Homeostatic Immune Responses Research Articles

Effective anti-tumor immune responses are orchestrated by immune cell partnership network that functions through tissue homeostatic pathways, not direct cytotoxicity.

The liver hosts a diverse array of immune cells that play pivotal roles in both maintaining tissue homeostasis and responding to disease. However, the precise contributions of these immune cells in the progression of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain unclear. Utilizing a systems immunology approach, we reveal that liver immune responses are governed by a dominant-subdominant hierarchy of ligand-receptor-mediated homeostatic pathways. In healthy individuals, inflammatory immune responses operate within these pathways, challenging the notion of the liver as a purely tolerogenic organ. Chronic consumption of a Western diet (WD) disrupts hepatocyte function and reconfigures immune interactions, resulting in hepatic stellate cells (HSCs), cancer cells, and NKT cells driving 80% of the immune activity during NAFLD. In HCC, 80% of immune response involves NKT cells and monocytes collaborating with hepatocytes and myofibroblasts to restore disrupted homeostasis. Interestingly, dietary correction during NAFLD yields nonlinear outcomes: tumor progression coincides with the failure of mounting homeostatic immune responses, whereas tumor prevention is associated with sustained immune responses, predominantly orchestrated by monocytes. These monocytes actively target fibroblasts and myofibroblasts, creating a tumor-suppressive microenvironment. Notably, only 5% of T cells displayed apoptosis-inducing activity, selectively contributing to the turnover of hepatic stromal cells, particularly myofibroblasts and fibroblasts. Our findings suggest that effective anti-tumor immune responses in the liver are primarily mediated by immune cells sustaining tissue homeostasis, rather than relying on direct cytotoxic mechanisms.

Postbiotics as Adjuvant Therapy in Cancer Care.

Postbiotics are defined as a preparation of inanimate microorganisms and/or their components that confers a health benefit to the host. They range from cell wall fragments to metabolites, bacterial lysates, extracellular vesicles, and short-chain fatty acids (SCFAs). Postbiotics may influence carcinogenesis via a variety of mechanisms. They can promote homeostatic immune responses, reduce inflammation, induce selective cytotoxicity against tumor cells, as well as the enabling the control of tumor cell proliferation and enhancing intestinal epithelial barrier function. Therefore, probiotics can serve as an adjunct strategy in anticancer treatment together with chemotherapy and immunotherapy. Up to now, the only relevant postbiotics used as interventions in oncological patients remain vitamin K molecules, with few phase-II and III trials available. In fact, postbiotics' levels are strictly dependent on the gut microbiota's composition, which may vary between individuals and can be altered under different physiological and pathological conditions. Therefore, the lack of consistent clinical evidence supporting postbiotics' efficacy is due to their poor bioavailability, short half-life, and fluctuating levels. Synbiotics, a mixture of prebiotics and probiotics, are expected to have a more homogeneous bioavailability with respect to postbiotics and may have greater potential for future development. In this review, we focus on the role of postbiotics as an adjuvant therapy in cancer treatment.

Skin, gut, and lung barrier: Physiological interface and target of intervention for preventing and treating allergic diseases.

The epithelial barriers of the skin, gut, and respiratory tract are critical interfaces between the environment and the host, and they orchestrate both homeostatic and pathogenic immune responses. The mechanisms underlying epithelial barrier dysfunction in allergic and inflammatory conditions, such as atopic dermatitis, food allergy, eosinophilic oesophagitis, allergic rhinitis, chronic rhinosinusitis, and asthma, are complex and influenced by the exposome, microbiome, individual genetics, and epigenetics. Here, we review the role of the epithelial barriers of the skin, digestive tract, and airways in maintaining homeostasis, how they influence the occurrence and progression of allergic and inflammatory conditions, how current treatments target the epithelium to improve symptoms of these disorders, and what the unmet needs are in the identification and treatment of epithelial disorders.

CRISPR-Cas9-Induced Gene Editing in Primary Human Monocytes.

Monocytes play important and diverse roles in both homeostatic and inflammatory immune responses. The CRISPR-Cas9 system in lentiviral vectors has been widely used to manipulate specific genes of immortal monocyte cell lines to study monocyte functions. However, human primary monocytes are refractory to this method with low gene knockout (KO) efficiency. In this chapter, we developed an in vitro gene-editing procedure for primary human monocytes with a consistent and high-gene KO efficiency via a ribonucleoprotein (RNP) complex consisting of Cas9 protein and single-guide RNA (sgRNA). This method can be adapted to study the functions of targeted signaling molecules involved in modulating monocyte polarization in primary human monocytes.

Regulatory T cells play a crucial role in maintaining sperm tolerance and male fertility

Regulatory T cells (Tregs) modulate tissue homeostatic processes and immune responses. Understanding tissue-Treg biology will contribute to developing precision-targeting treatment strategies. Here, we show that Tregs maintain the tolerogenic state of the testis and epididymis, where sperm are produced and mature. We found that Treg depletion induces severe autoimmune orchitis and epididymitis, manifested by an exacerbated immune cell infiltration [CD4 T cells, monocytes, and mononuclear phagocytes (MPs)] and the development of antisperm antibodies (ASA). In Treg-depleted mice, MPs increased projections toward the epididymal lumen as well as invading the lumen. ASA-bound sperm enhance sperm agglutination and might facilitate sperm phagocytosis. Tolerance breakdown impaired epididymal epithelial function and altered extracellular vesicle cargo, both of which play crucial roles in the acquisition of sperm fertilizing ability and subsequent embryo development. The affected mice had reduced sperm number and motility and severe fertility defects. Deciphering these immunoregulatory mechanisms may help to design new strategies to treat male infertility, as well as to identify potential targets for immunocontraception.

Fructose malabsorption in ChREBP-deficient mice disrupts the small intestine immune microenvironment and leads to diarrhea-dominant bowel habit changes.

The mechanism by which incompletely absorbed fructose causes gastrointestinal symptoms is not fully understood. In this study, we investigated the immunological mechanisms of bowel habit changes associated with fructose malabsorption by examining Chrebp-knockout mice exhibiting defective fructose absorption. Mice were fed a high-fructose diet (HFrD), and stool parameters were monitored. The gene expression in the small intestine was analyzed by RNA sequencing. Intestinal immune responses were assessed. The microbiota composition was determined by 16S rRNA profiling. Antibiotics were used to assess the relevance of microbes for HFrD-induced bowel habit changes. Chrebp-knockout (KO) mice fed HFrD showed diarrhea. Small-intestine samples from HFrD-fed Chrebp-KO mice revealed differentially expressed genes involved in the immune pathways, including IgA production. The number of IgA-producing cells in the small intestine decreased in HFrD-fed Chrebp-KO mice. These mice showed signs of increased intestinal permeability. Chrebp-KO mice fed a control diet showed intestinal bacterial imbalance, which the HFrD exaggerated. Bacterial reduction improved diarrhea-associated stool parameters and restored the decreased IgA synthesis induced in HFrD-fed Chrebp-KO mice. The collective data indicate that gut microbiome imbalance and disrupting homeostatic intestinal immune responses account for the development of gastrointestinal symptoms induced by fructose malabsorption.

Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19.

Acute viral infections can have durable functional impacts on the immune system long after recovery, but how they affect homeostatic immune states and responses to future perturbations remain poorly understood1-4. Here we use systems immunology approaches, including longitudinal multimodal single-cell analysis (surface proteins, transcriptome and V(D)J sequences) to comparatively assess baseline immune statuses and responses to influenza vaccination in 33 healthy individuals after recovery from mild, non-hospitalized COVID-19 (mean, 151 days after diagnosis) and 40 age- and sex-matched control individuals who had never had COVID-19. At the baseline and independent of time after COVID-19, recoverees had elevated T cell activation signatures and lower expression of innate immune genesincluding Toll-like receptors in monocytes. Male individuals who had recovered from COVID-19 had coordinately higher innate, influenza-specific plasmablast, and antibody responses after vaccination compared with healthy male individuals and female individuals who had recovered from COVID-19, in part because male recoverees had monocytes with higher IL-15 responses early after vaccination coupled with elevated prevaccination frequencies of 'virtual memory'-like CD8+ T cells poised to produce more IFNγ after IL-15 stimulation. Moreover, the expression of the repressed innate immune genes in monocytes increased by day 1 to day 28 after vaccination in recoverees, therefore moving towards the prevaccination baseline of the healthy control individuals. By contrast, these genes decreased on day 1 and returned to the baseline by day 28 in the control individuals. Our study reveals sex-dimorphic effects of previous mild COVID-19 and suggests that viral infections in humans can establish new immunological set-points that affect future immune responses in an antigen-agnostic manner.

Mouse tissue glycome atlas 2022 highlights inter-organ variation in major N-glycan profiles

This study presents “mouse tissue glycome atlas” representing the profiles of major N-glycans of mouse glycoproteins that may define their essential functions in the surface glycocalyx of mouse organs/tissues and serum-derived extracellular vesicles (exosomes). Cell surface glycocalyx composed of a variety of N-glycans attached covalently to the membrane proteins, notably characteristic “N-glycosylation patterns” of the glycocalyx, plays a critical role for the regulation of cell differentiation, cell adhesion, homeostatic immune response, and biodistribution of secreted exosomes. Given that the integrity of cell surface glycocalyx correlates significantly with maintenance of the cellular morphology and homeostatic immune functions, dynamic alterations of N-glycosylation patterns in the normal glycocalyx caused by cellular abnormalities may serve as highly sensitive and promising biomarkers. Although it is believed that inter-organs variations in N-glycosylation patterns exist, information of the glycan diversity in mouse organs/tissues remains to be elusive. Here we communicate for the first-time N-glycosylation patterns of 16 mouse organs/tissues, serum, and serum-derived exosomes of Slc:ddY mice using an established solid-phase glycoblotting platform for the rapid, easy, and high throughput MALDI-TOFMS-based quantitative glycomics. The present results elicited occurrence of the organ/tissue-characteristic N-glycosylation patterns that can be discriminated to each other. Basic machine learning analysis using this N-glycome dataset enabled classification between 16 mouse organs/tissues with the highest F1 score (69.7–100%) when neural network algorithm was used. A preliminary examination demonstrated that machine learning analysis of mouse lung N-glycome dataset by random forest algorithm allows for the discrimination of lungs among the different mouse strains such as the outbred mouse Slc:ddY, inbred mouse DBA/2Crslc, and systemic lupus erythematosus model mouse MRL-lpr/lpr with the highest F1 score (74.5–83.8%). Our results strongly implicate importance of “human organ/tissue glycome atlas” for understanding the crucial and diversified roles of glycocalyx determined by the organ/tissue-characteristic N-glycosylation patterns and the discovery research for N-glycome-based disease-specific biomarkers and therapeutic targets.

Akkermansia muciniphila phospholipid induces homeostatic immune responses

Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging1–3. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity4–7. Here we report the identification of a lipid from A. muciniphila’s cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays8. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure–activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2–TLR1 heterodimer9,10. Certain features of the phospholipid’s activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC50) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2–TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila’s ability to set immunological tone and its varied roles in health and disease.

Modulation of intestinal immune cell responses by eubiotic or dysbiotic microbiota in inflammatory bowel diseases

BackgroundAlterations of the gut microbiota have been linked to aberrant mucosal immune responses, leading to different intestinal and extraintestinal disorders, including inflammatory bowel diseases (IBD) in genetically susceptible hosts. Thus, restoration of immune homeostasis through the manipulation of the gut microbiota is now considered a possible therapeutic approach to treat IBD patients. Management of IBD patients is currently including the customization of microbe-targeted therapies, such as antibiotics, prebiotics, live biotherapeutics and faecal microbiota transplantation. In this narrative review, we will discuss recent advancements in the understanding of host-microbes interactions in IBD and the basis to promote homeostatic immune responses through microbe-targeted therapies. MethodsWe interrogated with no limit of publication time, the PubMed and Scopus databases using the following keywords: microbiota, inflammatory bowel diseases, IBD, immune system, microbe-targeted therapies. ResultsTherapeutic restoration of homeostatic immune function in IBD patients currently include the manipulation of the gut microbiota through antibiotics, prebiotics, probiotics, and faecal microbiota transplantation. Nonetheless, differences in efficacy has been reported according to existing microbe-targeted therapies, opening the venue for the search of novel approaches such as phage therapies and combinatorial therapies. ConclusionsAlterations in the composition of the gut microbiota have been implicated in a wide variety of pathologies, including IBD. Microbiome-modulating therapies have proven promising treatments targeting inflammation by modulating the microbiota to correct patients’ dysbiosis, normalize immune system responses and repair epithelial barrier deficiencies.

Pathophysiological Significance of GM3 Ganglioside Molecular Species With a Particular Attention to the Metabolic Syndrome Focusing on Toll-Like Receptor 4 Binding.

GM3 ganglioside, the first molecule in ganglioside family biosynthesis, is formed by transfer of sialic acid to lactosylceramide. Several dozen GM3 molecular species exist, based on diversity of ceramide structures. Among ceramide structures composed of sphingosine and fatty acids, there is a great diversity resulting from different combinations of chain length, hydroxylation, and unsaturation of fatty acid chains. Expression patterns of GM3 species in serum vary during pathogenesis of metabolic syndrome. Physiological activity of each species, and significance of the variability, are poorly understood. Our studies revealed that GM3 species with differing fatty acid structures act as pro- or anti-inflammatory endogenous Toll-like receptor 4 (TLR4) ligands. Very long-chain fatty acid (VLCFA) and α-hydroxyl VLCFA GM3 variants strongly enhanced TLR4 activation. In contrast, long-chain fatty acid (LCFA) and ω-9 unsaturated VLCFA GM3 variants suppressed TLR4 activation. GM3 interacted with extracellular TLR4/myeloid differentiation factor 2 (MD-2) complex, thereby promoting dimerization/oligomerization. In obesity and metabolic syndrome, VLCFA-variant GM3 species were elevated in serum and adipose tissue, whereas LCFA-variant species were reduced, and such imbalances were correlated with disease progression. Our findings summarized in this review demonstrate that GM3 molecular species are disease-related endogenous TLR4 ligands and modulate homeostatic and pathogenic innate immune responses.

Aging disrupts circadian gene regulation and function in macrophages.

Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.

Resolution of Th/Tc17-driven inflammation during anti-TNFα treatment of rheumatoid arthritis reveals a unique immune biomarker profiling pattern.

Rheumatoid arthritis (RA) is a chronic multisystem disease with a complex immunopathology. Its inflammatory state is dominated by pro-inflammatory cytokines such as TNFα and activated Th1/Th17. Only proportion of patients achieve clinical remission despite potent biologics targeting these pathways. This study investigated the resolution of inflammation in RA patients (naïve for biologics) receiving TNFα inhibitors (TNFi) and evaluated the biological mechanisms behind treatment response and assessed them using clinical scoring systems. The majority showed a good clinical response after six months (6M) and a significant drop in DAS28-CRP (P≤.002), CDAI (P≤.0001) and RheumXpert (P≤.0001). Before treatment, the patients demonstrated a chronic innate and adaptive inflammatory state. The improved clinical condition was reflected with a decrease in Th17/Tc17 (P≤.05) and an increase in Tregs after 6M (P≤.05). Using a logistic regression model on serum data, IL-6, IL-18, IL-21, IL-22, IFNγ and TNFα were identified as the main contributing biomarkers in the chronic inflammatory state of RA. A specific test score (STS) was defined and converted to a single cytokine composite test score (CCTS), which showed the disease outcome on a scale 0-100, providing sensitivity and specificity of ≥90%. Thus, the immunological complexity in RA is driven by a complex interplay of pro-inflammatory cytokines and effector T-cell response dominated by Th17/Tc17. In addition, the resolution of inflammation could be linked to a partially Treg-driven homeostatic innate immune response. Therefore, a more complex therapeutic approach against the above markers might be of value to obtain full clinical remission in the future.

Lactobacillus rhamnosus HDB1258 modulates gut microbiota-mediated immune response in mice with or without lipopolysaccharide-induced systemic inflammation

BackgroundGut microbiota closely communicate in the immune system to maintain a balanced immune homeostasis in the gastrointestinal tract of the host. Oral administration of probiotics modulates gut microbiota composition. In the present study, we isolated Lactobacillus rhamnosus HDB1258, which induced tumor necrosis factor (TNF)-α and interleukin (IL)-10 expression in macrophages, from the feces of breastfeeding infants and examined how HDB1258 could regulate the homeostatic immune response in mice with or without lipopolysaccharide (LPS)-induced systemic inflammation.ResultsOral administration of HDB1258 significantly increased splenic NK cell cytotoxicity, peritoneal macrophage phagocytosis, splenic and colonic TNF-α expression, TNF-α to IL-10 expression ratio, and fecal IgA level in control mice, while Th1 and Treg cell differentiation was not affected in the spleen. However, HDB1258 treatment significantly suppressed peritoneal macrophage phagocytosis and blood prostaglandin E2 level in mice with LPS-induced systemic inflammation. Its treatment increased LPS-suppressed ratios of Treg to Th1 cell population, Foxp3 to T-bet expression, and IL-10 to TNF-α expression. Oral administration of HDB1258 significantly decreased LPS-induced colon shortening, myeloperoxidase activity and NF-κB+/CD11c+ cell population in the colon, while the ratio of IL-10 to TNF-α expression increased. Moreover, HDB1258 treatment shifted gut microbiota composition in mice with and without LPS-induced systemic inflammation: it increased the Cyanobacteria and PAC000664_g (belonging to Bacteroidetes) populations and reduced Deferribacteres and EU622763_s group (belonging to Bacteroidetes) populations. In particular, PAC001066_g and PAC001072_s populations were negatively correlated with the ratio of IL-10 to TNF-α expression in the colon, while the PAC001070_s group population was positively correlated.ConclusionsOral administered HDB1258 may enhance the immune response by activating innate immunity including to macrophage phagocytosis and NK cell cytotoxicity in the healthy host and suppress systemic inflammation in the host with inflammation by the modulation of gut microbiota and IL-10 to TNF-α expression ratio in immune cells.

Host-Directed Therapies: Modulating Inflammation to Treat Tuberculosis.

Following infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), most human hosts are able to contain the infection and avoid progression to active TB disease through expression of a balanced, homeostatic immune response. Proinflammatory mechanisms aiming to kill, slow and sequester the pathogen are key to a successful host response. However, an excessive or inappropriate pro-inflammatory response may lead to granuloma enlargement and tissue damage, which may prolong the TB treatment duration and permanently diminish the lung function of TB survivors. The host also expresses certain anti-inflammatory mediators which may play either beneficial or detrimental roles depending on the timing of their deployment. The balance between the timing and expression levels of pro- and anti-inflammatory responses plays an important role in the fate of infection. Interestingly, M. tuberculosis appears to manipulate both sides of the human immune response to remodel the host environment for its own benefit. Consequently, therapies which modulate either end of this spectrum of immune responses at the appropriate time may have the potential to improve the treatment of TB or to reduce the formation of permanent lung damage after microbiological cure. Here, we highlight host-directed TB therapies targeting pro- or anti-inflammatory processes that have been evaluated in pre-clinical models. The repurposing of already available drugs known to modulate these responses may improve the future of TB therapy.

Abstract P143: Salt-sensitivity And Salt-resistance Differentially Modulate Renal And Colonic T Regulatory Cells

High salt diets (HSD) promote both inflammation and immunosuppression as shown in numerous studies utilizing salt-sensitive or hypertensive models. However, mechanisms involved in the homeostatic immune response to HSD, alone, have not been fully elucidated. Regulatory T cells (FOXP3 + CD4 + T cells) play a role in host protection against disease or environmental stressors. Further, recent studies show that RORt + expression by Tregs may represent a functional adaptation by Tregs in response to alterations to the diet. Thus, we hypothesized that these Treg populations may expand in response to HSD alone, and a hypertensive insult prior to the HSD blunts this response. We designed experiments to determine whether Tregs and RORt + Tregs expand in response to HSD or with LNAME hypertension followed by HSD. We evaluated the following groups in male C57BL/6J mice: NSD (normal salt diet, 0.4% NaCl), LNAME/NSD (0.5mg/ml for 3-wks in drinking water, followed by 3-wks NSD), HSD (4% NaCl+1% NaCl in drinking water, 2-wks), or LNAME/HSD (0.5mg/mL for 3-wks in drinking water, with 1-wk NSD followed by 2-wks HSD). Following immune cell isolation, we utilized flow cytometry to phenotype renal and colonic T cells. Data are expressed as frequency of means (% of CD4 + TCRbeta + T cells)±SEM (n=3-8/group) compared to NSD. In kidneys, HSD significantly expanded Tregs and RORt + Tregs, while LNAME/HSD group was unchanged compared to controls (% Treg: NSD: 5.7±0.5; L-NAME: 6.5±0.5; HSD: 9.2±1.0**; LNAME/HSD: 6.2±0.3; % RORt + Treg: NSD: 0.4±0.07; L-NAME: 0.6±0.13; HSD: 1.8±0.41***; LNAME/HSD: 0.6±0.14; **p<0.01, ***p<0.001). In the colon, HSD significantly expanded Tregs and RORt + Tregs, whereas the LNAME/HSD group had no change in these T cell populations (% Treg: NSD: 36±2; LNAME: 42±1; HSD: 46±2*; LNAME/HSD: 43±2; % RORt + Tregs: NSD: 16±1; LNAME: 19±1; HSD: 23±1*; LNAME/HSD: 20±2; *p<0.05). These data suggest that Tregs and RORt + Tregs expand in response to HSD in the kidney and colon, with a greater magnitude of expansion by RORt + Tregs. However, this expansion of T cell populations is not evident in mice pre-exposed to a hypertensive insult. We propose that HSD stimulates pathways that promote Treg expansion, which may be associated with salt-resistance and protective mechanisms.

Gut Microbiota Manipulation as a Tool for Colorectal Cancer Management: Recent Advances in Its Use for Therapeutic Purposes.

Colorectal cancer (CRC) is a multifaceted disease influenced by both environmental and genetic factors. A large body of literature has demonstrated the role of gut microbes in promoting inflammatory responses, creating a suitable microenvironment for the development of skewed interactions between the host and the gut microbiota and cancer initiation. Even if surgery is the primary therapeutic strategy, patients with advanced disease or cancer recurrence after surgery remain difficult to cure. Therefore, the gut microbiota has been proposed as a novel therapeutic target in light of recent promising data in which it seems to modulate the response to cancer immunotherapy. The use of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics, and fecal microbiota transplantation, is therefore considered to support current therapies in CRC management. In this review, we will discuss the importance of host−microbe interactions in CRC and how promoting homeostatic immune responses through microbe-targeted therapies may be useful in preventing/treating CRC development.

Cellular reactions of the mucous membrane of the intestinal system after uranium incorporation

A pilot study, which was performed on white laboratory male rats and included a morphological study of the mucous membrane of the jejunum and colon, revealed the long-term effect of a single oral exposure to an aqueous solution of depleted uranium oxides; this supported dynamic changes in the studied criteria determining metabolic, regenerative, and local regulatory processes in one, three and six months. A lymphoid component appeared to be the criterion of high radio sensitivity and a marker of nonspecific protection indicating deterioration of homeostasis. In the time dynamics of long-term periods, a change in all the parameters was detected when using immunohistochemical, histochemical, and specific methods at the level of the epithelium lining the relief formations of the mucous membranes of the intestinal system organs. The oxidative stress resulting in three months after exposure to depleted uranium, which was evidenced by a significant decrease in the content of anti-apoptotic Bcl-2 protein in the epithelial cells of the jejunely mucosa. Signs of its delayed effect after six months in the colon induced the pronounced nature of the reactions of stromal cell components that determined patterns of protective mechanisms of the intestinal-associated immune system with a greater expressiveness in the jejunum. The factual material cited in the work suggests the existence of a homeostatic immune response in the mucous membrane of the small and large intestines that controls cell proliferation, as a special form of immune surveillance of the state of cytodifferentiation.

The Role of Gut Microbiota Biomodulators on Mucosal Immunity and Intestinal Inflammation.

Alterations of the gut microbiota may cause dysregulated mucosal immune responses leading to the onset of inflammatory bowel diseases (IBD) in genetically susceptible hosts. Restoring immune homeostasis through the normalization of the gut microbiota is now considered a valuable therapeutic approach to treat IBD patients. The customization of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics and faecal microbiota transplantation, is therefore considered to support current therapies in IBD management. In this review, we will discuss recent advancements in the understanding of host−microbe interactions in IBD and the basis to promote homeostatic immune responses through microbe-targeted therapies. By considering gut microbiota dysbiosis as a key feature for the establishment of chronic inflammatory events, in the near future it will be suitable to design new cost-effective, physiologic, and patient-oriented therapeutic strategies for the treatment of IBD that can be applied in a personalized manner.

Targeting Leukotrienes as a Therapeutic Strategy to Prevent Comorbidities Associated with Metabolic Stress.

Leukotrienes (LTs) are potent lipid mediators that exert a variety of functions, ranging from maintaining the tone of the homeostatic immune response to exerting potent proinflammatory effects. Therefore,LTs are essential elements in the development and maintenance of different chronic diseases, such as asthma, arthritis, and atherosclerosis. Due to the pleiotropic effects of LTs in the pathogenesis of inflammatory diseases, studies are needed to discover potent and specific LT synthesis inhibitors and LT receptor antagonists. Even though most clinical trials using LT inhibitors or antagonists have failed due to low efficacy and/or toxicity, new drug development strategies are driving the discovery for LT inhibitors to prevent inflammatory diseases. A newly important detrimental role for LTs in comorbidities associated with metabolic stress has emerged in the last few years and managing LT production and/or actions could represent an exciting new strategy to prevent or treat inflammatory diseases associated with metabolic disorders. This review is intended to shed light on the synthesis and actions of leukotrienes, the most common drugs used in clinical trials, and discuss the therapeutic potential of preventing LT function in obesity, diabetes, and hyperlipidemia.