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1.
Cell Host Microbe ; 32(7): 1163-1176.e6, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38906158

ABSTRACT

Depletion of beneficial microbes by modern lifestyle factors correlates with the rising prevalence of food allergies. Re-introduction of allergy-protective bacteria may be an effective treatment strategy. We characterized the fecal microbiota of healthy and food-allergic infants and found that the anaerobe Anaerostipes caccae (A. caccae) was representative of the protective capacity of the healthy microbiota. We isolated a strain of A. caccae from the feces of a healthy infant and identified lactulose as a prebiotic to optimize butyrate production by A. caccae in vitro. Administration of a synbiotic composed of our isolated A. caccae strain and lactulose increased luminal butyrate in gnotobiotic mice colonized with feces from an allergic infant and in antibiotic-treated specific pathogen-free (SPF) mice, and prevented or treated an anaphylactic response to allergen challenge. The synbiotic's efficacy in two models and microbial contexts suggests that it may be a promising approach for the treatment of food allergy.


Subject(s)
Feces , Food Hypersensitivity , Gastrointestinal Microbiome , Lactulose , Synbiotics , Animals , Synbiotics/administration & dosage , Food Hypersensitivity/prevention & control , Mice , Humans , Feces/microbiology , Gastrointestinal Microbiome/drug effects , Infant , Butyrates/metabolism , Prebiotics/administration & dosage , Female , Disease Models, Animal , Specific Pathogen-Free Organisms , Germ-Free Life , Male
2.
Immunology ; 167(1): 64-76, 2022 09.
Article in English | MEDLINE | ID: mdl-35689599

ABSTRACT

In the gut, secretory immunoglobulin A is the predominant humoral response against commensals, although healthy hosts also produce microbiota-specific IgG antibodies. During intestinal inflammation, the content of IgG in the lumen increases along with the proportion of commensal bacteria coated with this antibody, suggesting signalling through the IgG-CD64 axis in the pathogenesis of inflammatory bowel diseases. In this work, we evaluated day by day the frequency of faecal bacteria coated with IgA and IgG during the development of DSS colitis. We studied the phenotype and phagocytic activity of F4/80+ CD64+ colonic macrophages, as well as the production of cytokines and nitric oxide by lamina propria or bone marrow-derived macrophages after stimulation with IgA+ , IgG+ and IgA+ IgG+ bacteria. We found that the percentage of faecal IgA+ IgG+ double-coated bacteria increased rapidly during DSS colitis. Also, analysis of the luminal content of mice with colitis showed a markedly superior ability to coat fresh bacteria. IgA+ IgG+ bacteria were the most potent stimulus for phagocytic activity involving CD64 and Dectin-1 receptors. IgA+ IgG+ bacteria observed during the development of DSS colitis could represent a new marker to monitor permeability and inflammatory progression. The interaction of IgA+ IgG+ bacteria with CD64+ F4/80+ macrophages could be part of the complex cascade of events in colitis. Interestingly, after stimulation, CD64+ colonic macrophages showed features similar to those of restorative macrophages that are relevant for tissue repair and healing.


Subject(s)
Colitis , Colon , Animals , Bacteria , Colitis/chemically induced , Colitis/pathology , Colon/pathology , Dextran Sulfate , Immunoglobulin A, Secretory , Immunoglobulin G , Inflammation/pathology , Macrophages , Mice , Receptors, IgG
3.
Mucosal Immunol ; 12(1): 108-116, 2019 01.
Article in English | MEDLINE | ID: mdl-30327533

ABSTRACT

Biological rhythms are periodic oscillations that occur in the physiology of the organism and the cells. The rhythms of the immune system are strictly regulated and the circadian alteration seems to have serious consequences. Even so, it is not clear how the immune cells of the intestinal mucosa synchronize with the external environment. Besides, little is known about the way in which biological rhythms affect the critical functions of intestinal immunity, such as oral tolerance. We studied fluctuations in the relevant parameters of intestinal immunity at four different times throughout the day. By using multivariate statistical tools, we found that these oscillations represent at least three different time frames with different conditions for tolerance induction that are altered in Per2ko mice lacking one of the clock genes. Our results allowed us to characterize a window in the final stage of the dark phase that promotes the induction of specific regulatory populations and favors its location in the lamina propria. We show here that, at the end of the intake, the entry of luminal antigens, soluble factors, and leukocyte populations converge in the mesenteric lymph nodes (MLN) and display the greatest potential of the tolerogenic machinery.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Eating , Immune Tolerance , Intestinal Mucosa/immunology , Lymph Nodes/immunology , Mesentery/immunology , Periodicity , Animals , Cells, Cultured , Immune System , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Period Circadian Proteins/genetics
4.
J Nutr Biochem ; 49: 110-116, 2017 11.
Article in English | MEDLINE | ID: mdl-28917953

ABSTRACT

Lamina propria dendritic cells (DCs) have a permanent turnover with constitutive migration to mesenteric lymph nodes and replenishment by progenitors. Luminal bacteria and dietary constituents provide key signals that endow DCs their unique properties in vivo. Taking into account that the intestinal immune system is greatly influenced by retinoids, we evaluated in B6 mice 3, 8, 16 and 24 h after feeding a single dose of vitamin A phenotype and function of cells present in mesenteric afferent lymph nodes as well as signals involved in migration. We studied the frequency of CD11c+MHC-II+CD103+CD86+ and RALDH+ DCs by flow cytometry, we determined CCL-21 and D6 levels in tissue homogenates by Western blot, and we co-cultured cells isolated from afferent lymphatics with sorted CD4+ lymphocytes to assess Foxp-3 induction and homing receptor expression. Sixteen hours after vitamin A administration, DCs isolated from afferent lymphatics were able to induce homing receptors and Foxp3 expression in CD4+ lymphocytes. Our results show that a single dose of vitamin A generated a stream of signals and amplified the tolerogenic activity of DCs migrating to lymphoid tissue.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Dendritic Cells/metabolism , Dietary Supplements , Forkhead Transcription Factors/agonists , Gene Expression Regulation , Receptors, Lymphocyte Homing/agonists , Vitamin A/administration & dosage , Animals , Antigens, CD/metabolism , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Cell Movement , Cells, Cultured , Coculture Techniques , Dendritic Cells/cytology , Dendritic Cells/immunology , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Immune Tolerance , Lymph/cytology , Lymph/immunology , Lymph/metabolism , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymph Nodes/metabolism , Mesentery , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Lymphocyte Homing/genetics , Receptors, Lymphocyte Homing/metabolism , Specific Pathogen-Free Organisms
5.
Biochem Pharmacol ; 115: 104-13, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27343762

ABSTRACT

TNF-α is involved in the mechanisms that initiate inflammatory bowel diseases (IBDs). Anti-TNF-α drugs, such as infliximab (IFX), cause non-responsiveness and side effects, indicating the need to investigate alternative therapies for these diseases. The anti-inflammatory protein, annexin A1 (AnxA1), has been associated with the protection of the gastrointestinal mucosa. To further address the role of endogenous AnxA1 on the TNF-α blockade efficacy in a murine model, we assessed colitis induced by Dextran Sulfate Sodium (DSS) in wild-type (WT) and AnxA1(-/-) Balb/c mice treated with IFX. We consistently observed endogenous AnxA1 prevented clinical and physiological manifestations of experimental colitis treated with IFX, additionally the manifestation of the disease was observed earlier in AnxA1(-)(/-) mice. Rectal bleeding, diarrhea, histological score, epithelial damages and collagen degradation caused by DSS were prevented following IFX treatment only in WT mice. IL-6 increased during colitis in WT and AnxA1(-)(/-) mice, decreasing under IFX treatment in WT. The influx of neutrophils and TNF-α secretion were largely elevated in AnxA1(-)(/-) mice when compared to WT mice. In the group WT/DSS+IFX, phagocytes were more susceptible to apoptosis following treatment with IFX. Endogenous expression of AnxA1 increased after DSS and decreased with IFX treatment, demonstrating an attenuated inflammatory response. The data indicate that AnxA1 contributes to the establishment of intestinal homeostasis after blocking of TNF-α was used as a treatment of IBD, constituting a key molecule in the mechanism of action and a potential biomarker of therapeutic efficacy.


Subject(s)
Annexin A1/physiology , Colitis/drug therapy , Gastrointestinal Agents/therapeutic use , Infliximab/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Annexin A1/deficiency , Biomarkers/metabolism , Caspase 3/metabolism , Colitis/chemically induced , Colitis/metabolism , Colitis/pathology , Dextran Sulfate , Female , Intestinal Mucosa/metabolism , Mice , Mice, Inbred BALB C , Peroxidase/metabolism
6.
Eur J Immunol ; 46(1): 70-80, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26464149

ABSTRACT

The intestinal immune system is complex and displays unique anatomic and functional characteristics. Numerous immune cell subsets are located beneath the epithelial barrier and their activity is highly regulated. Using hydrodynamic shear of IL-12 cDNA to achieve systemic expression of IL-12 in mice, we evaluated the effect of a transient burst of this cytokine on the activation status of T cells from Peyer's patches (PPs), mesenteric lymph nodes (MLNs), and colonic lamina propria (LP). Following systemic IL-12 release, intestinal T lymphocytes became activated, exhibiting a CD44(high) CD62L(-) phenotype. After 5 days of the cytokine burst, the frequency of α4ß7(+) CD4(+) and CD8(+) cells increased, and CD8(+) α4ß7(+) cells mainly expressed T bet, a critical regulator of the Th1 differentiation program. The incremental increase in α4ß7 expression involved the IL-12 receptor-signal transducer and activator of transcription (STAT)-4 axis, and occurred independently of IFN-γ, IL-4, IL-10, and TNF-α signaling. Moreover, IL-12 priming exacerbated the outcome of acute dextran sodium sulphate (DSS)-induced colitis with higher scores of weight loss, blood in stool, and diarrhea and lower hematocrit. Together, our findings demonstrate that systemic polarizing signals could effectively expand the number of effector cells able to home to the LP and contribute to local inflammation.


Subject(s)
Colitis/immunology , Integrins/immunology , Interleukin-12/immunology , Intestinal Mucosa/immunology , Lymphocyte Activation/immunology , T-Lymphocyte Subsets/immunology , Animals , Flow Cytometry , Inflammation/immunology , Lymph Nodes/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Peyer's Patches/immunology
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