Inflammasome-independent functions of NAIPs and NLRs in the intestinal epithelium

The gut relies on the complex interaction between epithelial, stromal and immune cells to maintain gut health in the face of food particles and pathogens. Innate sensing by the intestinal epithelium is critical for maintaining epithelial barrier function and also orchestrating mucosal immune responses. Numerous innate pattern recognition receptors (PRRs) are involved in such sensing. In recent years, several Nucleotide-binding-domain and Leucine-rich repeat-containing receptors (NLRs) have been found to partake in pathogen or damage sensing while also being implicated in gut pathologies, such as colitis and colorectal cancer (CRC). Here, we discuss the current literature focusing on NLR family apoptosis inhibitory proteins (NAIPs) and other NLRs that have non-inflammasome roles in the gut. The mechanisms behind NLR-mediated protection often converges on similar signalling pathways, such as STAT3, MAPK and NFκB. Further understanding of how these NLRs contribute to the maintenance of gut homeostasis will be important for understanding gut pathologies and developing new therapies.

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Effects of dietary fatty acids on gut health and function of pigs pre- and post-weaning

Journal of Animal Science ◽

10.1093/jas/skaa086 ◽

2020 ◽

Vol 98 (4) ◽

Cited By ~ 3

Author(s):

Charlotte Lauridsen

Keyword(s):

Oxidative Stress ◽

Fatty Acids ◽

Immune Responses ◽

Molecular Structures ◽

Epithelial Barrier ◽

Gut Health ◽

Inflammatory Reactions ◽

Epithelial Barrier Function ◽

Fa Composition ◽

And Function

Abstract Fatty acids (FA) play a major role in relation to mucosal immune responses, epithelial barrier functions, oxidative stress, and inflammatory reactions. The dietary FA composition and the molecular structures (chain length and number of double bonds) influence digestion, absorption and metabolism, and the bioactivity of the FA. Piglets post-weaning having an immature intestine and not fully formed immune functions are very vulnerable to invading microorganisms. Manipulation of the milk FA composition via sow nutrition, or inclusion of dietary fat sources in the feed for newly weaned pigs, may be used as a strategic tool to enhance pig performance and their gut health and function pre- and post-weaning. Medium-chain fatty acids (MCFA) are absorbed directly into the portal blood and may contribute to immediate energy for the enterocytes. In addition, the MCFA, similarly to the short-chain fatty acids (SCFA), possess antibacterial effects and may thereby prevent overgrowth of pathogenic bacteria in the gastrointestinal tract. The essential FA, linoleic (LA) and α-linolenic (ALA) FA, form the building blocks for the long-chain polyunsaturated n-3 and n-6 FA. The conversion of ALA and LA into n-3 and n-6 eicosanoids, respectively, influences the molecular structures of metabolites and inflammatory reactions and other immune responses upon bacterial challenges. Dietary manipulation of the lactating sow influences the transfer of the n-3 and n-6 polyunsaturated fatty acids (PUFA) from the sow milk to the piglet and the incorporation of the FA into piglet enteric tissues and cell membranes, which exerts bioactivity of importance for immune responses and the epithelial barrier function. Especially, the n-3 PUFA present in fish oil seem to influence the gut health and function of pigs, and this is of importance during the transition periods such as post-weaning in which piglets are prone to inflammation. The proportion of unsaturated FA in the cell membranes influences the susceptibility to oxidative stress. Oxidative stress accompanies infectious diseases, and the development of lipid peroxides and other reactive oxygen products may be harmful to the epithelial barrier function. Fatty acid peroxides from the feed may also be absorbed with other lipid-solubles and thereby harm the intestinal function. Hence, antioxidative protection is important for the enteric cells. In conclusion, manipulation of the dietary FA composition can influence the gut health and function in pigs and may support a normal immune system and modulate resistance to infectious diseases during especially stressful phases of a pig’s life such as post-weaning.

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A31 COMPLEX ROLE OF DIETARY FIBERS IN IBD: MICROBES MEDIATE FIBER-INDUCED INFLAMMATION

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.030 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 148-150

Author(s):

H Armstrong ◽

R Valcheva ◽

D Santer ◽

Z Zhang ◽

A Rieger ◽

...

Keyword(s):

Immune Responses ◽

Anaerobic Fermentation ◽

Ex Vivo ◽

Severe Disease ◽

Cytokine Secretion ◽

Dietary Fibers ◽

Gut Health ◽

T84 Cells ◽

Microbial Composition ◽

Barrier Integrity

Abstract Background Dietary fibers pass through the bowel undigested and are fermented within the intestine by microbes, typically promoting gut health. However, many IBD patients describe experiencing sensitivity to fibers. β-glucan, found on the surface of fungal cells during fungal infection, has been shown to bind to fiber receptors, such as Dectin-1, on host immune cells, resulting in a pro-inflammatory response. These fungal fibres share properties with dietary fibers. Aims As an altered gut microbial composition has been associated with IBD, we hypothesized that the loss of fiber-fermenting microbes populating the gut in IBD could lead to dietary fibers not being efficiently broken down into their beneficial biproducts (e.g. short chain fatty acids; SCFA), resulting in binding of intact fibers to pro-inflammatory host cell receptors. Methods Immune and epithelial cell lines and colonic biopsies cultured ex vivo were incubated with oligofructose or inulin (5g/L), or pre-fermented fibers (24hr anaerobic fermentation). Immune responses were measured by cytokine secretion (ELISA), and expression (qPCR). Barrier integrity was measured by transepithelial resistance (TEER). Food frequency questionnaire (FFQ) data of patient fiber consumption were correlated with gut microbes (shotgun sequencing) and immune responses to fiber in patient biopsies. Results Unfermented oligofructose induced IL-1β secretion in leukocytes (macrophage, T cell, neutrophil) and in colon biopsies from pediatric Crohn disease (CD; n=38) and ulcerative colitis (UC; n=20) patients cultured ex vivo, but not in non-IBD patients (n=21). IL-1β secretion was greater in patients with more severe disease. Pre-fermentation of oligofructose by whole-microbe intestinal washes from non-IBD patients or remission patients reduced secretion of IL-1β, while whole microbe intestinal washes from severe IBD patients were unable to ferment oligofructose or reduce cytokine secretion. Fiber effects on IL-1β secretion in biopsies positively correlated with effects on barrier integrity in T84 cells. Fiber-associated immune responses in patient biopsies cultured ex vivo (ELISA) correlated with fiber avoidance (FFQ) and gut microbiome (sequencing) in matching patient samples. Conclusions Our findings demonstrate that intolerance and avoidance of prebiotic fibers in select IBD patients is associated with the inability to ferment these fibers, leading to pro-inflammatory immune responses and intestinal barrier disruption. This highlights select disease state scenarios, in which administration of fermentable fibers should be avoided and tailored dietary interventions should be considered in IBD patients. Funding Agencies CIHRWeston Foundation

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A Novel Aminosaccharide Compound Blocks Immune Responses by Toll-like Receptors and Nucleotide-binding Domain, Leucine-rich Repeat Proteins

Journal of Biological Chemistry ◽

10.1074/jbc.m110.108001 ◽

2010 ◽

Vol 286 (7) ◽

pp. 5727-5735 ◽

Cited By ~ 8

Author(s):

Kyoung-Hee Lee ◽

Yuen-Joyce Liu ◽

Amlan Biswas ◽

Chikako Ogawa ◽

Koichi S. Kobayashi

Keyword(s):

Immune Responses ◽

Nucleotide Binding ◽

Binding Domain ◽

Leucine Rich Repeat ◽

Toll Like Receptors ◽

Nucleotide Binding Domain ◽

Repeat Proteins

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Immunity in human schistosomiasis mansoni: prevention by blocking antibodies of the expression of immunity in young children

Parasitology ◽

10.1017/s0031182000053956 ◽

1987 ◽

Vol 94 (2) ◽

pp. 281-300 ◽

Cited By ~ 98

Author(s):

A. E. Butterworth ◽

R. Bensted-Smith ◽

A. Capron ◽

M. Capron ◽

P. R. Dalton ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Young Children ◽

Immune Responses ◽

Blood Eosinophil ◽

Strongly Correlated ◽

Igg Antibodies ◽

Blood Samples ◽

Slow Development ◽

The Face ◽

Blocking Antibodies

SUMMARYA total of 129 children were treated forSchistosoma mansoniinfections, and followed for intensity of reinfection at3-monthly intervals over a 21-month period. Blood samples were taken before treatment and at 5 weeks and 6, 12 and 18 months after treatment. This paper presents a statistical analysis of the relationship between various immune responses and subsequent reinfection. Responses analysed were: blood eosinophil levels; IgE antibodies against schistosomulum antigens; IgG antibodies mediating eosinophil-dependent killing of schistosomula; antibodies inhibiting the binding to schistosomulum antigens of two rat monoclonal antibodies that also recognize egg antigens; the levels of anti-adult worm and of anti-egg (total, IgM and IgG) antibodies; and IgM anti-schistosomulum antibodies. Results for each assay were well correlated for each of the five separate blood samples. None of the assays were predictive of resistance to reinfection, butsusceptibilityto reinfection was strongly correlated with results in the preceding blood samples for total anti-egg antibodies and the inhibition of binding of one of the two monoclonal antibodies. Further analysis also revealed a correlation between reinfection intensities and both IgM anti-schistosomulum antibodies and IgM and IgG anti-egg antibodies. These results are consistent with the hypothesis that early infections elicit the development, in response to egg antigens, of antibodies that block immune mechanisms directed against schistosomula. Blocking antibodies may be IgM, but might also be of an ineffective IgG isotype. The existence of such antibodies in young children would explain the slow development of immunity in the face of a range of detectable, potentially protective immune responses.

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The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses in C. elegans

10.1101/2021.03.30.437693 ◽

2021 ◽

Author(s):

Bhoomi Madhu ◽

Tina L. Gumienny

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Signaling Pathway ◽

Defense Responses ◽

C Elegans ◽

Host Immune Responses ◽

Wide Range ◽

Independent Functions ◽

Multiple Cell

Innate immunity in animals is orchestrated by multiple cell signaling pathways, including the TGF-β; superfamily pathway. While the role of TGF-β signaling in innate immunity has been clearly identified, the requirement for this pathway in generating specific, robust responses to different bacterial challenges has not been characterized. Here, we address the role of DBL-1/TGF-β in regulating signature host defense responses to a wide range of bacteria in C. elegans. This work reveals a role of DBL-1/TGF-β in animal survival, organismal behaviors, and molecular responses in different environments. Additionally, we identify a novel role for SMA-4/Smad that suggests both DBL-1/TGF-β-dependent and -independent functions in host avoidance responses. RNA-seq analyses and immunity reporter studies indicate DBL-1/TGF-β differentially regulates target gene expression upon exposure to different bacteria. Furthermore, the DBL-1/TGF-β pathway is itself differentially affected by the bacteria exposure. Collectively, these findings demonstrate bacteria-specific host immune responses regulated by the DBL-1/TGF-β signaling pathway.

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On cell death in the intestinal epithelium and its impact on gut homeostasis

Current Opinion in Gastroenterology ◽

10.1097/mog.0000000000000481 ◽

2018 ◽

Vol 34 (6) ◽

pp. 413-419 ◽

Cited By ~ 9

Author(s):

J. Magarian Blander

Keyword(s):

Cell Death ◽

Intestinal Epithelium ◽

Gut Homeostasis

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A Comparative Overview of the Intracellular Guardians of Plants and Animals: NLRs in Innate Immunity and Beyond

Annual Review of Plant Biology ◽

10.1146/annurev-arplant-080620-104948 ◽

2021 ◽

Vol 72 (1) ◽

Author(s):

Zane Duxbury ◽

Chih-hang Wu ◽

Pingtao Ding

Keyword(s):

Immune Responses ◽

Genetic Architecture ◽

Pathogen Detection ◽

Current Knowledge ◽

Plant Immunity ◽

Innate Immune ◽

Plant Biology ◽

Annual Review ◽

Publication Date ◽

Nucleotide Binding Domain

Nucleotide-binding domain leucine-rich repeat receptors (NLRs) play important roles in the innate immune systems of both plants and animals. Recent breakthroughs in NLR biochemistry and biophysics have revolutionized our understanding of how NLR proteins function in plant immunity. In this review, we summarize the latest findings in plant NLR biology and draw direct comparisons to NLRs of animals. We discuss different mechanisms by which NLRs recognize their ligands in plants and animals. The discovery of plant NLR resistosomes that assemble in a comparable way to animal inflammasomes reinforces the striking similarities between the formation of plant and animal NLR complexes. Furthermore, we discuss the mechanisms by which plant NLRs mediate immune responses and draw comparisons to similar mechanisms identified in animals. Finally, we summarize the current knowledge of the complex genetic architecture formed by NLRs in plants and animals and the roles of NLRs beyond pathogen detection. Expected final online publication date for the Annual Review of Plant Biology, Volume 72 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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