backbones" within the cores of their elongated β-sheet host proteins.
A wide number of Lactic Acid Bacteria (LAB) species produce α-glucans with their ability to synthesize glucansucrases (GS) which use sucrose as substrate for the glucan production. Recently another group of enzymes in LAB gained special interest for their ability to produce α-glucans targeting the substrates containing α1-4-linkages and synthesizing new (α1-6) or (α1-3)–linkages as α‑glucanotransferases. In this study, a putative 4,6‑α‑glucanotransferase (GTFB) from sourdough isolate Lactobacillus reuteri E81 was identified and expressed in Escherichia coli. The biochemical characterization of the GTFB-E81 confirmed its function as it cleaved the α1-4-linkages in different substrates and produced new gluco-oligomers/polymers containing α1-6 linkages together with the α1-4-linkages detected by NMR analysis. GTFB-E81 produced malto-oligosaccharides targeting maltose and maltoheptaose as substrates with up to DP 8 detected by TLC and ESI-MS/MS analysis. The functional roles of these malto-oligosaccharides were determined by testing their immune-modulatory functions in HT29 cells and they triggered the production of anti-inflammatory 1L-4 and pro-inflammatory IL-12 cytokines.
The gastrointestinal (GI) tract represents a unique challenge to the mammalian immune system. It must tolerate the presence of the luminal microbiota and thus not respond to their products, but still protect the intestinal mucosa from potentially harmful dietary antigens and invading pathogens. The intestinal epithelium, composed of a single layer of cells, is crucial for preserving gut homeostasis and acts both as a physical barrier and as a coordinating hub for immune defense and crosstalk between bacteria and immune cells. We highlight here recent findings regarding communication between microbes and intestinal epithelial cells (IECs), as well as the immune mechanisms employed by distinct IEC subsets to promote homeostasis, emphasizing the central and active role that these cells play in host enteric defense.
Macrophage inflammatory protein-1 alpha (MIP-1α/CCL3) is a chemotactic chemokine secreted by macrophages. It performs various biological functions, such as recruiting inflammatory cells, wound healing, inhibition of stem cells, and maintaining effector immune response. It activates bone resorption cells and directly induces bone destruction. Cells that secrete MIP-1α/CCL3 are increased at sites of inflammation and bone resorption. MIP-1α/CCL3 plays an important role in the pathogenesis of various inflammatory diseases and conditions that exhibit bone resorption, such as periodontitis, multiple myeloma, Sjögren syndrome, and rheumatoid arthritis. Biological fluids from patients with these diseases exhibit elevated levels of MIP-1α/CCL3. This finding indicates that MIP-1α/CCL3 protein may have diagnostic potential for the detection of several inflammatory diseases and conditions. This chapter discusses the biological functions of MIP-1α/CCL3; describes several diseases associated with MIP-1α/CCL3, particularly periodontitis; and delineates the potential application of MIP-1α/CCL3 as a biomarker. © Springer Science+Business Media Dordrecht 2015. All rights reserved.
Monocytes and macrophages are part of the body's first line of defence, eliminating pathogens by phagocytosis or by releasing a broad array of inflammatory mediators, such as cytokines, chemokines, and proteases. In humans, 3 subsets of monocytes are described in blood with seemingly different functions, the classical (CD14CD16) monocytes, the intermediate (CD14CD16) monocytes, and the nonclassical (CD14CD16) monocytes. In the intestine, macrophages can be divided into resident and inflammatory macrophages that are distinguished by low and high expression of CD14, respectively. However, the roles and function of the 3 monocyte subsets in health and disease are not fully understood. In this review, we describe what is known about the origin of human intestinal macrophages and their blood monocytic counterparts and many of their numerous distinct mechanisms influencing the intestinal immune system.
Dietary fibres are at the forefront of nutritional research because they positively contribute to human health. Much of our processed foods contain, however, only small quantities of dietary fibre, because their addition often negatively affects the taste, texture and mouth feel. There is thus an urge for novel types of dietary fibres that do not cause unwanted sensory effects when applied as ingredient, while still positively contributing to the health of consumers. Here we report the generation and characterization of a novel type of soluble dietary fibre with prebiotic properties, derived from starch via enzymatic modification, yielding isomalto/malto-polysaccharides (IMMPs), which consist of linear (α1→6)-glucan chains attached to the non-reducing ends of starch fragments. The applied Lactobacillus reuteri 121 GTFB 4,6-α-glucanotransferase enzyme synthesizes these molecules by transferring the non-reducing glucose moiety of an (α1→4)-glucan chain to the non-reducing end of another (α1→4)-α-glucan chain, forming an (α1→6)-glycosidic linkage. Once elongated in this way, the molecule becomes a better acceptor substrate and is then further elongated with (α1→6)-linked glucose residues in a linear way. Comparison of thirty starches, maltodextrins and α-glucans of various botanical sources, demonstrated that substrates with long and linear (α1→4)-glucan chains deliver products with the highest percentage of (α1→6) linkages, up to 92%. In vitro experiments, serving as model of the digestive power of the gastrointestinal tract, revealed that the IMMPs, or more precisely the IMMP fraction rich in (α1→6) linkages, will largely pass the small intestine undigested and therefore end up in the large intestine. IMMPs are a novel type of dietary fibre, that may have health promoting activity.
Interleukin-15 (IL-15) is a cytokine important for the development, maturation, and function of many cells of the immune system including NK, NKT, gammadeltaT, and CD8(+) T cells. The relationship between IL-15 and B lymphocytes however, is not well characterized and is the focus of our study. Previous in vitro reports have shown that IL-15 increases proliferation of B lymphocytes and increases antibody secretion however, this relationship remains inadequately defined in vivo. The focus of this study was to examine the role of IL-15 in B cell homeostasis and function in vivo using mice that either over express IL-15 (IL-15tg mice) or are deficient in IL-15 (IL-15(-/-) mice) production. Here we report significant differences between the B cell populations of IL-15(-/-), C57BL/6, and IL-15tg mice. In fact, increased expression of IL-15 resulted in a significant decrease in the percentage and absolute number of CD19(+) cells. In vitro B cell co-cultures implicate interferon-gamma (IFN-gamma) as the factor responsible for inhibiting B cell proliferation. We also show that IL-15 expression affects B cell function, as B cells from IL-15 transgenic mice produce greater amounts of IgG and IgA than IL-15 knockout mice in vitro. Interestingly, despite significant differences in B cell numbers in these strains, there were no significant differences in total antibody titers in serum and vaginal washes of these mice. Results from our in vivo and in vitro experiments suggest that altered expression of IL-15 affects B cell homeostasis through the induction of NK cell-derived IFN-gamma.
The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.
TLR2 in association with TLR1 or TLR6 plays an important role in the innate immune response by recognizing microbial lipoproteins and lipopeptides. Here we present the crystal structures of the human TLR1-TLR2-lipopeptide complex and of the mouse TLR2-lipopeptide complex. Binding of the tri-acylated lipopeptide, Pam(3)CSK(4), induced the formation of an "m" shaped heterodimer of the TLR1 and TLR2 ectodomains whereas binding of the di-acylated lipopeptide, Pam(2)CSK(4), did not. The three lipid chains of Pam(3)CSK(4) mediate the heterodimerization of the receptor; the two ester-bound lipid chains are inserted into a pocket in TLR2, while the amide-bound lipid chain is inserted into a hydrophobic channel in TLR1. An extensive hydrogen-bonding network, as well as hydrophobic interactions, between TLR1 and TLR2 further stabilize the heterodimer. We propose that formation of the TLR1-TLR2 heterodimer brings the intracellular TIR domains close to each other to promote dimerization and initiate signaling.
USA) at 37 °C, 5% CO 2 for 4 h and the 198 absorbance was measured at 570 nm with a reference at 600 nm, using a FLUOstar Omega 199 microplate reader
- Reagent Alamar Blue
Alamar blue reagent (Thermo Fisher Scientific, USA) at 37 °C, 5% CO 2 for 4 h and the
198 absorbance was measured at 570 nm with a reference at 600 nm, using a FLUOstar Omega
199 microplate reader (BMG Labtech, Ortenberg, Germany) (Supplementary figure 1).
Both cytokines are a product of NF-B activation. However, the 626 mechanisms for this are still unknown. Our study is, to the best of our knowledge, the first 627 study proving that the immunomodulatory effects of IMMPs depend on the activation of 628 specific TLRs (i.e., TLR2, TLR4)
- Allaire
- Kim
The gastrointestinal tract represents an important entrance for pathogens (Allaire et
620 al., 2018). Therefore, immune-stimulating complex carbohydrates and functional foods are
(Kim et al., 2022). Previous studies have demonstrated that carbohydrates similar
623 to IMMPs can exert immune-stimulating effect (İspirli et al., 2019; Joe et al., 2016). Malto-624 oligosaccharides have been shown to increase the levels of IL-4 and IL-12 in HT-29 cells in vitro
625 (İspirli et al., 2019). Both cytokines are a product of NF-B activation. However, the
626 mechanisms for this are still unknown. Our study is, to the best of our knowledge, the first
627 study proving that the immunomodulatory effects of IMMPs depend on the activation of
628 specific TLRs (i.e., TLR2, TLR4). Together with this, our study opens new research horizons in
629 which other immune-stimulating complex carbohydrates, such as different types of resistant
630 starch (Bermudez-Brito et al., 2015; Lépine et al., 2019;
IMMPs are 634 complex carbohydrates that can act as dietary fibers that exert direct (i.e., microbiota-635 independent) immune-stimulating effect via TLR4 and TLR2, activating NF-B and inducing 636 the production of specific cytokines. Furthermore
- Altogether
Altogether, this study indicates that beyond their prebiotic potential, IMMPs are
634 complex carbohydrates that can act as dietary fibers that exert direct (i.e., microbiota-635 independent) immune-stimulating effect via TLR4 and TLR2, activating NF-B and inducing
636 the production of specific cytokines. Furthermore, IMMPs may prevent part of the immune-
Writing -review 648 & editing. Hans Leemhuis: Resources, Writing -review & editing. Edwin J.A. Veldhuizen: 649 Conceptualization, Writing -review & editing, Supervision
- Cynthia E Klostermann
Cynthia E. Klostermann: Investigation, Visualization, Writing -original draft, Writing -review
648 & editing. Hans Leemhuis: Resources, Writing -review & editing. Edwin J.A. Veldhuizen:
649 Conceptualization, Writing -review & editing, Supervision, Project administration. Henk A.