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The high susceptibility of neonates to infections has been assumed to be due to immaturity of the immune system, but the mechanism remains unclear. By colonizing adult germ-free mice with the cecal contents of neonatal and adult mice, we show that the neonatal microbiota is unable to prevent colonization by two bacterial pathogens that cause mortality in neonates. The lack of colonization resistance occurred when Clostridiales were absent in the neonatal microbiota. Administration of Clostridiales, but not Bacteroidales, protected neonatal mice from pathogen infection and abrogated intestinal pathology upon pathogen challenge. Depletion of Clostridiales also abolished colonization resistance in adult mice. The neonatal bacteria enhanced the ability of protective Clostridiales to colonize the gut.

Oral-vaccine-induced IgA cross-links growing bacteria into clonal aggregates, inhibiting pathogenesis, adaption and the spread of antimicrobial resistance genes. Clumping antibody protects gut Immunoglobulin A (IgA) is a key component in the body's first line of defence against many infections, but the physical processes that drive its protective function in the gut are poorly defined. Kathrin Moor et al . show that IgA protects against Salmonella infection in the intestines of mice by enchaining the progeny of dividing bacteria into clonal or oligoclonal clumps. This clumping mechanism enables IgA to directly disarm potentially invasive species and prevent bacterial invasion, while avoiding immune processes that could cause damage to the host. Vaccine-induced high-avidity IgA can protect against bacterial enteropathogens by directly neutralizing virulence factors or by poorly defined mechanisms that physically impede bacterial interactions with the gut tissues (‘immune exclusion’) 1 , 2 , 3 . IgA-mediated cross-linking clumps bacteria in the gut lumen and is critical for protection against infection by non-typhoidal Salmonella enterica subspecies enterica serovar Typhimurium ( S. Typhimurium). However, classical agglutination, which was thought to drive this process, is efficient only at high pathogen densities (≥10 8 non-motile bacteria per gram). In typical infections, much lower densities 4 , 5 (10 0 –10 7 colony-forming units per gram) of rapidly dividing bacteria are present in the gut lumen. Here we show that a different physical process drives formation of clumps in vivo : IgA-mediated cross-linking enchains daughter cells, preventing their separation after division, and clumping is therefore dependent on growth. Enchained growth is effective at all realistic pathogen densities, and accelerates pathogen clearance from the gut lumen. Furthermore, IgA enchains plasmid-donor and -recipient clones into separate clumps, impeding conjugative plasmid transfer in vivo . Enchained growth is therefore a mechanism by which IgA can disarm and clear potentially invasive species from the intestinal lumen without requiring high pathogen densities, inflammation or bacterial killing. Furthermore, our results reveal an untapped potential for oral vaccines in combating the spread of antimicrobial resistance.

Neutrophil extracellular traps (NETs) represent extracellular microbial trapping and killing. Recently, it has been implicated in thrombogenesis, autoimmune disease, and cancer progression. The aim of this study was to characterize NETs in various organs of a murine sepsis model in vivo and to investigate their associations with platelets, leukocytes, or vascular endothelium. NETs were classified as two distinct forms; cell-free NETs that were released away from neutrophils and anchored NETs that were anchored to neutrophils. Circulating cell-free NETs were characterized as fragmented or cotton-like structures, while anchored NETs were characterized as linear, reticular, membranous, or spot-like structures. In septic mice, both anchored and cell-free NETs were significantly increased in postcapillary venules of the cecum and hepatic sinusoids with increased leukocyte-endothelial interactions. NETs were also observed in both alveolar space and pulmonary capillaries of the lung. The interactions of NETs with platelet aggregates, leukocyte-platelet aggregates or vascular endothelium of arterioles and venules were observed in the microcirculation of septic mice. Microvessel occlusions which may be caused by platelet aggregates or leukocyte-platelet aggregates and heterogeneously decreased blood flow were also observed in septic mice. NETs appeared to be associated with the formation of platelet aggregates or leukocyte-platelet aggregates. These observational findings may suggest the adverse effect of intravascular NETs on the host during a sepsis.

Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface. Microfold cells (M cells) sit at the gut epithelial surface to sample antigens and maintain local immune homeostasis. Here the authors show that M cells are feedback-regulated by M cell-originated osteoprotegerin (OPG) to suppress RNAKL-induced M cell differentiation, and that OPG deficiency alters both gut colitis and infection phenotypes.

Organisms adapt to day–night cycles through highly specialized circadian machinery, whose molecular components anticipate and drive changes in organism behavior and metabolism. Although many effectors of the immune system are known to follow daily oscillations, the role of the circadian clock in the immune response to acute infections is not understood. Here we show that the circadian clock modulates the inflammatory response during acute infection with the pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium). Mice infected with S. Typhimurium were colonized to higher levels and developed a higher proinflammatory response during the early rest period for mice, compared with other times of the day. We also demonstrate that a functional clock is required for optimal S. Typhimurium colonization and maximal induction of several proinflammatory genes. These findings point to a clock-regulated mechanism of activation of the immune response against an enteric pathogen and may suggest potential therapeutic strategies for chronopharmacologic interventions.

Sepsis is a life-threatening condition caused by an immune response triggered by infection, and highly elevated cytokine/chemokine levels in the blood play crucial roles in the progression of sepsis. Serum exosomes are nanovesicles that have multiple biological functions, playing roles in antigen presentation, intercellular signal communication, inflammatory response and immune surveillance. However, the biological functions and related molecular bases remain to be elucidated. In this study, we investigated the profiles of cytokines/chemokines harbored in the exosomes of septic mice and explored the mechanisms of immunomodulation on T cells treated with exosomes harvested from septic mice. Blood cytokines/chemokines existed in both the soluble form and in the insoluble exosomal form; the profiles of the cytokines/chemokines in these two forms displayed different dynamics in the blood of mice challenged with LPS. Exosomes from septic mice induced the differentiation of Th1/Th2 cells, which was blocked by specific antibodies targeting IL-12 and IL-4. In addition, these exosomes significantly augmented the proliferation and migration of T lymphocytes. Furthermore, preadministration of exosomes by intravenous injection restrained the inflammatory response, attenuated lung and liver tissue damage, and prolonged the survival of cecal ligation and puncture (CLP) mice. Our results indicate that exosomes enriched with cytokines/chemokines play critical roles in T cell differentiation, proliferation and chemotaxis during the sepsis process and have a protective effect on cecal ligation and puncture (CLP) mice. Thus, these findings not only strengthen our understanding of the role of sepsis via exosomes but also provide potential targets for therapeutic applications.

Background To mimic systemic inflammation in humans, different animal models have been developed. Since these models are still discussed controversially, we aimed to comparatively evaluate the most widely used models with respect to the systemic effects, the influence on organ functions and to the underlying pathophysiological processes. Methods Systemic inflammation was induced in C57BL/6N mice with lipopolysaccharide (LPS) treatment, peritoneal contamination and infection (PCI), or cecal ligation and puncture (CLP). Blood glucose and circulating cytokine levels were evaluated at 0, 2, 4, 6, 12, 24, 48, and 72 h after induction of inflammation. Additionally, oxidative stress in various organs and liver biotransformation capacity were determined. Markers for oxidative stress, apoptosis, infiltrating immune cells, as well as cytokine expression patterns, were assessed in liver and spleen tissue by immunohistochemistry. Results Treating mice with LPS and PCI induced a very similar course of inflammation; however, LPS treatment elicited a stronger response. In both models, serum pro-inflammatory cytokine levels rapidly increased whereas blood glucose decreased. Organs showed early signs of oxidative stress, and apoptosis was increased in splenic cells. In addition, liver biotransformation capacity was reduced and there was pronounced immune cell infiltration in both the liver and spleen. Mice exposed to either LPS or PCI recovered after 72 h. In contrast, CLP treatment induced comparatively fewer effects, but a more protracted course of inflammation. Conclusions The LPS model of systemic inflammation revealed to be most suitable when being interested in the impact of new therapies for acute inflammation. When using the CLP model to mimic human sepsis more closely, a longer time course should be employed, as the treatment induces delayed development of systemic inflammation.

Probiotics reduce stress-related inflammation and abnormal behaviors in humans and rodents via regulation of the microbiota-gut-brain axis. The objective of this study was to determine if probiotic, Bacillus subtilis, has similar functions in broiler chickens under heat stress (HS). Two hundred forty 1-d-old broiler chicks were assigned to 48 pens with 4 treatments: Thermoneutral (TN)-RD (regular diet), TN-PD (the regular diet mixed with 1 × 106 CFU/g feed probiotic), HS-RD and HS-PD. Probiotic (Sporulin) was fed from day 1; and HS at 32°C for 10 h daily was initiated at day 15. The data showed that final BW, average daily gain , and feed conversion efficiency were improved in PD groups as compared to RD groups regardless of the ambient temperature (P < 0.01). Heterophil to lymphocyte ratio was affected by treatment and its value was in the order of HS-RD > HS-PD > TN-RD > TN-PD birds (P < 0.01). Compared to TN birds, HS birds spent more time in wing spreading, panting, squatting close to the ground, drinking, sleeping, dozing, and sitting but spent less time in eating, standing, and walking (P < 0.05 or 0.01). In addition, HS birds had greater levels of hepatic IL-6, IL-10, heat shock protein (HSP)70, and HSP70 mRNA expression (P < 0.01) and greater levels of cecal IgA and IgY (P < 0.01) compared to TN birds. Within TN groups, TN-PD birds had greater concentrations of hepatic IL-10 (P < 0.05) and cecal IgA (P < 0.01) than TN-RD birds. Within HS groups, HS-PD birds spent less time in wing spreading, panting, squatting close to the ground, drinking, sleeping, dozing, and sitting but spent more time in eating, foraging, standing, and walking than HS-RD birds (P < 0.05 or 0.01). The HS-PD birds also had lower concentrations of hepatic IL-6 and HSP70 (P < 0.01), whereas greater levels of IL-10 (P < 0.05) and lower concentrations of cecal IgA and IgY (P < 0.01). These results indicate that broilers fed the probiotic, B. subtilis, are able to cope with HS more effectively by ameliorating heat-induced behavioral and inflammatory reactions through regulation of microbiota-modulated immunity.

Summary Gastrointestinal nematode infections elicit robust type 2 immune responses that facilitate rapid parasite expulsion. Our previous studies demonstrated that 18-month-old mice exhibit both impaired nematode clearance and reduced type 2-cytokine production, suggesting that aging diminishes the host’s potential to mount effective immune defenses. To further investigate the underlying mechanisms, we compared young (3 months old) and aged mice (18 months old) infected with the nematode Heligmosomoides polygyrus (Hp), focusing on the interplay between type 2 immune responses and intestinal ecology. Hp infected young mice exhibited increased expression of Th2 cytokines (e.g., il-4 ) and short-chain fatty acid (SCFA) receptors GPR41/GPR43, while these responses were markedly diminished in aged mice. Correspondingly, cecal SCFA levels—particularly acetate and propionate—increased in Hp infected young mice but decreased in aged counterparts. Moreover, Hp infection induced a pronounced shift in the cecal microbiota composition of young mice, notably a reduced Bacillota/Bacteroidota ratio (F/B) ratio, a change much less evident in aged mice. These findings suggest that the age-related decline in type 2 immune responses to gastrointestinal nematode infection is linked to reduced gut microbiota responsiveness, which may compromise host resistance to the gastrointestinal parasites.

Mixed-linkage β-glucans are fermented by the colon microbiota that give rise to SCFA. Propionic and butyric acids have been found to play an important role in colonic health, as well as they may have extraintestinal metabolic effects. The aim of the present study was to investigate how two whole-grain barley varieties differing in dietary fibre and β-glucan content affected caecal SCFA, gut microbiota and some plasma inflammatory markers in rats consuming low-fat (LF) or high-fat (HF) diets. Barley increased the caecal pool of SCFA in rats fed the LF and HF diets compared with those fed the control diet, and the effect was generally dependent on fibre content, an exception was butyric acid in the LF setting. Furthermore, whole-grain barley reduced plasma lipopolysaccharide-binding protein and monocyte chemoattractant protein-1, increased the caecal abundance of Lactobacillus and decreased the Bacteroides fragilis group, but increased the number of Bifidobacterium only when dietary fat was consumed at a low level. Fat content influenced the effects of barley: rats fed the HF diets had a higher caecal pool of acetic and propionic acids, higher concentrations of amino acids and higher amounts of lipids in the portal plasma and liver than rats fed the LF diets; however, less amounts of butyric acid were generally formed. Interestingly, there was an increase in the caecal abundance of Akkermansia and the caecal pool of succinic acid, and a decrease in the proportion of Bifidobacterium and the Clostridium leptum group. In summary, whole-grain barley decreased HF diet-induced inflammation, which was possibly related to the formation of SCFA and changes in microbiota composition. High β-glucan content in the diet was associated with reduced plasma cholesterol levels.