Lactobacillus rhamnosus HDB1258 modulates gut microbiota-mediated immune response in mice with or without lipopolysaccharide-induced systemic inflammation

Abstract Background Gut microbiota closely communicate in the immune system to maintain a balanced immune homeostasis in the gastrointestinal tract of the host. Oral administration of probiotics modulates gut microbiota composition. In the present study, we isolated Lactobacillus rhamnosus HDB1258, which induced tumor necrosis factor (TNF)-α and interleukin (IL)-10 expression in macrophages, from the feces of breastfeeding infants and examined how HDB1258 could regulate the homeostatic immune response in mice with or without lipopolysaccharide (LPS)-induced systemic inflammation. Results Oral administration of HDB1258 significantly increased splenic NK cell cytotoxicity, peritoneal macrophage phagocytosis, splenic and colonic TNF-α expression, TNF-α to IL-10 expression ratio, and fecal IgA level in control mice, while Th1 and Treg cell differentiation was not affected in the spleen. However, HDB1258 treatment significantly suppressed peritoneal macrophage phagocytosis and blood prostaglandin E2 level in mice with LPS-induced systemic inflammation. Its treatment increased LPS-suppressed ratios of Treg to Th1 cell population, Foxp3 to T-bet expression, and IL-10 to TNF-α expression. Oral administration of HDB1258 significantly decreased LPS-induced colon shortening, myeloperoxidase activity and NF-κB+/CD11c+ cell population in the colon, while the ratio of IL-10 to TNF-α expression increased. Moreover, HDB1258 treatment shifted gut microbiota composition in mice with and without LPS-induced systemic inflammation: it increased the Cyanobacteria and PAC000664_g (belonging to Bacteroidetes) populations and reduced Deferribacteres and EU622763_s group (belonging to Bacteroidetes) populations. In particular, PAC001066_g and PAC001072_s populations were negatively correlated with the ratio of IL-10 to TNF-α expression in the colon, while the PAC001070_s group population was positively correlated. Conclusions Oral administered HDB1258 may enhance the immune response by activating innate immunity including to macrophage phagocytosis and NK cell cytotoxicity in the healthy host and suppress systemic inflammation in the host with inflammation by the modulation of gut microbiota and IL-10 to TNF-α expression ratio in immune cells. Keywords: Lactobacillus rhamnosus HDB1258; immunomodulation; immune enhancement; inflammation; gut microbiota.

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Hepatic DR5 Induces Apoptosis and Limits Adenovirus Gene Therapy Product Expression in the Liver

Journal of Virology ◽

10.1128/jvi.76.11.5692-5700.2002 ◽

2002 ◽

Vol 76 (11) ◽

pp. 5692-5700 ◽

Cited By ~ 28

Author(s):

Huang-Ge Zhang ◽

Jinfu Xie ◽

Liang Xu ◽

Pingar Yang ◽

Xin Xu ◽

...

Keyword(s):

Gene Therapy ◽

Immune Response ◽

Transgene Expression ◽

Cell Activation ◽

Nk Cell ◽

Death Domain ◽

Activated T Cells ◽

Tnf Α ◽

Product Expression ◽

Ifn Γ

ABSTRACT A major limitation of adenovirus (Ad) gene therapy product expression in the liver is subsequent elimination of the hepatocytes expressing the gene therapy product. This elimination is caused by both necrosis and apoptosis related to the innate and cell-mediated immune response to the Ad. Apoptosis of hepatocytes can be induced by the innate immune response by signaling through death domain receptors on hepatocytes including the tumor necrosis factor alpha (TNF-α) receptor (TNFR), Fas, and death domain receptors DR4 and DR5. We have previously shown that blocking signaling through TNFR enhances and prolongs gene therapy product expression in the liver. In the present study, we constructed an Ad that produces a soluble DR5-Fc (AdsDR5), which is capable of neutralizing TNF-related apoptosis-inducing ligand (TRAIL). AdsDR5 prevents TRAIL-mediated apoptosis of CD3-activated T cells and decreases hepatocyte apoptosis after AdCMVLacZ administration and enhances the level and duration of lacZ transgene expression in the liver. In addition to blocking TRAIL and directly inhibiting apoptosis, AdsDR5 decreases production of gamma interferon (IFN-γ) and TNF-α and decreases NK cell activation, all of which limit Ad-mediated transgene expression in the liver. These results indicate that (i) AdsDR5 produces a DR5-Fc capable of neutralizing TRAIL, (ii) AdsDR5 can reduce activation of NK cells and reduce induction of IFN-γ and TNF-α after Ad administration, and (iii) administration of AdsDR5 can enhance Ad gene therapy in the liver.

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CD69 Targeting Enhances Anti-vaccinia Virus Immunity

Journal of Virology ◽

10.1128/jvi.00553-19 ◽

2019 ◽

Vol 93 (19) ◽

Cited By ~ 2

Author(s):

Laura Notario ◽

Jennifer Redondo-Antón ◽

Elisenda Alari-Pahissa ◽

Almudena Albentosa ◽

Magdalena Leiva ◽

...

Keyword(s):

Immune Response ◽

Viral Infection ◽

Vaccinia Virus ◽

Immune Cells ◽

Nk Cell ◽

Mtor Signaling ◽

Cell Reactivity ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha

ABSTRACT CD69 is highly expressed on the leukocyte surface upon viral infection, and its regulatory role in the vaccinia virus (VACV) immune response has been recently demonstrated using CD69−/− mice. Here, we show augmented control of VACV infection using the anti-human CD69 monoclonal antibody (MAb) 2.8 as both preventive and therapeutic treatment for mice expressing human CD69. This control was related to increased natural killer (NK) cell reactivity and increased numbers of cytokine-producing T and NK cells in the periphery. Moreover, similarly increased immunity and protection against VACV were reproduced over both long and short periods in anti-mouse CD69 MAb 2.2-treated immunocompetent wild-type (WT) mice and immunodeficient Rag2−/− CD69+/+ mice. This result was not due to synergy between infection and anti-CD69 treatment since, in the absence of infection, anti-human CD69 targeting induced immune activation, which was characterized by mobilization, proliferation, and enhanced survival of immune cells as well as marked production of several innate proinflammatory cytokines by immune cells. Additionally, we showed that the rapid leukocyte effect induced by anti-CD69 MAb treatment was dependent on mTOR signaling. These properties suggest the potential of CD69-targeted therapy as an antiviral adjuvant to prevent derived infections. IMPORTANCE In this study, we demonstrate the influence of human and mouse anti-CD69 therapies on the immune response to VACV infection. We report that targeting CD69 increases the leukocyte numbers in the secondary lymphoid organs during infection and improves the capacity to clear the viral infection. Targeting CD69 increases the numbers of gamma interferon (IFN-γ)- and tumor necrosis factor alpha (TNF-α)-producing NK and T cells. In mice expressing human CD69, treatment with an anti-CD69 MAb produces increases in cytokine production, survival, and proliferation mediated in part by mTOR signaling. These results, together with the fact that we have mainly worked with a human-CD69 transgenic model, reveal CD69 as a treatment target to enhance vaccine protectiveness.

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Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis

Cellular and Molecular Gastroenterology and Hepatology ◽

10.1016/j.jcmgh.2019.01.004 ◽

2019 ◽

Vol 7 (4) ◽

pp. 709-728 ◽

Cited By ~ 28

Author(s):

Yun Han Kwon ◽

Huaqing Wang ◽

Emmanuel Denou ◽

Jean-Eric Ghia ◽

Laura Rossi ◽

...

Keyword(s):

Immune Response ◽

Gut Microbiota ◽

Microbiota Composition ◽

Serotonin Signaling ◽

Gut Microbiota Composition

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Targeting the Gut Microbiota in Chagas Disease: What Do We Know so Far?

Frontiers in Microbiology ◽

10.3389/fmicb.2020.585857 ◽

2020 ◽

Vol 11 ◽

Author(s):

Eduardo Duarte-Silva ◽

Livia H. Morais ◽

Gerard Clarke ◽

Wilson Savino ◽

Christina Peixoto

Keyword(s):

Immune Response ◽

Gut Microbiota ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Current Data ◽

Review Article ◽

Microbiota Composition ◽

Comorbid Conditions ◽

Therapeutic Approaches ◽

Gut Microbiota Composition

Chagas disease (CD) is a tropical and still neglected disease caused by Trypanosoma cruzi that affects >8 million of people worldwide. Although limited, emerging data suggest that gut microbiota dysfunction may be a new mechanism underlying CD pathogenesis. T. cruzi infection leads to changes in the gut microbiota composition of vector insects, mice, and humans. Alterations in insect and mice microbiota due to T. cruzi have been associated with a decreased immune response against the parasite, influencing the establishment and progression of infection. Further, changes in the gut microbiota are linked with inflammatory and neuropsychiatric disorders, comorbid conditions in CD. Therefore, this review article critically analyses the current data on CD and the gut microbiota of insects, mice, and humans and discusses its importance for CD pathogenesis. An enhanced understanding of host microbiota will be critical for the development of alternative therapeutic approaches to target CD, such as gut microbiota-directed interventions.

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Oral administration of Lactobacillus fermentum post-weaning improves the lipid profile and autonomic dysfunction in rat offspring exposed to maternal dyslipidemia

Food & Function ◽

10.1039/d0fo00514b ◽

2020 ◽

Vol 11 (6) ◽

pp. 5581-5594 ◽

Cited By ~ 1

Author(s):

Yohanna de Oliveira ◽

Raissa Georgianna Silva Cavalcante ◽

Marinaldo Pacífico Cavalcanti Neto ◽

Marciane Magnani ◽

Valdir de Andrade Braga ◽

...

Keyword(s):

Gut Microbiota ◽

Oral Administration ◽

Arterial Hypertension ◽

Lipid Profile ◽

Autonomic Dysfunction ◽

Lactobacillus Fermentum ◽

Microbiota Composition ◽

Rat Offspring ◽

Gut Microbiota Composition

Maternal dyslipidemia alters the gut microbiota composition and contributes to the development of arterial hypertension (AH) in offspring.

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Immunomodulatory consequences of oral administration of Lactobacillus rhamnosus strain GG in healthy volunteers

Journal of Dairy Research ◽

10.1017/s0022029903006034 ◽

2003 ◽

Vol 70 (2) ◽

pp. 165-173 ◽

Cited By ~ 91

Author(s):

Michael Schultz ◽

Hans-Jörg Linde ◽

Norbert Lehn ◽

Kurt Zimmermann ◽

Johannes Grossmann ◽

...

Keyword(s):

T Lymphocytes ◽

Oral Administration ◽

Healthy Volunteers ◽

Intestinal Flora ◽

Lactobacillus Rhamnosus ◽

Cytokine Secretion ◽

Tnf Α ◽

Ifn Γ ◽

Anti Inflammatory ◽

Cellular Immune

Probiotic microorganisms, especially lactic acid bacteria, are effective in the treatment of infectious diarrhoeal diseases and experimental colitis. Although the mechanisms by which these organisms exert their anti-inflammatory effects are largely unknown, immunomodulating effects are suggested. The objective of this study was to examine the effect of a 5-week oral administration of Lactobacillus rhamnosus subspecies GG (Lb. GG) on the cellular immune response to intestinal microorganisms in ten healthy volunteers. Peripheral blood cells (PB) were stimulated with either ‘self’ or ‘non-self’ preparations of faecal samples and isolated Bacteroides fragilis group-organisms (Bfg) or Escherichia coli (Esch. coli), and pro- and anti-inflammatory cytokines (IL-10, IL-4, IL-6, IFN-γ, TNF-α) were measured in the culture supernatant. CD4+ T-lymphocyte activation was determined by measurement of intracellular ATP following lysis of the cells. The activational response of CD4+ T-lymphocytes towards isolated and heat-inactivated intestinal organisms was increased after the probiotic treatment. Additionally, TNF-α, IL-6 and in part IFN-γ cytokine secretion by PB cells following stimulation with whole stool preparations and single members of the flora was significantly decreased, whereas the IL-10 and in part IL-4 cytokine secretion was increased at the end of the study. In contrast, the activational response of CD4+ T-lymphocytes following stimulation with whole ‘non-self’ intestinal flora was higher than by ‘self’ intestinal flora, but both responses showed a trend towards a reduction at the end of the study. This study documents a direct effect by Lb. GG on the cellular immune system of healthy volunteers and offers a promising tool to investigate systemic immunomodulation due to oral administration of probiotic microorganisms.

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Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells

Journal of Innate Immunity ◽

10.1159/000477172 ◽

2017 ◽

Vol 9 (5) ◽

pp. 511-525 ◽

Cited By ~ 5

Author(s):

Sophie M. Poznanski ◽

Amanda J. Lee ◽

Tina Nham ◽

Evan Lusty ◽

Margaret J. Larché ◽

...

Keyword(s):

Immune Response ◽

Nk Cells ◽

Natural Killer ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Nk Cell ◽

Critical Role ◽

Interleukin 12 ◽

Tnf Α ◽

Ifn Γ

The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN)-γ production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor-promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF)-α, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-γ and TNF-α production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation.

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