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Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. Sea conch peptide hydrolysate (CPH) was produced by enzymatic digestion of fresh conch meat with trypsin enzyme. To analyze the molecular composition, functional groups, and structural morphology of the hydrolysate, we employed liquid chromatography–mass spectrometry (LC–MS), Fourier‐transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). Results confirmed that crude protein could be effectively digested by enzymes to generate peptides. In this study, we evaluated the bioactivities of CPH on dextran sulfate solution (DSS)‐induced colitis in mice. The findings demonstrated that CPH supplementation improved body weight, food and water intake, and colon length. The therapeutic efficacy and immunoregulatory effect of CPH were further determined. Our results exhibited that CPH treatment significantly ameliorated pathological symptoms by enhancing intestinal integrity, mucin production, and goblet cell count. Moreover, the immunoregulatory effect of CPH on mRNA expression levels of different pro‐ and anti‐inflammatory cytokines was determined. Results exhibited a decrease in the expression of pro‐inflammatory cytokines and an increase in anti‐inflammatory cytokines in the colon. Additionally, the CPH administration modulates the nuclear factor kappa B (NF‐κB) pathway, preventing DNA damage and cell death. Assays for apoptosis and DNA damage revealed that CPH reduced oxidative DNA damage and apoptosis. These findings highlight the immunomodulatory and treatment amelioration effect of CPH in reducing the severity of colitis. [ABSTRACT FROM AUTHOR]

Aspirin, also named acetylsalicylate, can directly acetylate the side‐chain of lysine in protein, which leads to the possibility of unexplained drug effects. Here, the study used isotopic‐labeling aspirin‐d3 with mass spectrometry analysis to discover that aspirin directly acetylates 10 HDACs proteins, including SIRT1, the most studied NAD+‐dependent deacetylase. SIRT1 is also acetylated by aspirin in vitro. It is also identified that aspirin directly acetylates lysine 408 of SIRT1, which abolishes SIRT1 deacetylation activity by impairing the substrates binding affinity. Interestingly, the lysine 408 of SIRT1 can be acetylated by CBP acetyltransferase in cells without aspirin supplement. Aspirin can inhibit SIRT1 to increase the levels of acetylated p53 and promote p53‐dependent apoptosis. Moreover, the knock‐in mice of the acetylation‐mimic mutant of SIRT1 show the decreased production of pro‐inflammatory cytokines and maintain intestinal immune homeostasis. The study indicates the importance of the acetylated internal functional site of SIRT1 in maintaining intestinal immune homeostasis. [ABSTRACT FROM AUTHOR]

Background: The negative feedback circuit NIK-SIN could inhibit the systemic inflammation and protect mouse from endotoxic shock. However, the physiological significance of NIK-SIX feedback circuit in the maintenance of intestinal immune homeostasis and prevention of early-onset spontaneous colitis is not known.Objective: To explore the role of NIK-SIX axis in the maintenance of intestinal immune homeostasis.Methods: The conditional knockout of NIK encoding gene, Map3k14, in the Cd11c+ dendritic cells were generated by crossing Map3k14-flox mice with Cd11c-Cre mice. DSS was used for colitis models. The expression of cytokines in the intestinal immune cells, isolated from Map3k14-cKO mice were detected by qPCR. The siRNA molecules were used for the silencing of SIN-proteins. Then luciferase assays and chromatin immunoprecipitation combined with qPCR were applied for mechanism investigations.Results: The expression of SIX1 and SIX2 protein in BMDMs from WT were significantly lower than in the Map3k14-cKO mice. In vitro, the NIK-/- human-derived circulating monocytes also failed to express SIX-proteins under the stimulation of non-canonical NF-κB agonists. The expression of cytokines was significantly decreased in human circulating monocytes with overexpression SIN-proteins. The expression of cytokines in macrophages, DCs and T cells isolated from Map3k14-cKO mice were significantly increased in the DSS-induced models. Higher expression of cytokines was observed in the SIN1-/- and SIN2-/- cells including human circulating monocytes, mouse-derived BMDMs, intestinal macrophages and DCs. SIN-proteins directly bound the promoter region of inflammatory genes.Conclusion: NIK-SIX axis down-regulated inflammatory gene expression and plays a pivotal role in the maintenance of intestinal immune homeostasis.

Inflammatory bowel disorders (IBD) can lead to severe complications like perforation, bleeding, and colon cancer, posing life-threatening risks. Lycium ruthenicum Murray ( L. ruthenicum  Murr.), rich in polysaccharides, has been utilized in traditional diets for thousands of years. This study explores the protective effects of the polysaccharide of L. ruthenicum on mice with dextran sulfate sodium (DSS)-induced colitis. In the present study, a pectic polysaccharide (LRWP-A p ) containing arabinogalactan (AG) and homogalacturonic acid (HG) structural domains with a Mw of 4.34 kDa was obtained from L. ruthenicum Murr. Fruit. The gavage administration of LRWP-A p significantly alleviated symptoms of DSS-induced colitis in mice. In this process, LRWP-A p modulated the balance of Arg-1/iNOS to regulate the metabolism of arginine, and the levels of intestinal tight junction (TJ) (ZO-1, Occludin, and Claudin 1) were increased by LRWP-A p treatment, which promoted intestinal barrier function. In addition, LRWP-A p alleviated the inflammatory response while increasing the anti-inflammatory response by reducing the level of proinflammatory factors, enhancing the level of anti-inflammatory factors (IL-10) and improving the balance of Treg/Th17 cells. These effects resulted in the maintenance of intestinal immune homeostasis. Moreover, LRWP-A p modulated the gut microbiota composition and short-chain fatty acid (SCFA) content, which may maintain relatively favorable intestinal homeostasis. In general, LRWP-A p has the potential to alleviate IBD, and the use of L. ruthenicum Murr. As a natural functional food to improve gut health in the context of DSS-induced colitis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Glucocorticoids (GCs) are steroid hormones predominantly produced in the adrenal glands in response to physiological cues and stress. Adrenal GCs mediate potent anti-inflammatory and immunosuppressive functions. Accumulating evidence in the past two decades has demonstrated other extra-adrenal organs and tissues capable of synthesizing GCs. This review discusses the role and regulation of GC synthesis in the intestinal epithelium in the regulation of normal immune homeostasis, inflammatory diseases of the intestinal mucosa, and the development of intestinal tumors.

Intestinal homeostasis requires a balanced interaction between the host innate immune system and the gut microbiota. A dysregulation of this interdependency can result in inflammatory bowel diseases (IBDs), and this dysregulation is a key pathogenic factor during the development of colorectal cancer. CARD9 is a central signaling molecule in the innate immune system, which is essential for host defense against infection. Moreover, polymorphisms in CARD9 are key risk factors for IBD development, indicating that CARD9 signaling is critical for intestinal immune homeostasis. This review summarizes recent insights into the regulation of CARD9 signaling, its pathophysiological role during IBD development via effects on the microbiota and epithelial regeneration and the pro- and antitumor immune functions of CARD9 during intestinal carcinogenesis.

Glucocorticoids (GCs) are steroid hormones predominantly produced in the adrenal glands in response to physiological cues and stress. Adrenal GCs mediate potent anti-inflammatory and immunosuppressive functions. Accumulating evidence in the past two decades has demonstrated other extra-adrenal organs and tissues capable of synthesizing GCs. This review discusses the role and regulation of GC synthesis in the intestinal epithelium in the regulation of normal immune homeostasis, inflammatory diseases of the intestinal mucosa, and the development of intestinal tumors. [ABSTRACT FROM AUTHOR]

Intestinal homeostasis requires a balanced interaction between the host innate immune system and the gut microbiota. A dysregulation of this interdependency can result in inflammatory bowel diseases (IBDs), and this dysregulation is a key pathogenic factor during the development of colorectal cancer. CARD9 is a central signaling molecule in the innate immune system, which is essential for host defense against infection. Moreover, polymorphisms in CARD9 are key risk factors for IBD development, indicating that CARD9 signaling is critical for intestinal immune homeostasis. This review summarizes recent insights into the regulation of CARD9 signaling, its pathophysiological role during IBD development via effects on the microbiota and epithelial regeneration and the pro- and antitumor immune functions of CARD9 during intestinal carcinogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Inappropriate activation of intestinal innate immune receptors, such as toll‐like receptors (TLRs), by pathogenic bacteria is linked to chronic inflammation. In contrast, a “tonic” level of TLR activation by commensal bacteria is required for intestinal homeostasis. A technical challenge when studying this activation in vitro is the co‐culturing of oxygen‐requiring mammalian cells with obligate anaerobic commensal bacteria. To overcome this, we used a novel apical anaerobic co‐culture system to successfully adapt a TLR activation assay to be conducted in conditions optimised for both cell types. Live Faecalibacterium prausnitzii, an abundant obligate anaerobe of the colonic microbiota, induced higher TLR2 and TLR2/6 activation than the dead bacterium. This enhanced TLR induction by live F. prausnitzii, which until now has not previously been described, may contribute to maintenance of gastrointestinal homeostasis. This highlights the importance of using physiologically relevant co‐culture systems to decipher the mechanisms of action of live obligate anaerobes. [ABSTRACT FROM AUTHOR]

Many essential gastrointestinal functions, including motility, secretion, and blood flow, are regulated by the autonomic nervous system (ANS), both through intrinsic enteric neurons and extrinsic (sympathetic and parasympathetic) innervation. Recently identified neuroimmune mechanisms, in particular the interplay between enteric neurons and muscularis macrophages, are now considered to be essential for fine-tuning peristalsis. These findings shed new light on how intestinal immune cells can support enteric nervous function. In addition, both intrinsic and extrinsic neural mechanisms control intestinal immune homeostasis in different layers of the intestine, mainly by affecting macrophage activation through neurotransmitter release. In this mini-review, we discuss recent insights on immunomodulation by intrinsic enteric neurons and extrinsic innervation, with a particular focus on intestinal macrophages. In addition, we discuss the relevance of these novel mechanisms for intestinal immune homeostasis in physiological and pathological conditions, mainly focusing on motility disorders (gastroparesis and post-operative ileus) and inflammatory disorders (colitis). [ABSTRACT FROM AUTHOR]

Macrophages are becoming increasingly recognized as key cellular players in intestinal immune homeostasis. However, differentiating between macrophages and dendritic cells ( DCs) is often difficult, and finding a specific phenotypic signature for intestinal macrophage identification has remained elusive. In this issue of the European Journal of Immunology, Tamoutounour et al. [Eur. J. Immunol. 2012. 42: 3150-3166] identify CD64 as a specific macrophage marker that can be used to discriminate DCs from macrophages in the murine small and large intestine, under both steady-state and inflammatory conditions. The authors also propose a sequential 'monocyte-waterfall' model for intestinal macrophage differentiation, with implications for immune tolerance and inflammation at the gut mucosal interface. This Commentary will discuss the advantages and potential limitations of CD64 as a marker for intestinal macrophages. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GC) are lipophilic hormones commonly used as therapeutics in acute and chronic inflammatory disorders such as inflammatory bowel disease due to their attributed anti-inflammatory and immunosuppressive actions. Although the adrenal glands are the major source of endogenous GC, there is increasing evidence for the production of extra-adrenal GC in the brain, thymus, skin, vasculature, and the intestine. However, the physiological relevance of extra-adrenal-produced GC remains still ambiguous. Therefore, this review attracts attention to discuss possible biological benefits of extra-adrenal-synthesized GC, especially focusing on the impact of locally synthesized GC in the regulation of intestinal immune responses. [ABSTRACT FROM AUTHOR]

Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c + cells. Thus, weak agonistic LPS represents a promising agent to treat diseases involving pathological overactivation of the intestinal immune system, e.g., in inflammatory bowel diseases., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)