Sequential Changes in the Mesenteric Lymph Node Microbiome and Immune Response during Cirrhosis Induction in Rats

ABSTRACT Whether the interaction between the gut microbiota and the immune response influences the evolution of cirrhosis is poorly understood. We aimed to investigate modifications of the microbiome and the immune response during the progression of cirrhosis. Rats were treated with carbon tetrachloride (CCl4) to induce cirrhosis. We then assessed microbiome load and composition in stool, ileocecal contents (ICCs), mesenteric lymph nodes (MLNs), blood, and ascitic fluids (AFs) at 6, 8, and 10 weeks or ascites production and measured cytokine production in MLNs and blood. The microbiome of MLN, blood, and AF showed a distinct composition compared to that of stool and ICCs. Betaproteobacteria (Sutterella) were found associated with the appearance of a decompensated state of cirrhosis. Microbial load increased and showed a positive correlation with the relative abundance of pathobionts in the MLN of decompensated rats. Among several genera, Escherichia and “Candidatus Arthromitus” positively correlated with elevated levels of systemic proinflammatory cytokines. “Candidatus Arthromitus,” a segmented filamentous bacteria, was detected in ICC, MLN, and AF samples, suggesting a possible translocation from the gut to the AF through the lymphatic system, whereas Escherichia was detected in ICC, MLN, AF, and blood, suggesting a possible translocation from the gut to the AF through the bloodstream. In the present study, we demonstrate that microbiome changes in distinct intestinal sites are associated with microbial shifts in the MLNs as well as an increase in cytokine production, providing further evidence of the role the gut-liver-immunity axis plays in the progression of cirrhosis. IMPORTANCE Cirrhosis severity in patients was previously shown to be associated with progressive changes in the fecal microbiome in a longitudinal setting. Recent evidence shows that bacterial translocation from the gut to the extraintestinal sites could play a major role in poor disease outcome and patient survival. However, the underlying mechanisms involving the microbiota in the disease progression are not well understood. Here, using an animal model of cirrhosis in a longitudinal and multibody sites setting, we showed the presence of a distinct composition of the microbiome in mesenteric lymph nodes, blood, and ascitic fluid compared to that in feces and ileocecal content, suggesting compartmentalization of the gut microbiome. We also demonstrate that microbiome changes in intestinal sites are associated with shifts in specific microbial groups in the mesenteric lymph nodes as well as an increase in systemic cytokine production, linking inflammation to decompensated cirrhosis in the gut-liver-immunity axis.

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Inflammatory Mediators in the Mesenteric Lymph Nodes, Site of a Possible Intermediate Phase in the Immune Response to Feline Coronavirus and the Pathogenesis of Feline Infectious Peritonitis?

Journal of Comparative Pathology ◽

10.1016/j.jcpa.2018.11.001 ◽

2019 ◽

Vol 166 ◽

pp. 69-86 ◽

Cited By ~ 12

Author(s):

A.J. Malbon ◽

M.L. Meli ◽

E.N. Barker ◽

A.D. Davidson ◽

S. Tasker ◽

...

Keyword(s):

Immune Response ◽

Lymph Nodes ◽

Inflammatory Mediators ◽

Intermediate Phase ◽

Mesenteric Lymph Nodes ◽

Feline Infectious Peritonitis ◽

Mesenteric Lymph ◽

Feline Coronavirus

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Selenization of S. cerevisiae increases its protective potential in experimental autoimmune encephalomyelitis by triggering an intestinal immunomodulatory loop

Scientific Reports ◽

10.1038/s41598-020-79102-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Thais Fernanda de Campos Fraga-Silva ◽

Luiza Ayumi Nishiyama Mimura ◽

Larissa Ragozo Cardoso de Oliveira ◽

Juliana Helena dos Santos Toledo ◽

Patrícia Aparecida Borim ◽

...

Keyword(s):

Immune Response ◽

Experimental Autoimmune Encephalomyelitis ◽

Lymph Nodes ◽

Therapeutic Potential ◽

Clinical Signs ◽

Mesenteric Lymph Nodes ◽

Autoimmune Encephalomyelitis ◽

Complementary Medicines ◽

Mesenteric Lymph ◽

Experimental Autoimmune

AbstractMultiple sclerosis is an autoimmune disease that affects the myelinated central nervous system (CNS) neurons and triggers physical and cognitive disabilities. Conventional therapy is based on disease-modifying drugs that control disease severity but can also be deleterious. Complementary medicines have been adopted and evidence indicates that yeast supplements can improve symptoms mainly by modulating the immune response. In this investigation, we evaluated the therapeutic potential of Saccharomyces cerevisiae and its selenized derivative (Selemax) in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice submitted to EAE induction were orally supplemented with these yeasts by gavage from day 0 to day 14 after EAE induction. Both supplements determined significant reduction in clinical signs concomitantly with diminished Th1 immune response in CNS, increased proportion of Foxp3+ lymphocytes in inguinal and mesenteric lymph nodes and increased microbiota diversity. However, Selemax was more effective clinically and immunologically; it reduced disease prevalence more sharply, increased the proportion of CD103+ dendritic cells expressing high levels of PD-L1 in mesenteric lymph nodes and reduced the intestinal inflammatory process more strongly than S. cerevisiae. These results suggest a clear gut-brain axis modulation by selenized S. cerevisiae and suggest their inclusion in clinical trials.

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THE PRIMARY IMMUNE RESPONSE IN MICE

Journal of Experimental Medicine ◽

10.1084/jem.127.6.1109 ◽

1968 ◽

Vol 127 (6) ◽

pp. 1109-1126 ◽

Cited By ~ 13

Author(s):

Philip D. McMaster ◽

Robert E. Franzl

Keyword(s):

Immune Response ◽

Lymph Nodes ◽

Red Blood Cells ◽

Blood Cells ◽

Primary Immune Response ◽

Polymorphonuclear Cells ◽

Mesenteric Lymph Nodes ◽

Sheep Red Blood Cells ◽

Cellular Changes ◽

Mesenteric Lymph

The effects of a single injection of a bacterial endotoxin on the cellular changes of a primary immune response to a standard dose of sheep red blood cells were studied in the spleens and mesenteric lymph nodes of mice. Daily histological comparisons of these organs in mice, injected with endotoxin, or with antigen, or both, showed that endotoxin given simultaneously with sheep red blood cells, as antigen, significantly enhanced all of the cellular changes that appear in the mesenteric lymph nodes and spleens of mice that form antibody when that antigen is given alone. First, in the white pulp of the spleens and cortical regions of the nodes, there appeared an early and excessive proliferation of the large pyroninophilic cells which seems to be responsible for the earliest formation of antibody, as judged by this work and that of others cited in the body of the paper. Polymorphonuclear cells invaded the spleens of these animals early after simultaneous challenge with antigen and endotoxin, and in far greater numbers than have ever been seen in mice given the same antigen without endotoxin. "Activated" germinal centers formed in the lymphoid tissue either 1 day before the appearance of antibody in the blood stream or on the same day, and they became larger than in the mice given antigen only. On the other hand, these specific and characteristic cellular changes failed to appear in mice prevented from forming any antibody at all by injections of endotoxin given 2 days before the antigenic challenge. These findings are discussed in the light provided by data from recent reports of others as well as in the light of the accompanying paper (1) which demonstrated not only the enhancement of antibody formation following simultaneous injections of antigen and endotoxin, as already known, but a totally unexpected, complete suppression of its formation when endotoxin was given 2 days before antigen.

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Relationship between lymph concentration of cytokines and structural transformations in mesenteric lymph nodes in chemotherapy, surgical treatment, and chemotherapy of experimental breast cancer

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2020.02.37-45 ◽

2020 ◽

pp. 37-45

Author(s):

О.В. Казаков ◽

А.Ф. Повещенко ◽

Н.Б. Орлов ◽

Т.В. Райтер ◽

О.В. Повещенко ◽

...

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Surgical Treatment ◽

Lymph Nodes ◽

Thoracic Duct ◽

Plasma Cells ◽

Local Immune Response ◽

Mesenteric Lymph Nodes ◽

Mesenteric Lymph ◽

Medullary Cords

Цель исследования - анализ корреляции морфометрии брыжеечных лимфатических узлов и концентрации цитокинов в лимфе грудного протока при химиотерапии рака молочной железы, хирургическом лечении и последующей химиотерапии. Методика. Рак молочной железы индуцировали введением N-метил-N-нитрозомочевины 5 раз с интервалом 7 сут подкожно в область 2-й молочной железы справа. Курс химиотерапии проходил по схеме CMF. Корреляцию между концентрациями 24 цитокинов лимфы и числом клеток структурных зон лимфатических узлов оценивали по коэффициенту ранговой корреляции Спирмена. Результаты. После химиотерапии РМЖ, по сравнению с РМЖ без лечения, морфологические преобразования в лимфатических узлах свидетельствуют о снижении активности местного иммунного ответа. Исследование корреляции концентрации цитокинов в лимфе со структурными изменениями в лимфатических узлах выявило зависимости направленные на повышение иммуномодулирующего и противоопухолевого действия цитокинов. После оперативного лечения РМЖ и последующей химиотерапии, по сравнению только с химиотерапией РМЖ, выявлены положительные связи иммунобластов с цитокином GRO/KC в герминативных центрах, цитокина IL-6 - с митотически делящимися клетками в герминативных центрах и мозговых тяжах, IL-5 - с иммунобластами в мозговых тяжах, хемокина MIP-1a - со зрелыми плазматическими клетками в мозговых синусах. Увеличено количество иммунобластов, средних и малых лимфоцитов в герминативных центрах, возросло количество малых лимфоцитов, незрелых и зрелых плазматических клеток в мозговых синусах. Увеличены площади мозговых тяжей и паракортикальной зоны. Выявлена корреляция: цитокина IL-1α с малыми лимфоцитами, IL-6 с иммунобластами, IL-7 и IL-18 - со средними лимфоцитами, GRO/KC - с иммунобластами, IL-17 - с макрофагами в Т-зависимой зоне; IL-7 и IL-18 - с иммунобластами, IL-12 - с макрофагами, MIP-1a и MCP-1 со зрелыми плазматическими клетками в мозговых синусах. Заключение. После оперативного лечения РМЖ c последующей химиотерапией, по сравнению только с химиотерапией РМЖ, выявлены взаимозависимости концентрации цитокинов в лимфе грудного протока с морфологическими изменениями в брыжеечных лимфатических узлах, которые могут указывать на повышение активности местного звена иммунного ответа. The aim of this study was to analyze correlations of the morphometry of mesenteric lymph nodes with cytokine concentrations in thoracic duct lymph in chemotherapy and surgical treatment with subsequent chemotherapy of breast cancer. Methods. Breast cancer was induced by subcutaneous injection of N-methyl-N-nitrosourea 5 times with 7-day intervals, into the region of the 2nd breast on the right. The course of chemotherapy was performed according to the CMF scheme. Correlations between concentrations of 24 cytokines of the lymph and cells of lymph node structural regions were estimated by the Spearman rank correlation coefficient. Results. After chemotherapy for breast cancer compared to untreated breast cancer, morphological transformations in lymph nodes indicated decreased activity of the local immune response. Analysis of correlations between lymph concentrations of cytokines and structural changes in lymph nodes identified relationships aimed at increasing the immunomodulatory and antitumor effects of cytokines. After surgical treatment of breast cancer and subsequent chemotherapy compared to chemotherapy alone, positive correlations were found for immunoblasts with cytokine GRO/KC in germinative centers, for cytokine IL-6 with mitotically dividing cells in germinative centers and medullary cords, for IL-5 with immunoblasts in medullary cords, and for chemokine MIP-1a with mature plasma cells in medullary sinuses. Numbers of immunoblasts and medium and small lymphocytes were increased in germinative centers whereas numbers of small lymphocytes and immature and mature plasma cells were increased in medullary sinuses. Areas of medullary cords and the paracortical zone were increased. Correlations were found for cytokine IL-1α with small lymphocytes, for IL-6 with immunoblasts, for IL-7 and IL-18 with medium lymphocytes, for GRO/KC with immunoblasts, for IL-17 with macrophages in the T-dependent zone, for IL-7 and IL-18 with immunoblasts, for IL-12 with macrophages, and for MIP-1a and MCP-1 with mature plasma cells in medullary sinuses. Conclusion. After surgical treatment of breast cancer and subsequent chemotherapy compared to chemotherapy alone, cytokine concentrations in lymph of the thoracic duct were observed to correlate with morphological changes in mesenteric lymph nodes, which may indicate increased activity of the local immune response.

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The Efect of Probiotic Lactobacilli and Alginite on the Cellular Immune Response in Salmonella Infected Mice

Folia Veterinaria ◽

10.1515/fv-2017-0020 ◽

2017 ◽

Vol 61 (2) ◽

pp. 61-66

Author(s):

K. Hlubeňová ◽

D. Mudroňová ◽

R. Nemcová ◽

S. Gancarčíková ◽

M. Maďar ◽

...

Keyword(s):

Immune Response ◽

Lymph Nodes ◽

Cellular Immune Response ◽

Lactobacillus Reuteri ◽

Biological Effects ◽

Phagocytic Index ◽

Mesenteric Lymph Nodes ◽

Mesenteric Lymph ◽

Probiotic Lactobacilli ◽

Cellular Immune

Abstract Alginite is organic matter rich in humic substances and commonly found in nature, but despite that, the knowledge of its biological effects is limited. In our study we focused on monitoring the effects of alginite alone, as well as its effect as a carrier of probiotic lactobacilli on the cellular immune response in SPF mice after infection with Salmonella Typhimurium. Sixty six conventional SPF female mice of the Balb/c line were divided into 4 groups: 1. infection free negative control (NK) supplied neither alginite nor probiotic lactobacilli in the feed; 2. infection free alginite control (Alg) supplied feed with 10 % alginite; infected control supplied alginite in the feed but no lactobacilli; 3. infectious control (Alg + Sal) - animals infected with salmonella and supplied 10 % alginite in the feed but no lactobacilli;and 4. probiotic group (Lab + Alg + Sal) - animals infected with salmonella and administered 10 % alginite and Lactobacillus reuteri 2/6 in the feed. On day 21 of the experiments, the mice were bled and their mesenteric lymph nodes were taken after their death. The peripheral blood of the mice was analysed for the activity of phagocytes and the percentage of selected lymphocyte subpopulations was determined in the mesenteric lymph nodes and blood. The significantly highest phagocytic activity (FA) was noted in the infected group with alginite (Alg + Sal). The FA was significantly increased in groups Alg and Lab + Alg + Sal in comparison with the NK group. The highest engulfing ability of phagocytes (phagocytic index) was observed in the Lab + Alg + Sal group in comparison with other groups, but also in Alg group in comparison with NK. In the Lab + Alg + Sal group, we observed a significantly higher percentage of B-lymphocytes, CD4+CD8+ and natural killer T cells (NKT), but more significant impact on the numbers of subpopulations of lymphocytes was observed in the mesenteric lymph nodes, with the significantly highest proportions of CD4+CD8+lymphocytes and NK and NKT cells. Our results indicated immunomodulatory properties of alginite and L. reuteri 2/6 in salmonella infected mice, especially at the level of the innate immune system components. This activation of phagocytosis and NK cells can be used in the treatment of various infections.

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Dysregulated Immune Response in Mesenteric Lymph Nodes of Crohnʼs Disease

The American Journal of Gastroenterology ◽

10.14309/00000434-200509001-00873 ◽

2005 ◽

Vol 100 ◽

pp. S321

Author(s):

Toshiro Sato ◽

Atsushi Sakuraba ◽

Nagamu Inoue ◽

Toshifumi Hibi

Keyword(s):

Immune Response ◽

Lymph Nodes ◽

Mesenteric Lymph Nodes ◽

Mesenteric Lymph

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Social-Stress-Responsive Microbiota Induces Stimulation of Self-Reactive Effector T Helper Cells

mSystems ◽

10.1128/msystems.00292-18 ◽

2019 ◽

Vol 4 (4) ◽

Cited By ~ 9

Author(s):

Michal Werbner ◽

Yiftah Barsheshet ◽

Nir Werbner ◽

Mor Zigdon ◽

Itamar Averbuch ◽

...

Keyword(s):

Immune Response ◽

Lymph Nodes ◽

Social Stress ◽

Stressful Life Events ◽

T Helper ◽

Mesenteric Lymph Nodes ◽

Microbial Composition ◽

Bacterial Communication ◽

Mesenteric Lymph ◽

Stimulation Of

How do stressful life events increase the risk for autoimmune disorders? Here we show that chronic social stress in mice promotes the expression of virulent genes in the gut microbiota and alters the microbial translocation into the mesenteric lymph nodes. Our results also suggest that the consequent immune response to the stress-affected microbiota may endanger the tolerance for self. The presence of specific translocated bacteria and the immune response in the mesenteric lymph nodes can be diminished using an inhibitor of the bacterial communication system without drastically affecting the gut microbial composition as antibiotics do.

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