bims-bac4me 2023-01-22 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023‒01‒22
twenty-two papers selected by
Chun-Chi Chang
University Hospital Zurich

Inflammation Regulation by Bacterial Molecular Patterns.
Immunometabolism and microbial metabolites at the gut barrier: lessons for therapeutic intervention in Inflammatory Bowel Disease.
Interactions between microbiome and underlying mechanisms in asthma.
Glycolytic side pathways regulating macrophage inflammatory phenotypes and functions.
Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways.
Immunity to the microbiota promotes sensory neuron regeneration.
Immunological and inflammatory effects of infectious diseases in circadian rhythm disruption and future therapeutic directions.
IL-18 maintains the homeostasis of mucosal immune system via inflammasome-independent but microbiota-dependent manner.
S-Nitrosoglutathione Reduces the Density of Staphylococcus aureus Biofilms Established on Human Airway Epithelial Cells.
Community composition shapes microbial-specific phenotypes in a cystic fibrosis polymicrobial model system.
The clinical implications of bacterial pathogenesis and mucosal immunity in chronic urinary tract infection.
Dynamics of immune memory and learning in bacterial communities.
A review of topical probiotic therapy for atopic dermatitis.
Infection-elicited microbiota promotes host adaptation to nutrient restriction.
Development of a lactic acid bacteria strain that suppresses chronic inflammation and improves glucose and lipid metabolism.
An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells.
Mouse Tissue-Resident Peritoneal Macrophages in Homeostasis, Repair, Infection, and Tumor Metastasis.
HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages.
Novel 3D Flipwell system that models gut mucosal microenvironment for studying interactions between gut microbiota, epithelia and immunity.
Regulatory T cell and macrophage crosstalk in acute lung injury: future perspectives.
Endogenous Reverse Transcriptase Inhibition Attenuates TLR5-Mediated Inflammation.
Classical DC2 subsets and monocyte-derived DC: delineating the developmental and functional relationship.

Biomedicines. 2023 Jan 11. pii: 183. [Epub ahead of print]11(1):

Inflammation Regulation by Bacterial Molecular Patterns.

Svetlana V Guryanova, Anastasiya Kataeva.

  Stimulation of innate immunity by bacterial molecular patterns can induce an enhanced cellular immune response to pathogens that are associated with innate immune memory shaped by epigenetic changes. Immunological memory can be expressed in the acceleration/intensification of inflammation, as well as in the exact opposite-to maintain tolerance and non-response to a repeated stimulus. Tolerance is one of the central concepts of immunity and is ensured by the consistency of all parts of the immune response. The severe consequences of inflammation force researchers to study in detail all stages of the downstream pathways that are activated after exposure to a stimulus, while the formation of non-response to a pro-inflammatory stimulus has not yet received a detailed description. Elucidation of the mechanism of tolerance is an urgent task for the prevention and treatment of inflammatory diseases. The aim of this investigation was to study the dynamic changes in the gene expression of A20 and ATF3, the inflammation suppressors, against the background of the expression of the genes of the innate immunity receptors TLR4 and NOD2 and the pro-inflammatory cytokine TNF-α under the influence of TLR4 and NOD2 agonists, lipopolysaccharide (LPS) and glucosaminylmuramyl dipeptide (GMDP). The mechanism of inflammation regulation by bioregulators of bacterial origin-LPS and GMDP-was evaluated in vitro in human peripheral blood mononuclear cells and in vivo after i.p. administration of LPS and GMDP to mice. Gene expression was assessed by RT-PCR. Innate immune receptors and the pro-inflammatory cytokine TNF-α were found to develop early in response to LPS and GMDP, both in vitro and in vivo. Genes of cytosolic proteins controlling inflammation (A20 and ATF3) were expressed later. Prior exposure of the innate immune system to LPS and muramyl peptides may modulate host defense against acute inflammation. As a result of the study, new data were obtained on dynamic changes in deubiquitinase A20 and the transcription factor ATF3, which are involved in the limitation and suppression of inflammatory reactions caused by fragments of bacterial cell walls-LPS and GMDP. Thus, bioregulators of bacterial origin LPS and GMDP, along with pro-inflammatory factors, activate the expression of genes that suppress inflammation, which should be considered when analyzing data from studies of the pro-inflammatory properties of LPS and GMDP and when developing drugs based on them.

Keywords:  A20; ATF3; GMDP; LPS; NOD2; TLR4; TNF-α; innate immune memory; innate immunity; lipopolysaccharide; muramyl peptide; tolerance

DOI:  https://doi.org/10.3390/biomedicines11010183
Mucosal Immunol. 2023 Jan 12. pii: S1933-0219(22)01180-1. [Epub ahead of print]

Immunometabolism and microbial metabolites at the gut barrier: lessons for therapeutic intervention in Inflammatory Bowel Disease.

Margret Michaels, Karen L Madsen.

  The concept of immunometabolism has emerged recently whereby repolarizing of inflammatory immune cells towards anti-inflammatory profiles by manipulating cellular metabolism represents a new potential therapeutic approach in controlling inflammation.Metabolic pathways in immune cells are tightly regulated to maintain immune homeostasis and appropriate functional specificity. As effector and regulatory immune cell populations have different metabolic requirements, this allows for cellular selectivity when regulating immune responses based on metabolic pathways. Gut microbes have a major role in modulating immune cell metabolic profiles and functional responses through extensive interactions involving metabolic products and crosstalk between gut microbes, intestinal epithelial cells, and mucosal immune cells. Developing strategies to target metabolic pathways in mucosal immune cells through modulation of gut microbial metabolism has the potential for new therapeutic approaches for human autoimmune and inflammatory diseases, such as inflammatory bowel disease. This review will give an overview of the relationship between metabolic reprogramming and immune responses, how microbial metabolites influence these interactions, and how these pathways could be harnessed in the treatment of inflammatory bowel disease.

Keywords:  immunometabolism; inflammatory bowel disease; microbiome

DOI:  https://doi.org/10.1016/j.mucimm.2022.11.001
Respir Med. 2023 Jan 11. pii: S0954-6111(23)00006-9. [Epub ahead of print] 107118

Interactions between microbiome and underlying mechanisms in asthma.

Purevsuren Losol, Milena Sokolowska, Yoon-Seok Chang.

  Microbiome primes host innate immunity in utero and play fundamental roles in the development, training, and function of the immune system throughout the life. Interplay between the microbiome and immune system maintains mucosal homeostasis, while alterations of microbial community dysregulate immune responses, leading to distinct phenotypic features of immune-mediated diseases including asthma. Microbial imbalance within the mucosal environments, including upper and lower airways, skin, and gut, has consistently been observed in asthma patients and linked to increased asthma exacerbations and severity. Microbiome research has increased to uncover hidden microbial members, function, and immunoregulatory effects of bacterial metabolites within the mucosa. This review provides an overview of environmental and genetic factors that modulate the composition and function of the microbiome, and the impacts of microbiome metabolites and skin microbiota on immune regulation in asthma.

Keywords:  Asthma; Diet; Immunity; Metabolite; Microbiome

DOI:  https://doi.org/10.1016/j.rmed.2023.107118
Am J Physiol Cell Physiol. 2023 Jan 16.

Glycolytic side pathways regulating macrophage inflammatory phenotypes and functions.

Flávio Dionísio, Lukas Tomas, Christian Schulz.

  Macrophages are crucial effector cells of the innate immune system and have important roles in the initiation and resolution of inflammation as well as in tissue homeostasis. In order to fulfill these diverse roles, macrophages exhibit metabolic flexibility to quickly adapt to the needs of the effector functions required, as well as to the microenvironment. This metabolic flexibility is exemplified by pro-inflammatory macrophages, which upregulate glycolysis to both initiate and sustain the process of inflammation. Upregulation of glycolysis does not only represent a fast means of ATP generation. It also fuels glycolytic side pathways that are crucial for an effective inflammatory response by influencing the cell's redox balance as well as by providing building blocks and substrates for epigenetic reprogramming. The aim of this short review is to explore how three of these pathways - the pentose phosphate pathway, the glycerol phosphate shuttle, and the serine synthesis pathway - help macrophages sustain their pro-inflammatory phenotype and functions.

Keywords:  glycolysis; immunometabolism; macrophage

DOI:  https://doi.org/10.1152/ajpcell.00276.2022
Immunol Rev. 2023 Jan 19.

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways.

George R Dubyak, Brandon A Miller, Eric Pearlman.

  Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.

Keywords:  NETosis; gasdermin; inflammasome; interleukin-1β; neutrophil; pyroptosis

DOI:  https://doi.org/10.1111/imr.13186
Cell. 2023 Jan 06. pii: S0092-8674(22)01580-X. [Epub ahead of print]

Immunity to the microbiota promotes sensory neuron regeneration.

Michel Enamorado, Warakorn Kulalert, Seong-Ji Han, Indira Rao, Jérémie Delaleu, Verena M Link, Daniel Yong, Margery Smelkinson, Louis Gil, Saeko Nakajima, Jonathan L Linehan, Nicolas Bouladoux, Josette Wlaschin, Juraj Kabat, Olena Kamenyeva, Liwen Deng, Inta Gribonika, Alexander T Chesler, Isaac M Chiu, Claire E Le Pichon, Yasmine Belkaid.

  Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process.

Keywords:  S. aureus; Th17; commensal; dorsal root ganglion; interleukin 17; interleukin 17 receptor A; microbiota; neuronal regeneration; repair; sensory neuron

DOI:  https://doi.org/10.1016/j.cell.2022.12.037
Mol Biol Rep. 2023 Jan 19.

Immunological and inflammatory effects of infectious diseases in circadian rhythm disruption and future therapeutic directions.

Helen Huang, Aashna Mehta, Jacob Kalmanovich, Ayush Anand, Maria Chilo Bejarano, Tulika Garg, Nida Khan, Gauvain Kankeu Tonpouwo, Anastasiia D Shkodina, Mainak Bardhan.

  BACKGROUND: Circadian rhythm is characterised by daily variations in biological activity to align with the light and dark cycle. These diurnal variations, in turn, influence physiological functions such as blood pressure, temperature, and sleep-wake cycle. Though it is well established that the circadian pathway is linked to pro-inflammatory responses and circulating immune cells, its association with infectious diseases is widely unknown.OBJECTIVE: This comprehensive review aims to describe the association between circadian rhythm and host immune response to various kinds of infection.
METHODS: We conducted a literature search in databases Pubmed/Medline and Science direct. Our paper includes a comprehensive analysis of findings from articles in English which was related to our hypothesis.
FINDINGS: Molecular clocks determine circadian rhythm disruption in response to infection, influencing the host's response toward infection. Moreover, there is a complex interplay with intrinsic oscillators of pathogens and the influence of specific infectious processes on the CLOCK: BMAL1 pathway. Such mechanisms vary for bacterial and viral infections, both well studied in the literature. However, less is known about the association of parasitic infections and fungal pathogens with circadian rhythm modulation.
CONCLUSION: It is shown that bidirectional relationships exist between circadian rhythm disruption and infectious process, which contains interplay between the host's and pathogens' circadian oscillator, immune response, and the influence of specific infectious. Further studies exploring the modulations of circadian rhythm and immunity can offer novel explanations of different susceptibilities to infection and can lead to therapeutic avenues in circadian immune modulation of infectious diseases.

Keywords:  Chrono-immunology; Circadian rhythm; Immune response; Infectious diseases; Inflammation; Melatonin; Molecular clocks

DOI:  https://doi.org/10.1007/s11033-023-08276-w
Sci Bull (Beijing). 2021 Oct 30. pii: S2095-9273(21)00061-X. [Epub ahead of print]66(20): 2115-2123

IL-18 maintains the homeostasis of mucosal immune system via inflammasome-independent but microbiota-dependent manner.

Xuesen Zheng, Lei Liu, Guangxun Meng, Shu Zhu, Rongbin Zhou, Wei Jiang.

  Inflammasomes and their product interleukin 18 (IL-18) play important roles in gut microbiota monitoring and homeostasis, and their loss of function could lead to microbiota dysbiosis and accelerate disease progression. However, the impacts of the resulting microbiota dysbiosis on the mucosal immune system are largely unknown. Here, we show that dysbiotic microbiota from Il18-/- mice induced immune cell loss in the small intestine (SI) in an inflammasome-independent manner. Cohousing experiments revealed that the immunotoxic phenotype of these microbiota was transferable to wild type (WT) mice and induced immune cell death through the receptor-interacting protein kinase 3 (RIP3)-mixed lineage kinase domain like pseudokinase (MLKL) pathway. Analysis of microbiota composition identified two types of bacteria at the genus level, Ureaplasma and Parasutterella, that accumulated in Il18-/- mice and negatively mediated changes in immune cells in the SI. Furthermore, dysbiosis in Il18-/- mice also contributed to increased susceptibility to Listeria infection. Collectively, our results demonstrate that IL-18 is essential to microbiota homeostasis and that dysbiotic microbiota could significantly shape the landscape of the immune system.

Keywords:  Dysbiosis; IL-18; Immune system; Inflammasome

DOI:  https://doi.org/10.1016/j.scib.2021.01.025
ACS Omega. 2023 Jan 10. 8(1): 846-856

S-Nitrosoglutathione Reduces the Density of Staphylococcus aureus Biofilms Established on Human Airway Epithelial Cells.

Alex Wolf, Mohsen Tabasi, Mark Zacharek, Glenn Martin, Marc B Hershenson, Mark E Meyerhoff, Umadevi Sajjan.

Patients with chronic rhinosinusitis (CRS) often show persistent colonization by bacteria in the form of biofilms which are resistant to antibiotic treatment. One of the most commonly isolated bacteria in CRS is Staphylococcus aureus (S. aureus). Nitric oxide (NO) is a potent antimicrobial agent and disperses biofilms efficiently. We hypothesized that S-nitrosoglutathione (GSNO), an endogenous NO carrier/donor, synergizes with gentamicin to disperse and reduce the bacterial biofilm density. We prepared GSNO formulations which are stable up to 12 months at room temperature and show the maximum amount of NO release within 1 h. We examined the effects of this GSNO formulation on the S. aureus biofilm established on the apical surface of the mucociliary-differentiated airway epithelial cell cultures regenerated from airway basal (stem) cells from cystic fibrosis (CF) and CRS patients. We demonstrate that for CF cells, which are defective in producing NO, treatment with GSNO at 100 μM increased the NO levels on the apical surface and reduced the biofilm bacterial density by 2 log units without stimulating pro-inflammatory effects or inducing epithelial cell death. In combination with gentamicin, GSNO further enhanced the killing of biofilm bacteria. Compared to placebo, GSNO significantly increased the ciliary beat frequency (CBF) in both infected and uninfected CF cell cultures. The combination of GSNO and gentamicin also reduced the bacterial density of biofilms grown on sinonasal epithelial cells from CRS patients and improved the CBF. These findings demonstrate that GSNO in combination with gentamicin may effectively reduce the density of biofilm bacteria in CRS patients. GSNO treatment may also enhance the mucociliary clearance by improving the CBF.

DOI: https://doi.org/10.1021/acsomega.2c06212
Elife. 2023 Jan 20. pii: e81604. [Epub ahead of print]12

Community composition shapes microbial-specific phenotypes in a cystic fibrosis polymicrobial model system.

Fabrice Jean-Pierre, Thomas H Hampton, Daniel Schultz, Deborah A Hogan, Marie-Christine Groleau, Eric Déziel, George A O'Toole.

  Interspecies interactions can drive the emergence of unexpected microbial phenotypes that are not observed when studying monocultures. The cystic fibrosis (CF) lung consists of a complex environment where microbes, living as polymicrobial biofilm-like communities, are associated with negative clinical outcomes for persons with CF (pwCF). However, the current lack of in vitro models integrating the microbial diversity observed in the CF airway hampers our understanding of why polymicrobial communities are recalcitrant to therapy in this disease. Here, integrating computational approaches informed by clinical data, we built a mixed community of clinical relevance to the CF lung composed of Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus sanguinis and Prevotella melaninogenica. We developed and validated this model biofilm community with multiple isolates of these four genera. When challenged with tobramycin, a front-line antimicrobial used to treat pwCF, the microorganisms in the polymicrobial community show altered sensitivity to this antibiotic compared to monospecies biofilms. We observed that wild-type P. aeruginosa is sensitized to tobramycin in a mixed community versus monoculture, and this observation holds across a range of community relative abundances. We also report that LasR loss-of-function, a variant frequently detected in the CF airway, drives tolerance of P. aeruginosa to tobramycin specifically in the mixed community. Our data suggest that the molecular basis of this community-specific recalcitrance to tobramycin for the P. aeruginosa LasR mutant is increased production of phenazines. Our work support the importance of studying a clinically-relevant model polymicrobial biofilms to understand community-specific traits relevant to infections.

Keywords:  infectious disease; microbiology

DOI:  https://doi.org/10.7554/eLife.81604
Mucosal Immunol. 2023 Jan 12. pii: S1933-0219(22)01768-8. [Epub ahead of print]

The clinical implications of bacterial pathogenesis and mucosal immunity in chronic urinary tract infection.

Catherine C Y Chieng, Qingyang Kong, Natasha S Y Liou, Rajvinder Khasriya, Harry Horsley.

  Urinary tract infections (UTIs) exert a significant health and economic cost globally. Approximately one in four people with a previous history of UTI continue to develop recurrent or chronic infections. Research on UTI has primarily concentrated on pathogen behavior, with the focus gradually shifting to encompass the host immune response. However, these are centered on mouse models of Escherichia coli infection, which may not fully recapitulate the infective etiology and immune responses seen in humans. The emerging field of the urobiome also inadvertently confounds the discrimination of true UTI-causing pathogens from commensals. This review aims to present a novel perspective on chronic UTI by linking microbiology with immunology, which are commonly divergent in this field of research. It also describes the challenges in understanding chronic UTI pathogenesis and the human bladder immune response, largely conjectured from murine studies. Lastly, it outlines the shortcomings of current diagnostic methods in identifying individuals with chronic UTI and consequently treating them, potentially aggravating their disease due to mismanagement of prior episodes. This discourse highlights the need to consider these knowledge gaps and encourages more relevant studies of UTI in humans.

Keywords:  Urinary tract infection; chronic; immune response; treatment; uropathogen

DOI:  https://doi.org/10.1016/j.mucimm.2022.12.003
Elife. 2023 Jan 16. pii: e81692. [Epub ahead of print]12

Dynamics of immune memory and learning in bacterial communities.

Madeleine Bonsma-Fisher, Sidhartha Goyal.

  From bacteria to humans, adaptive immune systems provide learned memories of past infections. Despite their vast biological differences, adaptive immunity shares features from microbes to vertebrates such as emergent immune diversity, long-term coexistence of hosts and pathogens, and fitness pressures from evolving pathogens and adapting hosts, yet there is no conceptual model that addresses all of these together. To this end, we propose and solve a simple phenomenological model of CRISPR-based adaptive immunity in microbes. We show that in coexisting phage and bacteria populations, immune diversity in both populations is coupled and emerges spontaneously, that bacteria track phage evolution with a context-dependent lag, and that high levels of diversity are paradoxically linked to low overall CRISPR immunity. We define average immunity, an important summary parameter predicted by our model, and use it to perform synthetic time-shift analyses on available experimental data to reveal different modalities of coevolution. Finally, immune cross-reactivity in our model leads to qualitatively different states of evolutionary dynamics, including an influenza-like traveling wave regime that resembles a similar state in models of vertebrate adaptive immunity. Our results show that CRISPR immunity provides a tractable model, both theoretically and experimentally, to understand general features of adaptive immunity.

Keywords:  physics of living systems

DOI:  https://doi.org/10.7554/eLife.81692
Clin Exp Dermatol. 2023 Jan 20. pii: llac138. [Epub ahead of print]

A review of topical probiotic therapy for atopic dermatitis.

Samantha Herbert, Reneé Haughton, Jordan Nava, Antonio Ji-Xu, Stephanie T Le, Emanual Maverakis.

Atopic dermatitis (AD) is a common, chronic skin disorder that is associated with dysbiosis of the skin microbiome along with an impaired skin barrier and abnormal immune signaling. Particularly, AD has been associated with increased abundance of S. aureus and decreased overall bacterial diversity. Topical probiotic formulations are garnering further interest in the treatment of AD and may be derived from commensal bacteria found on healthy epithelium, or from exogenous bacteria. Strains chosen for clinical trials have often demonstrated antimicrobial actions to S. aureus in-vitro. Multiple randomized clinical trials with topical probiotics have resulted in significant improvements in clinical severity, decreased abundance of S. aureus in treated lesional skin, and increased bacterial diversity. Side effects from available studies have been minimal apart from one patient who developed a furuncle in the treatment area. Although further research including larger, longer-term clinical trials need to be performed before topical probiotics should be recommended to patients, topical probiotics have been shown to be safe and efficacious in AD.

DOI: https://doi.org/10.1093/ced/llac138
Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2214484120

Infection-elicited microbiota promotes host adaptation to nutrient restriction.

Mirian Krystel De Siqueira, Vinicius Andrade-Oliveira, Apollo Stacy, João Pedro Tôrres Guimarães, Ricardo Wesley Alberca-Custodio, Angela Castoldi, Jaqueline Marques Santos, Marcela Davoli-Ferreira, Luísa Menezes-Silva, Walter Miguel Turato, Seong-Ji Han, Arielle Glatman Zaretsky, Timothy Wesley Hand, Niels Olsen Saraiva Câmara, Momtchilo Russo, Sonia Jancar, Denise Morais da Fonseca, Yasmine Belkaid.

  The microbiota performs multiple functions vital to host fitness, including defense against pathogens and adaptation to dietary changes. Yet, how environmental challenges shape microbiota resilience to nutrient fluctuation remains largely unexplored. Here, we show that transient gut infection can optimize host metabolism toward the usage of carbohydrates. Following acute infection and clearance of the pathogen, mice gained more weight as a result of white adipose tissue expansion. Concomitantly, previously infected mice exhibited enhanced carbohydrate (glucose) disposal and insulin sensitivity. This metabolic remodeling depended on alterations to the gut microbiota, with infection-elicited Betaproteobacteria being sufficient to enhance host carbohydrate metabolism. Further, infection-induced metabolic alteration protected mice against stunting in the context of limited nutrient availability. Together, these results propose that alterations to the microbiota imposed by acute infection may enhance host fitness and survival in the face of nutrient restriction, a phenomenon that may be adaptive in settings where both infection burden and food precarity are prevalent.

Keywords:  Yersinia; carbohydrate; host metabolism; malnutrition; white adipose tissue

DOI:  https://doi.org/10.1073/pnas.2214484120
Biosci Microbiota Food Health. 2023 ;42(1): 3-7

Development of a lactic acid bacteria strain that suppresses chronic inflammation and improves glucose and lipid metabolism.

Takayuki Toshimitsu.

  Chronic inflammation caused by aging, obesity, and lifestyle disturbances can lead to the production of inflammatory cytokines and insulin resistance, reducing glucose and lipid metabolism. Lactic acid bacteria (LAB) have various bioactivities, and certain types of LAB have been reported to exhibit anti-inflammatory effects. We hypothesized that LAB strains, which can strongly induce the production of anti-inflammatory cytokines by immune cells in the intestinal tract, may improve glucose and lipid metabolism by suppressing chronic inflammation. We selected Lactiplantibacillus plantarum OLL2712 (OLL2712) from the LAB library owned by Meiji Co., Ltd. based on its ability to induce the production of interleukin-10 (IL-10), optimized the culture conditions of OLL2712 for industrial applications, and verified the efficacy of the strain in animal and clinical studies. The results showed that OLL2712 bacterial cells in the exponential phase had notably higher anti-inflammatory properties than the cells in the stationary phase and led to the inhibition of chronic inflammation and improvement of glucose and lipid metabolism in animal studies. Two randomized controlled trials consisting of healthy adults with elevated blood glucose levels or body mass indices (BMIs) also showed that the intake of OLL2712 suppressed the aggravation of chronic inflammation and improved glucose and lipid metabolism. This review identified a novel LAB strain that may contribute to diabetes and obesity prevention and demonstrated its clinical efficacy. In addition, the mechanism of action of this LAB strain through the intestinal immune system was partially elucidated, and the importance of optimizing the culture conditions of LAB was clarified.

Keywords:  chronic inflammation; culture condition; diabetes mellitus; insulin resistance; interleukin 10; lactic acid bacteria; metabolic syndrome

DOI:  https://doi.org/10.12938/bmfh.2022-054
Nat Immunol. 2023 Jan 19.

An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells.

Simona Ceglia, Alyssa Berthelette, Kelsey Howley, Yun Li, Benedikt Mortzfeld, Shakti K Bhattarai, Nicole K H Yiew, Ying Xu, Robert Brink, Jason G Cyster, Lora V Hooper, Gwendalyn J Randolph, Vanni Bucci, Andrea Reboldi.

Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown. Although antibody secretion is considered to be imprinted during B cell differentiation and therefore largely unaffected by environmental changes, a rapid modulation of IgA levels in response to intestinal fluctuations might be beneficial to the host. In the present study, we showed that dietary cholesterol absorption and commensal recognition by duodenal intestinal epithelial cells lead to the production of oxysterols, evolutionarily conserved lipids with immunomodulatory functions. Using conditional cholesterol 25-hydroxylase deleter mouse line we demonstrated that 7α,25-dihydroxycholesterol from epithelial cells is critical to restrain IgA secretion against commensal- and pathogen-derived antigens in the gut. Intestinal plasma cells sense oxysterols via the chemoattractant receptor GPR183 and couple their tissue positioning with IgA secretion. Our findings revealed a new mechanism linking dietary cholesterol and humoral immune responses centered around plasma cell localization for efficient mucosal protection.

DOI: https://doi.org/10.1038/s41590-022-01413-w
Adv Sci (Weinh). 2023 Jan 19. e2206617

Mouse Tissue-Resident Peritoneal Macrophages in Homeostasis, Repair, Infection, and Tumor Metastasis.

Carlos Ardavín, Natalia Alvarez-Ladrón, Margarita Ferriz, Alejandra Gutiérrez-González, Adrián Vega-Pérez.

  Large peritoneal macrophages (LPMs) are long-lived, tissue-resident macrophages, formed during embryonic life, developmentally and functionally confined to the peritoneal cavity. LPMs provide the first line of defense against life-threatening pathologies of the peritoneal cavity, such as abdominal sepsis, peritoneal metastatic tumor growth, or peritoneal injuries caused by trauma, or abdominal surgery. Apart from their primary phagocytic function, reminiscent of primitive defense mechanisms sustained by coelomocytes in the coelomic cavity of invertebrates, LPMs fulfill an essential homeostatic function by achieving an efficient clearance of apoptotic, that is crucial for the maintenance of self-tolerance. Research performed over the last few years, in mice, has unveiled the mechanisms by which LPMs fulfill a crucial role in repairing peritoneal injuries and controlling microbial and parasitic infections, reflecting that the GATA6-driven LPM transcriptional program can be modulated by extracellular signals associated with pathological conditions. In contrast, recent experimental evidence supports that peritoneal tumors can subvert LPM metabolism and function, leading to the acquisition of a tumor-promoting potential. The remarkable functional plasticity of LPMs can be nevertheless exploited to revert tumor-induced LPM protumor potential, providing the basis for the development of novel immunotherapeutic approaches against peritoneal tumor metastasis based on macrophage reprogramming.

Keywords:  macrophages; monocyte-derived macrophages; peritoneal cavity; peritoneal injury; peritoneal metastasis; peritoneal sepsis; tissue-resident macrophages

DOI:  https://doi.org/10.1002/advs.202206617
Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2212813120

HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages.

Kaustav Das Gupta, Divya Ramnath, Jessica B von Pein, James E B Curson, Yizhuo Wang, Rishika Abrol, Asha Kakkanat, Shayli Varasteh Moradi, Kimberley S Gunther, Ambika M V Murthy, Claudia J Stocks, Ronan Kapetanovic, Robert C Reid, Abishek Iyer, Zoe C Ilka, William M Nauseef, Manuel Plan, Lin Luo, Jennifer L Stow, Kate Schroder, Denuja Karunakaran, Kirill Alexandrov, Melanie R Shakespear, Mark A Schembri, David P Fairlie, Matthew J Sweet.

  The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1β production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic Escherichia coli (UPEC). HDAC7-mediated PPP engagement via 6-phosphogluconate dehydrogenase (6PGD) generates NADPH for antimicrobial ROS production, as well as D-ribulose-5-phosphate (RL5P) that both synergizes with ROS for UPEC killing and suppresses selective inflammatory responses. This dual functionality of the HDAC7-6PGD-RL5P axis prioritizes responses to proximal threats. Our findings thus reveal that the PPP metabolite RL5P has both antimicrobial and immunomodulatory activities and that engagement of enzymes in catabolic versus anabolic metabolic pathways triages responses to different types of danger for generation of inflammatory versus antimicrobial responses, respectively.

Keywords:  immunometabolism; inflammation; macrophages; pentose phosphate pathway; uropathogenic Escherichia coli

DOI:  https://doi.org/10.1073/pnas.2212813120
Sci Rep. 2023 Jan 17. 13(1): 870

Novel 3D Flipwell system that models gut mucosal microenvironment for studying interactions between gut microbiota, epithelia and immunity.

Maria A Beamer, Cassandra Zamora, Andrea L Nestor-Kalinoski, Veani Fernando, Vandana Sharma, Saori Furuta.

Gut mucosa consists of stratified layers of microbes, semi-permeable mucus, epithelium and stroma abundant in immune cells. Although tightly regulated, interactions between gut commensals and immune cells play indispensable roles in homeostasis and cancer pathogenesis in the body. Thus, there is a critical need to develop a robust model for the gut mucosal microenvironment. Here, we report our novel co-culture utilizing 3D Flipwell system for establishing the stratified layers of discrete mucosal components. This method allows for analyzing synchronous effects of test stimuli on gut bacteria, mucus, epithelium and immune cells, as well as their crosstalks. In the present report, we tested the immuno-stimulatory effects of sepiapterin (SEP, the precursor of the cofactor of nitric oxide synthase (NOS)-BH4) on the gut mucosal community. We previously reported that SEP effectively reprogrammed tumor-associated macrophages and inhibited breast tumor cell growth. In our co-cultures, SEP largely promoted mucus integrity, bacterial binding, and M1-like polarization of macrophages. Conversely, these phenomena were absent in control-treated cultures. Our results demonstrate that this novel co-culture may serve as a robust in vitro system to recapitulate the effects of pharmacological agents on the gut mucosal microenvironment, and could potentially be expanded to test the effects outside the gut.

DOI: https://doi.org/10.1038/s41598-023-28233-8
Cell Death Discov. 2023 Jan 16. 9(1): 9

Regulatory T cell and macrophage crosstalk in acute lung injury: future perspectives.

Tianshu Guan, Xv Zhou, Wenwen Zhou, Hui Lin.

Acute lung injury (ALI) describes the injury to endothelial cells in the lungs and associated vessels due to various factors. Furthermore, ALI accompanied by inflammation and thrombosis has been reported as a common complication of SARS-COV-2 infection. It is widely accepted that inflammation and the cytokine storm are main causes of ALI. Two classical anti-inflammatory cell types, regulatory T cells (Tregs) and M2 macrophages, are theoretically capable of resisting uncontrolled inflammation. Recent studies have indicated possible crosstalk between Tregs and macrophages involving their mutual activation. In this review, we discuss the current findings related to ALI pathogenesis and the role of Tregs and macrophages. In particular, we review the molecular mechanisms underlying the crosstalk between Tregs and macrophages in ALI pathogenesis. Understanding the role of Tregs and macrophages will provide the potential targets for treating ALI.

DOI: https://doi.org/10.1038/s41420-023-01310-7
mBio. 2023 Jan 16. e0328022

Endogenous Reverse Transcriptase Inhibition Attenuates TLR5-Mediated Inflammation.

Nicholas Dopkins, Bhavya Singh, Stephanie Michael, Morgan M O'Mara, Jez L Marston, Tongyi Fei, Matthew L Bendall, Douglas F Nixon.

  Transposable elements (TEs) are mobile genomic sequences that encompass roughly 50% of the human genome. Class 1 TEs, or "retrotransposons," mobilize through the production of an RNA intermediate that is then reverse transcribed to form complementary DNA (cDNA) molecules capable of genomic reinsertion. While TEs are traditionally silenced to maintain genomic integrity, the recognition of immunostimulatory cues, such as those provided by microorganisms, drastically alters host transcription to induce the differential expression of TEs. Emerging evidence demonstrates that the inducible production of TE cDNA is not an inert phenomenon but instead has been coopted by host immunity to facilitate cross talk between host and constituents of the microbiota by agonizing intrinsic antiviral receptors. Here, we demonstrate that immunostimulation of toll-like receptor 4 (TLR4) with lipopolysaccharide (LPS) and TLR5 with bacterial flagella (FLA) alters the expression of retrotransposons, such as human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs). Next, we demonstrate that reverse transcriptase inhibitor (RTi) delivery ameliorates the acute production of the proinflammatory cytokine "tumor necrosis factor alpha" (TNF-α) in response to FLA in a monocytic cell line (THP-1). Collectively, our findings demonstrate that TLR5-mediated cross talk between the host and microbiota is partially dependent on the reverse transcription (RT) of retrotransposons. IMPORTANCE The microbiota is a potent reservoir of immunostimulatory and immunosuppressive motifs that fundamentally shape host immunity. Despite broad associations between microbial composition and host immunity, the mechanisms underlying host microbiota-induced immunoregulation remain poorly defined. Here, we demonstrate a novel mechanism by which motifs overabundant during dysbiotic conditions influence host immunity through the upregulation of endogenous RT to produce motifs that agonize antiviral receptors.

Keywords:  flagella; human endogenous retrovirus (HERV); innate immunity; long interspersed nuclear element (LINE); toll-like receptors (TLRs)

DOI:  https://doi.org/10.1128/mbio.03280-22
Eur J Immunol. 2023 Jan 15. e2149548

Classical DC2 subsets and monocyte-derived DC: delineating the developmental and functional relationship.

Ronald A Backer, Hans Christian Probst, Björn E Clausen.

  To specifically tailor immune responses to a given pathogenic threat, dendritic cells (DC) are highly heterogeneous and comprise many specialized subtypes, including conventional DC (cDC) and monocyte-derived DC (MoDC), each with distinct developmental and functional characteristics. However, the functional relationship between cDC and MoDC is not fully understood, as the overlapping phenotypes of certain type 2 cDC (cDC2) subsets and MoDC do not allow satisfactory distinction of these cells in the tissue, particularly during inflammation. Yet, precise cDC2 and MoDC classification is required for studies addressing how these diverse cell types control immune responses and is therefore currently one of the major interests in the field of cDC research. This review will revise murine cDC2 and MoDC biology in the steady-state and under inflammatory conditions and discusses the commonalities and differences between ESAMlo cDC2, inflammatory cDC2, and MoDC and their relative contribution to the initiation, propagation, and regulation of immune responses. This article is protected by copyright. All rights reserved.

Keywords:  ESAMlo cDC2; inflammatory cDC2; monocyte-derived DC (MoDC)

DOI:  https://doi.org/10.1002/eji.202149548