Search

Journal of nephrology JN (2022). doi:10.1007/s40620-022-01454-2, Published by Springer, Milano

IEEE transactions on plasma science : PS 50(5), 1237-1245 (2022). doi:10.1109/TPS.2022.3164220, Published by IEEE, New York, NY

The gut and the liver are characterized by mutual interactions between both organs, the microbiome, diet and other environmental factors. The sum of these interactions is conceptualized as the gut-liver axis. In this Review we discuss the gut-liver axis, concentrating on the barriers formed by the enterohepatic tissues to restrict gut-derived microorganisms, microbial stimuli and dietary constituents. In addition, we discuss the establishment of barriers in the gut and liver during development and their cooperative function in the adult host. We detail the interplay between microbial and dietary metabolites, the intestinal epithelium, vascular endothelium, the immune system and the various host soluble factors, and how this interplay establishes a homeostatic balance in the healthy gut and liver. Finally, we highlight how this balance is disrupted in diseases of the gut and liver, outline the existing therapeutics and describe the cutting-edge discoveries that could lead to the development of novel treatment approaches.In this Review, Pabst and colleagues discuss the gut-liver axis, with an emphasis on the establishment and regulation of structural and functional barriers, dynamics within the axis (immune responses and microbiome) and clinical implications.

Diabetic peripheral neuropathy (DPN) may lead to several changes in the skin, and some of these may influence the skin impedance spectrum. In the present study we have developed a prototype solution for skin impedance spectroscopy at selected skin sites (big toe pulp, heel and toe ball) that was tested in a pilot study on five patients with DPN and five healthy controls. At the big toe, most of the controls had markedly lower impedance than the DPN group, especially in the range of 1-100 kHz. The separation between the groups seems to be weaker at the heel and weakest at the toeball. The results may indicate that monitoring of the skin impedance spectrum may be a method for detection of skin changes associated with DPN, encouraging further studies with the big toe sensor in particular.

All leukocytes can get entrance into the draining lymph nodes via the afferent lymphatics but only lymphoid cells can leave the nodes. The molecular mechanisms behind this phenomenon have remained unknown. We employed genome wide microarray analyses of the subcapsular sinus and lymphatic sinus (LS) endothelial cells and found Robo4 to be selectively expressed on LS lymphatics. Further analyses showed high Robo4 expression in lymphatic vessels of Peyer’s patches, which only have efferent lymphatic vessels. In functional assays, Robo4-deficient animals showed accumulation of naive B cells (CD19+/CD62Lhi/CD44lo) in Peyer’s patches, whereas no difference was seen within other lymphocyte subtypes. Short-term lymphocyte homing via high endothelial venules to peripheral and mesenteric lymph nodes and Peyer’s patches was also slightly impaired in Robo4 knockout animals. These results show for the first time, selective expression of Robo4 in the efferent arm of the lymphatics and its role in controlling the turnover of a subset of B lymphocytes from Peyer’s patches.

Microbial invasion into the intestinal mucosa after allogeneic hematopoietic cell transplantation (allo-HCT) triggers neutrophil activation and requires antibiotic interventions to prevent sepsis. However, antibiotics lead to a loss of microbiota diversity, which is connected to a higher incidence of acute graft-versus-host disease (aGVHD). Antimicrobial therapies that eliminate invading bacteria and reduce neutrophil-mediated damage without reducing the diversity of the microbiota are therefore highly desirable. A potential solution would be the use of antimicrobial antibodies that target invading pathogens, ultimately leading to their elimination by innate immune cells. In a mouse model of aGVHD, we investigated the potency of active and passive immunization against the conserved microbial surface polysaccharide poly-N-acetylglucosamine (PNAG) that is expressed on numerous pathogens. Treatment with monoclonal or polyclonal antibodies to PNAG (anti-PNAG) or vaccination against PNAG reduced aGVHD-related mortality. Anti-PNAG treatment did not change the intestinal microbial diversity as determined by 16S ribosomal DNA sequencing. Anti-PNAG treatment reduced myeloperoxidase activation and proliferation of neutrophil granulocytes (neutrophils) in the ileum of mice developing GVHD. In vitro, anti-PNAG treatment showed high antimicrobial activity. The functional role of neutrophils was confirmed by using neutrophil-deficient LysM(cre) Mcl1(fl/fl) mice that had no survival advantage under anti-PNAG treatment. In summary, the control of invading bacteria by anti-PNAG treatment could be a novel approach to reduce the uncontrolled neutrophil activation that promotes early GVHD and opens a new avenue to interfere with aGVHD without affecting commensal intestinal microbial diversity.

The impact of food antigens on intestinal homeostasis and immune function is poorly understood. Here, we explored the impact of dietary antigens on the phenotype and fate of intestinal T cells. Physiological uptake of dietary proteins generated a highly activated CD44(+)Helios(+)CD4(+) T cell population predominantly in Peyer patches. These cells are distinct from regulatory T cells and develop independently of the microbiota. Alimentation with a protein-free, elemental diet led to an atrophic small intestine with low numbers of activated T cells, including Tfh cells and decreased amounts of intestinal IgA and IL-10. Food-activated CD44(+)Helios(+)CD4(+) T cells in the Peyer patches are controlled by the immune checkpoint molecule PD-1. Blocking the PD-1 pathway rescued these T cells from apoptosis and triggered proinflammatory cytokine production, which in IL-10–deficient mice was associated with intestinal inflammation. In support of these findings, our study of patients with Crohn’s disease revealed significantly reduced frequencies of apoptotic CD4(+) T cells in Peyer patches as compared with healthy controls. These results suggest that apoptosis of diet-activated T cells is a hallmark of the healthy intestine.

Oral tolerance to soluble antigens is critically important for the maintenance of immunological homeostasis in the gut. The mechanisms of tolerance induction to antigens of the gut microbiota are still less well understood. Here, we investigate whether the subcellular localization of antigens within non-pathogenic E. coli has a role for its ability to induce antigen-specific tolerance. E. coli that express an ovalbumin (OVA) peptide in the cytoplasm, at the outer membrane or as secreted protein were generated. Intestinal colonization of mice with non-pathogenic E. coli expressing OVA at the membrane induced the expansion of antigen-specific Foxp3+ Tregs and mediated systemic immune tolerance. In contrast, cytoplasmic OVA was ignored by antigen-specific CD4+ T cells and failed to induce tolerance. In vitro experiments revealed that surface-displayed OVA of viable E. coli was about two times of magnitude more efficient to activate antigen-specific CD4+ T cells than soluble antigens, surface-displayed antigens of heat-killed E. coli or cytoplasmic antigen of viable or heat-killed E. coli. This effect was independent of the antigen uptake efficiency in dendritic cells. In summary, our results show that subcellular antigen localization in viable E. coli strongly influences antigen-specific CD4+ cell expansion and tolerance induction upon intestinal colonization.

It has been demonstrated before that human skin can be modeled as a memristor (memory resistor). Here we realize a memristor bridge by applying two voltages of opposite signs at two different skin sites. By this setup it is possible to use human skin as a frequency doubler and half-wave rectifier which is an application of the non-linear electrical properties of human skin. The corresponding electrical measurements are non-linear since these are affected by the applied stimulus itself.

Key aspects of intestinal T cells, including their antigen specificity and their selection by the microbiota and other intestinal antigens, as well as the contribution of individual T cell clones to regulatory and effector functions, remain unresolved. Here we tracked adoptively transferred T cell populations to specify the interrelation of T cell receptor repertoire and the gut antigenic environment. We show that dominant TCRα clonotypes were shared between interferon-γ- and interleukin-17-producing but not regulatory Foxp3

Human skin has been classified as a non-volatile memristor and it is shown that information can be stored within for at least three minutes. Here we investigate whether it is possible to store information up to 20 minutes. Furthermore, we investigate whether the information can be based on four different states, not just two (binary). We stored the information into the skin of the forehead of the test subjects under three different electrodes, which allows in principle for 64 different combinations (3 electrodes, 4 states) and one can think of numbers on the base of four. For this experiment, we decided on the numbers 1234 and 3024 (that correspond to numbers 27 and 50 in the decimal system). Writing of the different states was done by the application of DC voltage pulses that cause electro-osmosis in the sweat ducts (nonlinear electrical measurements). Based on our results, we were not able to distinguish between four different states. However, we can show that binary information storage in human skin is possible for up to 20 minutes.

World Allergy Organization journal 14(11), 100586 (2021). doi:10.1016/j.waojou.2021.100586, Published by Wolters Kluwer Health Lippincott Williams & Wilkins, Hagerstown, Md.

Seminars in immunopathology (2021). doi:10.1007/s00281-021-00879-4, Published by Springer, Berlin; Heidelberg

Background During Inflammatory Bowel Diseases (IBD), CD4+ effector T cells are main mediators of the tissue damage. Among them, Th17 cells strongly contribute to the inflammatory response. Interestingly, our lab previously showed that Th17 cells can convert into regulatory T cells, thereby controlling inflammation. However, the forces controlling the plasticity of T cells during IBD remain largely unknown. Our aim is to understand, how CD4+ T-cell plasticity can be modulated from a pro-inflammatory towards an anti-inflammatory profile during IBD. It is currently known that both Th17 and Foxp3 Treg cells can recognize microbiota-derived antigens and that changes in the microbiota are commonly observed in IBD. We hypothesize that the microbiota is a key candidate to modulate T-cell plasticity. Methods T-cell transfer mouse IBD model was performed by transferring CD4+ naïve T-cells into Rag1 -/- receptors. To study Th17 T-cell plasticity, we used as donors IL-17A Fate-mapping mice. These mice comprise of an IL-17ACRE/R26fl/fl YFP construct where the cells that previously expressed IL-17A turn into YFP+ cells. Ciprofloxacin and metronidazole, two antibiotics commonly given to IBD patients, were used to treat the mice. Stool microbiota composition was analysed longitudinally by 16S rRNA amplicon sequencing. Colitis development was evaluated by colonoscopy. CD4+ T cells were isolated from the colon and reporter expression was analysed by Flow Cytometry. Results After T-cell transfer colitis induction, ciprofloxacin and metronidazole treatment alleviated gut inflammation, as determined by weight loss (p=0.005), colitis score (p=0.004) and colon length (p=0.01). Antibiotic treatment increased the relative abundance of bacteria previously associated with beneficial IBD outcomes (e.g. Bifidobacterium). Interestingly, colonic CD4+ T-cells showed an increased conversion from Th17 towards a Foxp3+ Treg profile (Foxp3ExTh17) (p=0.03). Conclusion The conversion of CD4+ effector T cells into Treg cells is a promising approach to counteract inflammation in IBD patients. We showed that antibiotic treatment not only correlates with a relative expansion of beneficial bacteria, but perhaps most interesting, with an increased conversion of effector Th17 cells towards Foxp3+ Treg cells in the colon. Altogether, these data support the manipulation of the microbiota as a tool to revert intestinal inflammation in IBD patients.

Immune cell trafficking is an important mechanism for the pathogenesis of inflammatory bowel disease (IBD). The oxysterol receptor GPR183 and its ligands, dihydroxylated oxysterols, can mediate positioning of immune cells including innate lymphoid cells. GPR183 has been mapped to an IBD risk locus, however another gene, Ubac2 is encoded on the reverse strand and associated with Behçet's disease, therefore the role of GPR183 as a genetic risk factor requires validation. GPR183 and production of its oxysterol ligands are up-regulated in human IBD and murine colitis. Gpr183 inactivation reduced severity of colitis in group 3 innate lymphoid cells-dependent colitis and in IL-10 colitis but not in dextran sodium sulphate colitis. Irrespectively, Gpr183 knockout strongly reduced accumulation of intestinal lymphoid tissue in health and all colitis models. In conclusion, genetic, translational and experimental studies implicate GPR183 in IBD pathogenesis and GPR183-dependent cell migration might be a therapeutic drug target for IBD. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

The authors reveal a mechanism of SIgA–microbiota interaction in the adult human gut. They describe antibodies with a high capacity to bind phylogenetically distant members of the microbiota. Such cross-species reactivity does not correlate with antibody polyreactivity but crucially depends on somatic mutations., The gut is home to the body’s largest population of plasma cells. In healthy individuals, IgA is the dominating isotype, whereas patients with inflammatory bowel disease also produce high concentrations of IgG. In the gut lumen, secretory IgA binds pathogens and toxins but also the microbiota. However, the antigen specificity of IgA and IgG for the microbiota and underlying mechanisms of antibody binding to bacteria are largely unknown. Here we show that microbiota binding is a defining property of human intestinal antibodies in both healthy and inflamed gut. Some bacterial taxa were commonly targeted by different monoclonal antibodies, whereas others selectively bound single antibodies. Interestingly, individual human monoclonal antibodies from both healthy and inflamed intestines bound phylogenetically unrelated bacterial species. This microbiota cross-species reactivity did not correlate with antibody polyreactivity but was crucially dependent on the accumulation of somatic mutations. Therefore, our data suggest that a system of affinity-matured, microbiota cross-species–reactive IgA is a common aspect of SIgA–microbiota interactions in the gut.

Secretory IgA has long been a divisive molecule. Some immunologists point to the mild phenotype of IgA deficiency to justify ignoring it, while some consider its abundance and evolutionary history as grounds for its importance. Further, there is extensive and growing disagreement over the relative importance of affinity-matured, T cell-dependent IgA vs. “natural” and T cell-independent IgA in both microbiota and infection control. As with all good arguments, there is good data supporting different opinions. Here we revisit longstanding questions in IgA biology. We start the discussion from the question of intestinal IgA antigen specificity and critical definitions regarding IgA induction, specificity, and function. These definitions must then be tessellated with the cellular and molecular pathways shaping IgA responses, and the mechanisms by which IgA functions. On this basis we propose how IgA may contribute to the establishment and maintenance of beneficial interactions with the microbiota. ISSN:1933-0219 ISSN:1935-3456

The gut mounts secretory immunoglobulin A (SIgA) responses to commensal bacteria through nonredundant T cell-dependent (TD) and T cell-independent (TI) pathways that promote the establishment of mutualistic host-microbiota interactions. SIgAs from the TD pathway target penetrant bacteria, and their induction requires engagement of CD40 on B cells by CD40 ligand on T follicular helper cells. In contrast, SIgAs from the TI pathway bind a larger spectrum of bacteria, but the mechanism underpinning their production remains elusive. Here, we show that the intestinal TI pathway required CD40-independent B cell-activating signals from TACI, a receptor for the innate CD40 ligand-like factors BAFF and APRIL. TACI-induced SIgA responses targeted a fraction of the gut microbiota without shaping its overall composition. Of note, TACI was dispensable for TD induction of IgA in gut-associated lymphoid organs. Thus, BAFF/APRIL signals acting on TACI orchestrate commensal bacteria-specific SIgA responses through an intestinal TI program.

Much is already understood about the anatomical and physiological mechanisms behind the linear, electrical properties of biological tissues. Studying the non-linear electrical properties, however, opens up for the influence from other processes that are driven by the electric field or movement of charges. An electrical measurement that is affected by the applied electrical stimulus is non-linear and reveals the non-linear electrical properties of the underlying (biological) tissue; if it is done with an alternating current (AC) stimulus, the corresponding voltage current plot may exhibit a pinched hysteresis loop which is the fingerprint of a memristor. It has been shown that human skin and other biological tissues are memristors. Here we performed non-linear electrical measurements on human skin with applied direct current (DC) voltage pulses. By doing so, we found that human skin exhibits non-volatile memory and that analogue information can actually be stored inside the skin at least for three minutes. As demonstrated before, human skin actually contains two different memristor types, one that originates from the sweat ducts and one that is based on thermal changes of the surrounding tissue, the stratum corneum; and information storage is possible in both. Finally, assuming that different physiological conditions of the skin can explain the variations in current responses that we observed among the subjects, it follows that non-linear recordings with DC pulses may find use in sensor applications.

An electrical measurement is non-linear when it is affected by the applied stimulus, i.e. when the measured phenomenon changes with amplitude. If pinched hysteresis loops can be observed in the voltage current representation, the underlying tissue can be classified as a memristor. Several biological memristors have been published, like human skin and apples. However, changes in the polarization impedance of electrodes may also cause pinched hysteresis loops. The question whether the reported biological memristors are real or whether the results just reflect changes in the polarization impedance arises. If the impedance of the measured object is close to or smaller than the polarization impedance of the used electrodes, the latter may dominate the measurement. In this study, we investigated the non-linear electrical properties of silver/silver chloride electrodes in a sodium chloride solution that has a similar concentration as human sweat and compared these to results from human skin. First of all, we found that silver/silver chloride electrodes in sodium chloride solution can be classified as memristors. However, the currents obtained from the sodium chloride solution are much higher than the currents recorded from human skin and there is a qualitative difference in the pinched hysteresis loops in both cases. We can conclude that the non-linear electrical measurements with silver/silver chloride on human skin are actually dominated by the skin and we can confirm that the human skin memristor really exists.

Non-linear electrical properties of a (biological) tissue can be revealed by non-linear electrical measurements, which means that the applied stimulus itself affects the measurement. If resulting voltage–current plots exhibit pinched hysteresis loops, the underlying tissue may be classified as a memristor, a state dependent resistor. The aloe vera plant and apples have been found to be memristors. However, polarization processes on the electrodes are also non-linear and may affect the measurement. Apples and aloe vera conduct electrical current very well and it is likely that the recordings are actually dominated by the polarization impedance of the electrodes. Here, we study the non-linear properties of aloe vera and apples with two different measurement electrode types. Furthermore, we measured also on the extracted liquids from one aloe vera leaf and one apple, leading to similar results. We concluded, unlike previous studies on these subjects, that the memristive properties originate from electrochemical reactions on the electrodes rather than the apples or aloe vera themselves.

Open tubular liquid chromatography columns with organic polymer layers can be powerful tools for high sensitivity measurements in e.g. proteomics. However, these narrow columns are challenging to characterize. A two-electrode system, often used for bioimpendance measurements, was used to study poly(styrene-co-divinylbenzene = PS-DVB) polymer layered open tubular (PLOT) liquid chromatography columns with 10 μm inner diameters. The system performed electrical resistance measurements (ERM) for assessing layer thickness and porosity. Layer determination results were comparable (but more precise) to that obtained with scanning electron microscopy (SEM). Porosity examinations with ERM casted doubt on the presence/availability of pores in the layers investigated.

Immunity (2021). doi:10.1016/j.immuni.2021.08.014, Published by Cell Press, [Cambridge, Mass.]

Recording electrodermal activity is a well-accepted physiological measurement for clinical approaches and research. Historically, applying a DC (direct current) signal to the skin to measure the conductance is the most common practice for exogenous recordings. However, this method can be subject to error due to electrode polarization even with "nonpolarizing" electrodes-a problem that can be eliminated with alternating current (AC) methodology. For that reason, Boucsein et al. () called for research demonstrating an AC method that is validated by comparison to standard DC methodology. Additionally, the complex structure of human skin has electrical properties that include both resistance and capacitance, and AC recording enables the measurement of skin susceptance (associated with current flow through capacitors). Finally, AC recording permits the simultaneous recording of the endogenous skin potential. In this paper, the results from a direct comparison between both methods are presented, which has not been reported previously. The results demonstrated excellent agreement between a 20 Hz AC method and a standard DC method, supporting the validity of the AC recording methodology employed. The results also showed that an applied voltage of 0.2 V is sufficient for DC recordings.

Microbial invasion into the intestinal mucosa after allogeneic hematopoietic cell transplantation (allo-HCT) triggers neutrophil activation and requires antibiotic interventions to prevent sepsis. However, antibiotics lead to a loss of microbiota diversity, which is connected to a higher incidence of acute graft-versus-host disease (aGVHD). Antimicrobial therapies that eliminate invading bacteria and reduce neutrophil-mediated damage without reducing the diversity of the microbiota are therefore highly desirable. A potential solution would be the use of antimicrobial antibodies that target invading pathogens, ultimately leading to their elimination by innate immune cells. In a mouse model of aGVHD, we investigated the potency of active and passive immunization against the conserved microbial surface polysaccharide poly-N-acetylglucosamine (PNAG) that is expressed on numerous pathogens. Treatment with monoclonal or polyclonal antibodies to PNAG (anti-PNAG) or vaccination against PNAG reduced aGVHD-related mortality. Anti-PNAG treatment did not change the intestinal microbial diversity as determined by 16S ribosomal DNA sequencing. Anti-PNAG treatment reduced myeloperoxidase activation and proliferation of neutrophil granulocytes (neutrophils) in the ileum of mice developing GVHD. In vitro, anti-PNAG treatment showed high antimicrobial activity. The functional role of neutrophils was confirmed by using neutrophil-deficient LysM(cre) Mcl1(fl/fl) mice that had no survival advantage under anti-PNAG treatment. In summary, the control of invading bacteria by anti-PNAG treatment could be a novel approach to reduce the uncontrolled neutrophil activation that promotes early GVHD and opens a new avenue to interfere with aGVHD without affecting commensal intestinal microbial diversity.