Acute small intestinal inflammation results in persistent lymphatic alterations

Inflammatory bowel disease (IBD) has a complex pathophysiology with limited treatments. Structural and functional changes in the intestinal lymphatic system have been associated with the disease, with increased risk of IBD occurrence linked to a history of acute intestinal injury. To examine the potential role of the lymphatic system in inflammation recurrence, we evaluated morphological and functional changes in mouse mucosal and mesenteric lymphatic vessels, and within the mesenteric lymph nodes during acute ileitis caused by a 7-day treatment with dextran sodium sulfate (DSS). We monitored whether the changes persisted during a 14-day recovery period and determined their potential consequences on dendritic cell (DC) trafficking between the mucosa and lymphoid tissues. DSS administration was associated with marked lymphatic abnormalities and dysfunctions exemplified by lymphangiectasia and lymphangiogenesis in the ileal mucosa and mesentery, increased mesenteric lymphatic vessel leakage, and lymphadenopathy. Lymphangiogenesis and lymphadenopathy were still evident after recovery from intestinal inflammation and correlated with higher numbers of DCs in mucosal and lymphatic tissues. Specifically, a deficit in CD103+ DCs observed during acute DSS in the lamina propria was reversed and further enhanced during recovery. We concluded that an acute intestinal insult caused alterations of the mesenteric lymphatic system, including lymphangiogenesis, which persisted after resolution of inflammation. These morphological and functional changes could compromise DC function and movement, increasing susceptibility to further gastrointestinal disease. Elucidation of the changes in mesenteric and intestinal lymphatic function should offer key insights for new therapeutic strategies in gastrointestinal disorders such as IBD. NEW & NOTEWORTHY Lymphatic integrity plays a critical role in small intestinal homeostasis. Acute intestinal insult in a mouse model of acute ileitis causes morphological and functional changes in mesenteric and intestinal lymphatic vessels. While some of the changes significantly regressed during inflammation resolution, others persisted, including lymphangiogenesis and altered dendritic cell function and movement, potentially increasing susceptibility to the recurrence of gastrointestinal inflammation.

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Chylomicrons-Simulating Sustained Drug Release in Mesenteric Lymphatics for the Treatment of Crohn’s-Like Colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa200 ◽

2020 ◽

Author(s):

Yi Yin ◽

Jingjing Yang ◽

Yongchun Pan ◽

Zhen Guo ◽

Yanfeng Gao ◽

...

Keyword(s):

Drug Delivery ◽

Drug Release ◽

Drug Delivery System ◽

Delivery System ◽

Lymphatic System ◽

Intestinal Inflammation ◽

Lymphatic Vessels ◽

Experimental Colitis ◽

Therapeutic Effects ◽

Sustained Drug Release

Abstract Background and Aims Alteration to both the structures and functions of mesenteric lymphatic vessels is a typical hallmark of Crohn’s disease [CD]. Dysfunctional lymphatics was observed in patients with both CD and experimental colitis, suggesting mesenteric lymphatics could be potential therapeutic targets. This study aimed to develop a nano-delivery system which can enhance drug delivery in mesenteric lymphatic tissue [MLT] and evaluate the therapeutic effects in Crohn’s colitis. Methods We designed a mesoporous silica nanoparticle [MSN] conjugated with long-chain fatty acid [LMSN] and covered with enteric coating [ELMSN] which can be specifically transported via the mesenteric lymphatic system. The therapeutic efficacy of laquinimod-loaded nanoparticles [LAQ@ELMSN] was evaluated in the well-established interleukin [IL]-10−/− spontaneous experimental colitis. Results ELMSNs induced sustainable drug release that markedly increased drug concentration in MLT. In experimental colitis, the lymphatics-targeting drug delivery system suppressed lymphangitis and promoted lymphatic drainage. The downregulation of pro-inflammatory cytokines and the downstream NF-κB-related proteins efficiently inhibited lymphangiogenesis and restored tight junctions of mesenteric lymphatic vessels [MLVs]. LAQ@ELMSN showed a superior therapeutic effect in ameliorating intestinal inflammation compared with free drug administration. Alteration of gut microbiota and metabolites in experimental colitis was also reversed by LAQ@ELMSN. Conclusion Our study demonstrates a convenient, orally administered drug delivery system which enhances drug release in MLT. The results confirm the contribution of the mesenteric lymphatic system to the pathogenesis of gut inflammation and shed light on the application of lymphatics-targeting drug delivery therapy as a potential therapeutic strategy for CD treatment.

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Effect of human synovial fluid from osteoarthritis patients and healthy individuals on lymphatic contractility

10.1101/2020.12.02.408294 ◽

2020 ◽

Author(s):

Eleftheria Michalaki ◽

Zhanna Nepiyushchikh ◽

Fabrice C. Bernard ◽

Josephine M. Rudd ◽

Anish Mukherjee ◽

...

Keyword(s):

Synovial Fluid ◽

Lymphatic System ◽

Treatment Time ◽

Ex Vivo ◽

Critical Role ◽

Lymphatic Vessels ◽

Healthy Individuals ◽

Arthritic Joints ◽

Lymphatic Contractility

AbstractThe lymphatic system has been proposed to play a crucial role in the development and progression of osteoarthritis (OA). The synovial fluid (SF) of arthritic joints contains mediators of the inflammatory response and products of the injury to articular tissues, while lymphatic system plays a critical role in resolving inflammation and overall joint homeostasis. Despite the importance of both the lymphatic system and SF in OA disease, their relationship is still poorly understood. Here, we utilized SF derived from osteoarthritis patients (OASF) and healthy individuals (HSF) to investigate potential effects of SF on migration of lymphatic endothelial cells (LECs) in vitro, and lymphatic contractility of femoral lymphatic vessels (LVs) ex vivo. Both OASF and HSF treatments led to an increased migratory response in vitro compared to LECs treatment with media without serum. Ex vivo, both OASF and HSF treatments to the lumen of isolated LVs led to significant differences in the tonic and phasic contractions and these observations were dependent on the SF treatment time. Specifically, OASF treatment transiently enhanced the RFLVs tonic contractions. Regarding the phasic contractions, OASF generated either an abrupt reduction after 1 hr of treatment or a complete cease of contractions after an overnight treatment, while HSF treatment displayed a gradual decrease in lymphatic contractility. The observed variations after SF treatments suggest that the pump function of lymphatic vessel draining the joint could be directly compromised in OA and thus might present a new therapeutic target.

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Selective Generation of Gut Tropic T Cells in Gut-associated Lymphoid Tissue (GALT)

Journal of Experimental Medicine ◽

10.1084/jem.20031244 ◽

2003 ◽

Vol 198 (6) ◽

pp. 963-969 ◽

Cited By ~ 336

Author(s):

Bengt Johansson-Lindbom ◽

Marcus Svensson ◽

Marc-André Wurbel ◽

Bernard Malissen ◽

Gabriel Márquez ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Intestinal Epithelium ◽

Critical Role ◽

Lymphoid Tissues ◽

Transfer Model ◽

Small Intestinal Epithelium ◽

Selective Generation ◽

Small Intestinal

In the current study, we address the underlying mechanism for the selective generation of gut-homing T cells in the gut-associated lymphoid tissues (GALT). We demonstrate that DCs in the GALT are unique in their capacity to establish T cell gut tropism but in vivo only confer this property to T cells in the presence of DC maturational stimuli, including toll-like receptor-dependent and -independent adjuvants. Thus, DCs from mesenteric LNs (MLNs), but not from spleen, supported expression of the chemokine receptor CCR9 and integrin α4β7 by activated CD8+ T cells. While DCs were also required for an efficient down-regulation of CD62L, this function was not restricted to MLN DCs. In an adoptive CD8+ T cell transfer model, antigen-specific T cells entering the small intestinal epithelium were homogeneously CCR9+α4β7+CD62Llow, and this phenotype was only generated in GALT and in the presence of adjuvant. Consistent with the CCR9+ phenotype of the gut-homing T cells, CCR9 was found to play a critical role in the localization of T cells to the small intestinal epithelium. Together, these results demonstrate that GALT DCs and T cell expression of CCR9 play critical and integrated roles during T cell homing to the gut.

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Type 1 diabetes in pregnancy is associated with distinct changes in the composition and function of the gut microbiome

Microbiome ◽

10.1186/s40168-021-01104-y ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Alexandra J. Roth-Schulze ◽

Megan A. S. Penno ◽

Katrina M. Ngui ◽

Helena Oakey ◽

Esther Bandala-Sanchez ◽

...

Keyword(s):

Type 1 Diabetes ◽

Gut Microbiome ◽

Intestinal Inflammation ◽

Physiological Adaptation ◽

Fatty Acid Binding ◽

Functional Changes ◽

Increased Risk ◽

And Function ◽

In Pregnancy

Abstract Background The gut microbiome changes in response to a range of environmental conditions, life events and disease states. Pregnancy is a natural life event that involves major physiological adaptation yet studies of the microbiome in pregnancy are limited and their findings inconsistent. Pregnancy with type 1 diabetes (T1D) is associated with increased maternal and fetal risks but the gut microbiome in this context has not been characterized. By whole metagenome sequencing (WMS), we defined the taxonomic composition and function of the gut bacterial microbiome across 70 pregnancies, 36 in women with T1D. Results Women with and without T1D exhibited compositional and functional changes in the gut microbiome across pregnancy. Profiles in women with T1D were distinct, with an increase in bacteria that produce lipopolysaccharides and a decrease in those that produce short-chain fatty acids, especially in the third trimester. In addition, women with T1D had elevated concentrations of fecal calprotectin, a marker of intestinal inflammation, and serum intestinal fatty acid-binding protein (I-FABP), a marker of intestinal epithelial damage. Conclusions Women with T1D exhibit a shift towards a more pro-inflammatory gut microbiome during pregnancy, associated with evidence of intestinal inflammation. These changes could contribute to the increased risk of pregnancy complications in women with T1D and are potentially modifiable by dietary means.

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Dichotomous roles of neutrophils in modulating pathogenic and repair processes of inflammatory bowel diseases

Precision Clinical Medicine ◽

10.1093/pcmedi/pbab025 ◽

2021 ◽

Author(s):

Huimin Chen ◽

Xiaohan Wu ◽

Chunjin Xu ◽

Jian Lin ◽

Zhanju Liu

Keyword(s):

Immune Cells ◽

Inflammatory Bowel Diseases ◽

Intestinal Inflammation ◽

Critical Role ◽

Mucosal Inflammation ◽

Repair Processes ◽

Microbial Invasion ◽

Increased Risk ◽

Bowel Diseases ◽

Inflammatory Bowel

Abstract Neutrophils are considered as complex innate immune cells and play a critical role in maintaining intestinal mucosal homeostasis. They exert robust pro-inflammatory effects and recruit other immune cells in the acute phase of pathogen infection and intestinal inflammation, but paradoxically, they also limit exogenous microbial invasion and facilitate mucosal restoration. Hyperactivation or dysfunction of neutrophils results in abnormal immune responses, leading to multiple autoimmune and inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases (IBD). As a refractory intestinal inflammatory disease, the pathogenesis and progression of IBD are associated with complicated immune response processes in which neutrophils are profoundly involved. However, the consensus on potential roles of neutrophils in modulating pathogenic and repair processes of IBD remains not fully understood. Accumulated infiltrating neutrophils cross the epithelial barrier and contribute to microbial dysbiosis, aggravated intestinal architectural damage, compromised resolution of intestinal inflammation and increased risk of thrombosis during IBD. Paradoxically, activated neutrophils are also associated with effective elimination of invaded microbiota, promoted angiogenesis and tissue restoration of gut mucosa in IBD. Here, we discuss the beneficial and detrimental roles of neutrophils in the onset and resolution of intestinal mucosal inflammation and provide a precise overview of neutrophil functions in the pathogenesis of IBD.

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Type 1 Diabetes in Pregnancy Is Associated With Distinct Changes in the Composition and Function of the Gut Microbiome

10.21203/rs.3.rs-376289/v1 ◽

2021 ◽

Author(s):

Alexandra J. Roth-Schulze ◽

Megan A. S. Penno ◽

Katrina M. Ngui ◽

Helena Oakey ◽

Esther Bandala-Sanchez ◽

...

Keyword(s):

Type 1 Diabetes ◽

Gut Microbiome ◽

Intestinal Inflammation ◽

Physiological Adaptation ◽

Fatty Acid Binding ◽

Functional Changes ◽

Increased Risk ◽

And Function ◽

In Pregnancy

Abstract BackgroundThe gut microbiome changes in response to a range of environmental conditions, life events and disease states. Pregnancy is a natural life event that involves major physiological adaptation yet studies of the microbiome in pregnancy are limited and their findings inconsistent. Pregnancy with type 1 diabetes (T1D) is associated with increased maternal and fetal risks but the gut microbiome in this context has not been characterized. By whole metagenome sequencing (WMS) we defined the taxonomic composition and function of the gut bacterial microbiome across 70 pregnancies, 36 in women with T1D. ResultsWomen with and without T1D exhibited compositional and functional changes in the gut microbiome across pregnancy. Profiles in women with T1D were distinct, with an increase in bacteria that produce lipopolysaccharides and a decrease in those that produce short chain fatty acids, especially in the third trimester. In addition, women with T1D had elevated concentrations of fecal calprotectin, a marker of intestinal inflammation, and serum intestinal fatty acid-binding protein (I-FABP), a marker of intestinal epithelial damage.ConclusionsWomen with T1D exhibit a shift towards a more pro-inflammatory gut microbiome during pregnancy, associated with evidence of intestinal inflammation. These changes could contribute to the increased risk of pregnancy complications in women with T1D and are potentially modifiable by dietary means.

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The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6

Gut ◽

10.1136/gut.2009.183772 ◽

2009 ◽

Vol 59 (2) ◽

pp. 197-206 ◽

Cited By ~ 106

Author(s):

Stefania Vetrano ◽

Elena M Borroni ◽

Adelaida Sarukhan ◽

Benedetta Savino ◽

Raffaella Bonecchi ◽

...

Keyword(s):

Colon Cancer ◽

Lymphatic System ◽

Intestinal Inflammation ◽

Lymphatic Vessels ◽

Experimental Colitis ◽

Distal Segment ◽

Wild Type ◽

Decoy Receptor ◽

Inflammatory Chemokines ◽

Cc Chemokines

Background and aimsInflammatory CC chemokines have long been associated with cancer, but unequivocal evidence of a role in clinically relevant models of carcinogenesis is lacking. D6, a promiscuous decoy receptor that scavenges inflammatory CC chemokines, plays a non-redundant role in reducing the inflammatory response in various organs. As inflammation is a key player in the development of inflammatory bowel disease (IBD) and IBD-associated colorectal cancer, we investigated D6 expression in human colitis and colon cancer, and its role in experimental colitis and inflammation-associated colon cancer.ResultsIn humans, D6 was mainly expressed by lymphatic vessels and leukocytes in the mucosa of individuals with IBD and colon cancer, as well as the mucosa of control individuals. Mice lacking expression of D6 were significantly more susceptible to experimental colitis than wild-type mice and failed to resolve colitis, with significantly higher levels of several pro-inflammatory chemokines. In bone marrow chimeric mice, the ability of D6 to regulate colitis was tracked to the stromal/lymphatic compartment, with no contribution of haemopoietic cells. Finally, after administration of the carcinogen azoxymethane, D6−/− mice showed increased susceptibility to colitis-associated cancer in the distal segment of the colon compared with wild-type mice.ConclusionsD6 expressed on lymphatic vessels plays a key role in the control of intestinal inflammation and the development of inflammation-associated colon cancer. Our results reveal a new unexpected role for the lymphatic system in the pathogenesis of IBD and intestinal cancer, and candidate chemokines as novel players in tumour promotion and progression.

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Infrared fluorescence lymphography in experimental and clinical practice

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2018-17-2-84-91 ◽

2018 ◽

Vol 17 (2) ◽

pp. 84-91 ◽

Cited By ~ 1

Author(s):

G. V. Papayan ◽

A. L. Akopov ◽

P. A. Antonyan ◽

A. A. Ilin ◽

N. N. Petrishchev

Keyword(s):

Lymph Nodes ◽

Near Infrared ◽

Lymphatic System ◽

Lymphatic Vessels ◽

Diagnostic System ◽

Biological Tissues ◽

Peritumoral Injection ◽

Intradermal Administration ◽

Nir Fluorescence ◽

Real Time Visualization

Introduction. Near infrared (NIR) fluorescent diagnostics is promising due to a deeper penetration into biological tissues. Material and methods. In experiments on rabbits and in clinical studies evaluation the lymphatic system with the use of the instrument complex FLUM-808 was analysed. Results. For visualization of the lymphatic vessels of the skin, the intradermal administration of ICG, dissolved in 20 % albumin in the order of 0.02 mg/ml, is optimal. Peritumoral injection of ICG allows visualizing sentinel lymph nodes in patients with lung cancer. Conclusions. The developed NIR fluorescence diagnostic system FLUM-808 allows to real time visualization of lymphatic vessels and lymph nodes.

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