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Immunoglobulin A (IgA) is an important factor in maintaining homeostasis at mucosal surfaces, yet luminal IgA levels vary widely. Total IgA levels are thought to be driven by individual immune responses to specific microbes. Here, we found that the prebiotic, pectin oligosaccharide (pec-oligo), induced high IgA levels in the small intestine in a T cell-dependent manner. Surprisingly, this IgA-high phenotype was retained after cessation of pec-oligo treatment, and microbiome transmission either horizontally or vertically was sufficient to retain high IgA levels in the absence of pec-oligo. Interestingly, the bacterial taxa enriched in the overall pec-oligo bacterial community differed from IgA-coated microbes in this same community. Rather, a group of ethanol-resistant microbes, highly enriched for Lachnospiraceae bacterium A2, drove the IgA-high phenotype. These findings support a model of intestinal adaptive immunity in which a limited number of microbes can promote durable changes in IgA directed to many symbionts., Competing Interests: Declaration of interests T.S.S. is on the scientific advisory board for Janssen Pharmaceuticals and Amgen. T.S.S. is a founder of Mobius Care, Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls., Methods: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti-tumor necrosis factor and anti-interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted., Results: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-tumor necrosis factor rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders., Conclusions: Reduced SB but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease, but normalized after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Although chronic gastrointestinal dysmotility syndromes are a common worldwide health problem, underlying causes for these disorders are poorly understood. We show that flavivirus infection of enteric neurons leads to acute neuronal injury and cell death, inflammation, bowel dilation, and slowing of intestinal transit in mice. Flavivirus-primed CD8 + T cells promote these phenotypes, as their absence diminished enteric neuron injury and intestinal transit delays, and their adoptive transfer reestablished dysmotility after flavivirus infection. Remarkably, mice surviving acute flavivirus infection developed chronic gastrointestinal dysmotility that was exacerbated by immunization with an unrelated alphavirus vaccine or exposure to a non-infectious inflammatory stimulus. This model of chronic post-infectious gastrointestinal dysmotility in mice suggests that viral infections with tropism for enteric neurons and the ensuing immune response might contribute to the development of bowel motility disorders in humans. These results suggest an opportunity for unique approaches to diagnosis and therapy of gastrointestinal dysmotility syndromes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Microbially derived metabolites in the intestine regulate host immunity and impact disease pathophysiology in various organs. Sun et al. (2015) suggest a direct effect of microbial metabolites on pancreatic endocrine cells in regulating type 1 diabetes pathophysiology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

There is growing interest in understanding the effects of host-microbial interactions on host physiologic processes. Much of the work in this arena is logically focused on the interaction at mucosal surfaces as this is a primary site of interaction. However, there is ample evidence to suggest that the effects of the microbiota have a much farther reach including the systemic immune system. While there are some similarities to effects at mucosal surfaces (i.e. reduced numbers of adaptive immune cells, diminished innate responses), there are some important differences that we highlight such as the response to immunogens and bacterial antigens. We propose that understanding the details of how specific components of the microbiota influence the systemic immune system likely will have significant impact on our understanding the pathophysiology of a variety of autoimmune diseases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Nutrient absorption is the basic function that drives mammalian intestinal biology. To facilitate nutrient uptake, the host's epithelial barrier is composed of a single layer of cells. This constraint is problematic, as a design of this type can be easily disrupted. The solution during the course of evolution was to add numerous host defense mechanisms that can help prevent local and systemic infection. These mechanisms include specialized epithelial cells that produce a physiochemical barrier overlying the cellular barrier, robust and organized adaptive and innate immune cells, and the ability to mount an inflammatory response that is commensurate with a specific threat level. The autophagy pathway is a critical cellular process that strongly influences all these functions. Therefore, a fundamental understanding of the components of this pathway and their influence on inflammation, immunity, and barrier function will facilitate our understanding of homeostasis in the gastrointestinal tract.

Pathogenic simian immunodeficiency virus (SIV) infection is associated with enteropathy, which likely contributes to AIDS progression. To identify candidate etiologies for AIDS enteropathy, we used next-generation sequencing to define the enteric virome during SIV infection in nonhuman primates. Pathogenic, but not nonpathogenic, SIV infection was associated with significant expansion of the enteric virome. We identified at least 32 previously undescribed enteric viruses during pathogenic SIV infection and confirmed their presence by using viral culture and PCR testing. We detected unsuspected mucosal adenovirus infection associated with enteritis as well as parvovirus viremia in animals with advanced AIDS, indicating the pathogenic potential of SIV-associated expansion of the enteric virome. No association between pathogenic SIV infection and the family-level taxonomy of enteric bacteria was detected. Thus, enteric viral infections may contribute to AIDS enteropathy and disease progression. These findings underline the importance of metagenomic analysis of the virome for understanding AIDS pathogenesis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose of Review: Study of developmental signaling pathways suggests that the intestinal stem cell niche regulates the activity of the crypt-based epithelial progenitors during homeostasis and injury states. The cellular origin of these signals, however, remains poorly defined. Here, we examine the current state of knowledge regarding intestinal epithelial progenitor niches and highlight applicable lessons learned from other systems., Recent Findings: Cell-cell contact, regulatory factor delivery, stem cell polarity, and mesenchymal stem cells are considered., Summary: Based on the findings in other niche systems as well as the overall complexity and unique organization of the intestinal progenitor niche, future studies will focus on defining peri-cryptal architecture, cellular sources of regulatory factors, and the dynamic nature of the niche during homeostasis and injury repair. These insights may lead to novel cell-based therapies for a variety of conditions that damage the mucosal lining of the gut.

Background: p38-Alpha mitogen-activated protein kinase (p38-MAPK) is a tumor suppressor often mutated in human cancers, but its specific role in colorectal cancer is not completely understood. Previous studies have found that p38-MAPK activity inhibits epithelial proliferation and promotes apoptosis in the intestine. Therefore, we sought to test the hypothesis that intestinal disruption of p38-MAPK would lead to increased tumorigenesis in the colon. Methods: p38-MAPK was deleted in mice within the intestinal epithelium using a tamoxifen-inducible Cre system under control of the villin promoter [villin-Cre ERT2(+), MAPK14(f/f)]. An azoxymethane and dextran sodium sulfate protocol was used to drive intestinal tumor development. Tumor measurements were made using computer software from photographs of excised colon specimens. Results: The number of mice that developed tumors was not statistically different when comparing wild-type mice (7/14) to inducible, intestine epithelial-deleted p38-MAPK (9/11) mice after azoxymethane/dextran sodium sulfate treatment (P = .21). However, the epithelial-deleted p38-MAPK mice developed significantly more tumors (3.7 vs 1.1; P = .008) and nearly 4 times the total tumor burden as wild-type mice (17.4 vs 4.8 mm2; P = .03). Wild-type and epithelial-deleted p38-MAPK groups demonstrated a similar degree of colon inflammation. Conclusion: Deletion of p38-MAPK within the colonic mucosa leads to a hyperplastic state promoting greater tumor development. Because the severity of colitis was not augmented in mice with p38-MAPK deficiency, tumor development is likely mediated by impaired cell cycle regulation within the colonic epithelium. Manipulation of p38-MAPK activity may provide a novel treatment and/or prevention strategy in the management of colorectal cancer, particularly in the setting of inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

The CDC25 protein phosphatases drive cell cycle advancement by activating cyclin-dependent protein kinases (CDKs). Humans and mice encode three family members denoted CDC25A, -B and -C and genes encoding these family members can be disrupted individually with minimal phenotypic consequences in adult mice. However, adult mice globally deleted for all three phosphatases die within one week after Cdc25 disruption. A severe loss of absorptive villi due to a failure of crypt epithelial cells to proliferate was observed in the small intestines of these mice. Because the Cdc25s were globally deleted, the small intestinal phenotype and loss of animal viability could not be solely attributed to an intrinsic defect in the inability of small intestinal stem and progenitor cells to divide. Here, we report the consequences of deleting different combinations of Cdc25s specifically in intestinal epithelial cells. The phenotypes arising in these mice were then compared with those arising in mice globally deleted for the Cdc25s and in mice treated with irinotecan, a chemotherapeutic agent commonly used to treat colorectal cancer. We report that the phenotypes arising in mice globally deleted for the Cdc25s are due to the failure of small intestinal stem and progenitor cells to proliferate and that blocking cell division by inhibiting the cell cycle engine (through Cdc25 loss) versus by inducing DNA damage (via irinotecan) provokes a markedly different response of small intestinal epithelial cells. Finally, we demonstrate that CDC25A and CDC25B but not CDC25C compensate for each other to maintain the proliferative capacity of intestinal epithelial stem and progenitor cells. [ABSTRACT FROM AUTHOR]

The adult mouse intestine contains an intricate vascular network. The factors that control development of this network are poorly understood. Quantitative three-dimensional imaging studies revealed that a plexus of branched interconnected vessels developed in small intestinal villi during the period of postnatal development that coincides with assembly of a complex society of indigenous gut microorganisms (microbiota). To investigate the impact of this environmental transition on vascular development, we compared the capillary networks of germ-free mice with those of ex-germfree animals colonized during or after completion of postnatal gut development. Adult germ-free mice had arrested capillary network formation. The developmental program can be restarted and completed within 10 days after colonization with a complete microbiota harvested from conventionally raised mice, or with Bacteroides thetaiotaomicron, a prominent inhabitant of the normal mouse/human gut. Paneth cells in the intestinal epithelium secrete antibacterial peptides that affect luminal microbial ecology. Comparisons of germ-free and B. thetaiotaomicron-colonized transgenic mice lacking Paneth cells established that microbial regulation of angiogenesis depends on this lineage. These findings reveal a previously unappreciated mechanism of postnatal animal development, where microbes colonizing a mucosal surface are assigned responsibility for regulating elaboration of the underlying microvasculature by signaling through a bacteria-sensing epithelial cell. [ABSTRACT FROM AUTHOR]

The organization of the lining of the gastrointestinal tube is similar for the stomach, small intestine and colon. It is composed of a continuous simple epithelium and underlying mesenchyme, including blood vessels, fibroblasts/myofibroblasts and immune cells. Individual organs contain modifications of this mucosa that are critical for their functions. We hypothesize that changes in the composition of the epithelial basement membrane are a critical determinant for structure and function of the local mucosa. Laminins are excellent candidates for such a role, as they comprise a large family of αβγ heterotrimeric glycoproteins that demonstrate developmental, organ and cell type specificity. We have found that adult mice lacking the normal villus laminin, α5, demonstrate a compensatory increase in α1 and α4, which are normally present in the colon. This laminin switch results in colonic metaplasia of the distal small intestine, which showed deepened crypts, villus atrophy and subsequent replacement by flat surface epithelial structures, and expression of colonic markers. This change was associated with aberrant intestinal epithelial cell proliferation, differentiation and migration. Here, unlike pathologic processes in humans that result in colonic metaplasia, there was no infiltration of inflammatory cells. These observations highlight the important and distinct roles of different laminin isoforms on the patterning of intestinal crypt-villus architecture and the regulation of intestinal epithelial cell behavior. Our data also suggest that differences in laminin composition along the gut's rostrocaudal axis contribute to its regionalization into small and large intestine. [ABSTRACT FROM AUTHOR]

Loss of differentiated cells to tissue damage is a hallmark of many diseases. In slow-turnover tissues, long-lived differentiated cells can re-enter the cell cycle or transdifferentiate to another cell type to promote repair. Here, we show that in a high-turnover tissue, severe damage to the differentiated compartment induces progenitors to transiently acquire a unique transcriptional and morphological postmitotic state. We highlight this in an acute villus injury model in the mouse intestine, where we identified a population of progenitor-derived cells that covered injured villi. These atrophy-induced villus epithelial cells (aVECs) were enriched for fetal markers but were differentiated and lineage committed. We further established a role for aVECs in maintaining barrier integrity through the activation of yes-associated protein (YAP). Notably, loss of YAP activity led to impaired villus regeneration. Thus, we define a key repair mechanism involving the activation of a fetal-like program during injury-induced differentiation, a process we term "adaptive differentiation." [Display omitted] • Epithelial dynamics in human enteropathy captured in an acute gastroenteritis model • Villus injury triggers TA cells to differentiate and acquire a fetal-like state • Adaptive epithelial differentiation restores barrier integrity • Proper adaptive differentiation is required for rebuilding damaged villi Ohara et al. demonstrate that, following injury, intestinal villus cells transiently adopt a unique differentiated state that incorporates a fetal program. Cells in this differentiated state can quickly re-establish the epithelial barrier to help restore the villus architecture. [ABSTRACT FROM AUTHOR]

Bacteria express multiple diverse capsular polysaccharides (CPSs) for protection against environmental and host factors, including the host immune system. Using a mouse TCR transgenic CD4+ T cell, BuOM, that is specific for B. thetaiotaomicron and a complete set of single CPS-expressing B. thetaiotaomicron strains, we ask whether CPSs can modify the immune responses to specific bacterial Ags. Acapsular B. thetaiotaomicron, which lacks all B. thetaiotaomicron CPSs, stimulated BuOM T cells more strongly than wild-type B. thetaiotaomicron. Despite similar levels of BuOM Ag expression, many single CPS-expressing B. thetaiotaomicron strains were antistimulatory and weakly activated BuOM T cells, but a few strains were prostimulatory and strongly activated BuOM T cells just as well or better than an acapsular strain. B. thetaiotaomicron strains that expressed an antistimulatory CPS blocked Ag delivery to the immune system, which could be rescued by Fc receptor-dependent Ab opsonization. All single CPS- expressing B. thetaiotaomicron strains stimulated the innate immune system to skew toward M1 macrophages and release inflammatory cytokines in an MyD88-dependent manner, with antistimulatory CPS activating the innate immune system in a weaker manner than prostimulatory CPS. The expression of antistimulatory versus prostimulatory CPSs on outer membrane vesicles also regulated immune responses. Moreover, antistimulatory and prostimulatory single CPS-expressing B. thetaiotaomicron strains regulated the activation of Ag-specific and polyclonal T cells as well as clearance of dominant Ag in vivo. These studies establish that the immune responses to specific bacterial Ags can be modulated by a diverse set of CPSs. [ABSTRACT FROM AUTHOR]