Cross talk between Paneth and tuft cells drives dysbiosis and inflammation in the gut mucosa.

Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells are considered to be guardians of the gut microbiota, but the events linking Paneth cell dysfunction with dysbiosis remain unclear. We report a three-step mechanism for dysbiosis initiation. Initial alterations in Paneth cells, as frequently observed in obese and inflammatorybowel diseases patients, cause a mild remodeling of microbiota, with amplification of succinate-producing species. SucnR1-dependent activation of epithelial tuft cells triggers a type 2 immune response that, in turn, aggravates the Paneth cell defaults, promoting dysbiosis and chronic inflammation. We thus reveal a function of tuft cells in promoting dysbiosis following Paneth cell deficiency and an unappreciated essential role of Paneth cells in maintaining a balanced microbiota to prevent inappropriate activation of tuft cells and deleterious dysbiosis. This succinate-tuft cell inflammation circuit may also contribute to the chronic dysbiosis observed in patients.

Identification of a muropeptide precursor transporter from gut microbiota and its role in preventing intestinal inflammation.

The gut microbiota is a considerable source of biologically active compounds that can promote intestinal homeostasis and improve immune responses. Here, we used large expression libraries of cloned metagenomic DNA to identify compounds able to sustain an anti-inflammatory reaction on host cells. Starting with a screen for NF-κB activation, we have identified overlapping clones harbouring a heterodimeric ATP-binding cassette (ABC)-transporter from a Firmicutes. Extensive purification of the clone's supernatant demonstrates that the ABC-transporter allows for the efficient extracellular accumulation of three muropeptide precursor, with anti-inflammatory properties. They induce IL-10 secretion from human monocyte-derived dendritic cells and proved effective in reducing AIEC LF82 epithelial damage and IL-8 secretion in human intestinal resections. In addition, treatment with supernatants containing the muropeptide precursor reduces body weight loss and improves histological parameters in Dextran Sulfate Sodium (DSS)-treated mice. Until now, the source of peptidoglycan fragments was shown to come from the natural turnover of the peptidoglycan layer by endogenous peptidoglycan hydrolases. This is a report showing an ABC-transporter as a natural source of secreted muropeptide precursor and as an indirect player in epithelial barrier strengthening. The mechanism described here might represent an important component of the host immune homeostasis.

Post-traumatic seizures and factors associated among adult patients with depressed skull fractures at Mulago National Referral hospital; cross-sectional study.

INTRODUCTION: Post-traumatic seizures (PTS) are common among patients with depressed skull fractures (DSF). Understanding the burden of post traumatic seizures and the factors associated among adult patients with DSF is important to improve clinical care. OBJECTIVE: To determine the prevalence and factors associated with post-traumatic seizures among adult patients with DSF at Mulago National Referral hospital (MNRH). METHODS: A cross-sectional study was conducted among 333 study participants between March 2021 and February 2022. Socio-demographic, clinical laboratory factors and anti-seizure medications were collected using a study questionnaire. Data was analysed to determine the prevalence of PTS and factors associated with occurrence of PTS among patients with DSF. RESULTS: The mean age (±SD) of study participants was 31.2, (±10.5) years, with a male to female ratio of 10.4:1. Nearly half of the study participants had attained secondary level of education, while 31.6 % (105) were peasants (subsistence farmers). The overall prevalence of PTS among DSF study participants was 16.2 % (54participants). Late presentation of PTS was the highest at 9.0 % (30) followed by early PTS at 3.9 % [13] and immediate PTS at 3.3 % [11]. Moderate Glasgow coma score (GCS: 9-13), p < 0.015, severe traumatic brain injury (GCS: 3-8), p < 0.026 at the time of admission and midline brain shift (≥5mm), p < 0.009 were associated with PTS. Phenytoin (94.3 %) was the most commonly used ASM followed by phenobarbitone (1.4 %) and Valproate (1.1 %) among study participants. CONCLUSION: Patients with moderate and severe traumatic brain injury and midline brain shift were associated with post traumatic seizures. Early identification and intervention may reduce the burden of posttraumatic seizures in this category of patients.

Psychometric properties of the French Infant-Toddler Working Alliance Inventory Short version (IT-WAI-S).

OBJECTIVE: Therapeutic alliance has been little investigated in infant and toddler therapy, with no tools specifically adapted to this population. However, we have developed the Infant-Toddler Working Alliance Inventory-Short form (IT-WAI-S) which is based on the Working Alliance Inventory. The aim of this study was to assess the psychometric properties of this original French tool, in its two versions: for parent (IT-WAI-SP) and for therapist (IT-WAI-STh). METHOD: This study included 227 families consulting with their 18-48-month-old child for emotional or behavioral disorders. The scales were filled in at the first three therapy sessions. The IT-WAI-S acceptability, internal validity, reliability and predictive validity (association with child and mother's outcomes) were evaluated. RESULTS: Confirmatory then exploratory factor analyses revealed a three-factor structure for the both scales: Negative Experience of Care Relationship, Positive Alliance and Alliance with the Child. Acceptability, reproducibility and construct validity were satisfactory for both versions. The two versions predicted the child's outcome. The IT-WAI-SP predicted also the mother's outcome. The IT-WAI-STh gave more reproducible results, whereas the IT-WAI-SP was a better predictor of the child's progress. CONCLUSION: The two IT-WAI-S versions showed good psychometric properties and could be used to study the therapeutic alliance in young children.

From Ultrafast Photoinduced Small Polarons to Cooperative and Macroscopic Charge-Transfer Phase Transition.

We study by femtosecond infrared spectroscopy the ultrafast and persistent photoinduced phase transition of the Rb0.94Mn0.94Co0.06[Fe(CN)6]0.98 ⋅ 0.2H2O material, induced at room temperature by a single laser shot. This system exhibits a charge-transfer based phase transition with a 75 K wide thermal hysteresis, centred at room temperature, from the low temperature Mn3+-N-C-Fe2+ tetragonal phase to the high temperature Mn2+-N-C-Fe3+ cubic phase. At room temperature, the photoinduced phase transition is persistent. However, the out-of-equilibrium dynamics leading to this phase is multi-scale. Femtosecond infrared spectroscopy, particularly sensitive to local reorganizations through the evolution of the frequency of the N-C vibration modes with the different characteristic electronic states, reveals that at low laser fluence and on short time scale, the photoexcitation of the Mn3+-N-C-Fe2+ phase creates small charge-transfer polarons [Mn2+-N-C-Fe3+]* within ≃250 fs. The local trapping of photoinduced intermetallic charge-transfer is characterized by the appearance of a polaronic infrared band, due to the surrounding Mn2+-N-C-Fe2+ species. Above a threshold fluence, when a critical fraction of small CT-polarons is reached, the macroscopic phase transition to the persistent Mn2+-N-C-Fe3+ cubic phase occurs within ≃ 100 ps. This non-linear photo-response results from elastic cooperativity, intrinsic to a switchable lattice and reminiscent of a feedback mechanism.

An Insight into Functional Metagenomics: A High-Throughput Approach to Decipher Food-Microbiota-Host Interactions in the Human Gut.

Our understanding of the symbiotic relationship between the microbiota and its host has constantly evolved since our understanding that the "self" was not only defined by our genetic patrimony but also by the genomes of bugs living in us. The first culture-based methods highlighted the important functions of the microbiota. However, these methods had strong limitations and did not allow for a full understanding of the complex relationships that occur at the interface between the microbiota and the host. The recent development of metagenomic approaches has been a groundbreaking step towards this understanding. Its use has provided new insights and perspectives. In the present chapter, we will describe the advances of functional metagenomics to decipher food-microbiota and host-microbiota interactions. This powerful high-throughput approach allows for the assessment of the microbiota as a whole (including non-cultured bacteria) and enabled the discovery of new signaling pathways and functions involved in the crosstalk between food, the gut microbiota and its host. We will present the pipeline and highlight the most important studies that helped to develop the field. To conclude, we will emphasize the most recent developments and hot topics in functional metagenomics.

Adlercreutzia equolifaciens Is an Anti-Inflammatory Commensal Bacterium with Decreased Abundance in Gut Microbiota of Patients with Metabolic Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) affects about 20-40% of the adult population in high-income countries and is now a leading indication for liver transplantation and can lead to hepatocellular carcinoma. The link between gut microbiota dysbiosis and NAFLD is now clearly established. Through analyses of the gut microbiota with shotgun metagenomics, we observe that compared to healthy controls, Adlercreutzia equolifaciens is depleted in patients with liver diseases such as NAFLD. Its abundance also decreases as the disease progresses and eventually disappears in the last stages indicating a strong association with disease severity. Moreover, we show that A. equolifaciens possesses anti-inflammatory properties, both in vitro and in vivo in a humanized mouse model of NAFLD. Therefore, our results demonstrate a link between NAFLD and the severity of liver disease and the presence of A. equolifaciens and its anti-inflammatory actions. Counterbalancing dysbiosis with this bacterium may be a promising live biotherapeutic strategy for liver diseases.

Adaptation of the working alliance inventory to therapeutic interventions for early-age regulatory and behavioral symptoms: French versions of the infant-toddler WAI for parents and therapists.

OBJECTIVES: The therapeutic alliance, an essential component of the therapeutic process, has been investigated in adult and child therapy, but studies in the context of parent-infant or parent-toddler therapeutic interventions are scarce. This monocentric study aims to produce a French cross-cultural adaptation of a therapeutic alliance scale for the context of early consultations in a child and psychiatry department. METHOD: Fifty-five young children aged 3 to 30 months consulting for regulation or behavioral disorders and their mothers were included in the study. The working alliance inventory (WAI) was translated into French by two bilingual translators and adapted to early-age consultations in parent and therapist versions. Assessments of the child's symptoms and the parents' anxiety and depression were carried out at the start and end of therapy. We studied the association of the alliance with the initial clinical characteristics and with the outcome of the child and the mother. An exploratory factor analysis was performed considering the items most associated with expected outcomes. RESULTS: The alliance coded by the mother was lower in case of child behavioral problems and was associated with the mother and child outcome. Short versions of the infant-toddler WAI were developed based on factor analysis, highlighting four factors: positive goals and tasks, bond with the mother, alliance with the child, negative experience of care relationship. DISCUSSION: Results were similar to those found in therapy with adults or older children. The alliance issue in mother-baby therapies was as essential as in other therapy contexts. The short Infant-Toddler WAI resulting from this work must be validated in future studies.

Predictive factors for the outcome of emotional and/or behavioural disorders in 18- to 48-month-old children after parent-child psychotherapy: Protocol of a European prospective cohort study.

OBJECTIVES: Several studies have shown that in young children, behavioural and/or emotional disorders are more difficult to manage than regulatory disorders. Moreover, data are lacking on outcome predictive factors. This article presents a short synthesis of previous research about outcome predictive factors in child psychiatry. It also describes the protocol of a longitudinal observational European multicentre study the main objective of which was to identify predictive factors of behavioural and emotional disorder outcome in toddlers after parent-child psychotherapy. The secondary objectives were to study predictive factors of the outcome in parents (anxiety/depression symptoms) and parent-child relationship. METHOD: In order to highlight medium-effect size, 255 toddlers (age: 18 to 48 months) needed to be included. Outcomes will be assessed by comparing the pre- and post-therapy scores of a battery of questionnaires that assess the child's symptoms, the parents' anxiety/depression, and the parent-child relationship. Multivariate linear regression analysis will be used to identify predictive factors of the outcome among the studied variables (child age and sex, socio-economic status, life events, disorder type, intensity and duration, social support, parents' psychopathology, parents' attachment, parent-child relationships, therapy length and frequency, father's involvement in the therapy, and therapeutic alliance). EXPECTED RESULTS AND CONCLUSION: This study should allow identifying some of the factors that contribute to the outcome of externalizing and internalizing disorders, and distinguishing between pre-existing and treatment-related variables. It should also help to identify children at higher risk of poor outcome who require special vigilance on the part of the therapist. It should confirm the importance of therapeutic alliance. TRIAL REGISTRATION: ID-RCB 2008-A01088-47.

Out-of-equilibrium dynamics driven by photoinduced charge transfer in CsCoFe Prussian blue analogue nanocrystals.

In this paper we study the out-of-equilibrium dynamics associated with photoinduced charge-transfer (CT) in cyanide-bridged Co-Fe Prussian blue analogue nanocrystals. In these coordination networks, the structural trapping of the photoinduced CT polaron involves local electronic and structural reorganizations. Femtosecond X-ray and optical absorption spectroscopies show that the local structural trapping process occurs on similar timescale for particles with 11 nm and 70 nm sizes. The local photoinduced spin transition, elongating the Co-N bonds and driving the CoIIIFeII → CoIIFeIII CT, activates coherent lattice torsion modes. The elastic deformation waves, launched by these bond elongations, drive macroscopic volume expansion and breathing of the particles. The timescale of this macroscopic deformation depends strongly on the size of the particle, which is more evidence of the multiscale nature of photoinduced phenomena in molecular materials.

Biological properties and structural characterization of a novel rhamnolipid like-biosurfactants produced by Lactobacillus casei subsp. casei TM1B.

Biosurfactants are microbial surface-active compounds with antimicrobial and antioxidant activities that display a range of physiological functions. In this study, a strain isolated from a Cameroonian fermented milk "pendidam" and identified as Lactobacillus casei subsp. casei TM1B was used for biosurfactants production. The biosurfactants produced by L. casei TM1B with molasses as the substrate had a good surface (40.77 mN/m) and emulsifying (84.50%) activities. The scavenging of the ABTS+• radical (IC50 value of 0.60 ± 0.03 mg/mL) by the biosurfactants was found to be higher than that of DPPH• radical (IC50 value of 0.97 ± 0.13 mg/mL). The maximum chelating activity of biosurfactants (82.29%) was observed at 3.5 mg/mL. The biologically active compound of the biosurfactants produced by L. casei TM1B was identified as 2,5-O-methylrhamnofuranosyl-palmitate, a novel rhamnolipid-like biosurfactant by using chemical, Fourier transform infrared spectroscopy, gas chromatography-mass spectrometry, and NMR analysis. The biosurfactants were bactericidal against several Gram-negative and Gram-positive pathogens (minimum inhibitory concentration values ranged from 3.22 to 12.83 mg/mL), and scanning electron microscope analysis revealed bacterial cell walls and membranes as main targets.

Why Phonon Scattering in Glasses is Universally Small at Low Temperatures.

We present a novel view of the standard model of tunneling two level systems (TLSs) to explain the puzzling universal value of a quantity, C∼3×10^{-4}, that characterizes phonon scattering in glasses below 1 K as reflected in thermal conductivity, ultrasonic attenuation, internal friction, and the change in sound velocity. Physical considerations lead to a broad distribution of phonon-TLS couplings that (1) exponentially renormalize tunneling matrix elements, and (2) reduce the TLS density of states through TLS-TLS interactions. We find good agreement between theory and experiment for a variety of individual glasses.

Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism.

Current fructose consumption levels often overwhelm the intestinal capacity to absorb fructose. We investigated the impact of fructose malabsorption on intestinal endocrine function and addressed the role of the microbiota in this process. To answer this question, a mouse model of moderate fructose malabsorption [ketohexokinase mutant (KHK)-/-] and wild-type (WT) littermate mice were used and received a 20%-fructose (KHK-F and WT-F) or 20%-glucose diet. Cholecystokinin (Cck) mRNA and protein expression in the ileum and cecum, as well as preproglucagon (Gcg) and neurotensin (Nts) mRNA expression in the cecum, increased in KHK-F mice. In KHK-F mice, triple-label immunohistochemistry showed major up-regulation of CCK in enteroendocrine cells (EECs) that were glucagon-like peptide-1 (GLP-1)+/Peptide YY (PYY-) in the ileum and colon and GLP-1-/PYY- in the cecum. The cecal microbiota composition was drastically modified in the KHK-F in association with an increase in glucose, propionate, succinate, and lactate concentrations. Antibiotic treatment abolished fructose malabsorption-dependent induction of cecal Cck mRNA expression and, in mouse GLUTag and human NCI-H716 cells, Cck mRNA expression levels increased in response to propionate, both suggesting a microbiota-dependent process. Fructose reaching the lower intestine can modify the composition and metabolism of the microbiota, thereby stimulating the production of CCK from the EECs possibly in response to propionate.-Zhang, X., Grosfeld, A., Williams, E., Vasiliauskas, D., Barretto, S., Smith, L., Mariadassou, M., Philippe, C., Devime, F., Melchior, C., Gourcerol, G., Dourmap, N., Lapaque, N., Larraufie, P., Blottière, H. M., Herberden, C., Gerard, P., Rehfeld, J. F., Ferraris, R. P., Fritton, J. C., Ellero-Simatos, S., Douard, V. Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism.

Control of H_{2} Dissociative Ionization in the Nonlinear Regime Using Vacuum Ultraviolet Free-Electron Laser Pulses.

The role of the nuclear degrees of freedom in nonlinear two-photon single ionization of H_{2} molecules interacting with short and intense vacuum ultraviolet pulses is investigated, both experimentally and theoretically, by selecting single resonant vibronic intermediate neutral states. This high selectivity relies on the narrow bandwidth and tunability of the pulses generated at the FERMI free-electron laser. A sustained enhancement of dissociative ionization, which even exceeds nondissociative ionization, is observed and controlled as one selects progressively higher vibronic states. With the help of ab initio calculations for increasing pulse durations, the photoelectron and ion energy spectra obtained with velocity map imaging allow us to identify new photoionization pathways. With pulses of the order of 100 fs, the experiment probes a timescale that lies between that of ultrafast dynamical processes and that of steady state excitations.

TLR ligands and butyrate increase Pyy expression through two distinct but inter-regulated pathways.

The intestinal epithelium is an active barrier separating the host from its microbiota. It senses microbial compounds through expression of a wide range of receptors including the Toll-like receptors (TLRs). TLRs have been shown to regulate epithelium permeability or secretion of defensin by Paneth cells. However, the expression and function of TLRs in enteroendocrine L-cells, a specific subtype of intestinal cells secreting PYY and GLP-1, have not yet been assessed. PYY and GLP-1 are implicated in regulation of gut motility, food intake and insulin secretion, and are of great interest regarding obesity and type 2 diabetes. Using a cellular model of human L-cells and a reporter system for NF-κB activation pathway, we reported functional expression of TLRs in these cells. Stimulation with specific TLR-agonists increased expression of Pyy but not Proglucagon in an NF-κB-dependent manner. Moreover, the effect of TLR stimulation was additive to butyrate, a product of bacterial fermentation, on Pyy expression. Additionally, butyrate also increased Tlr expression, including Tlr4, and the NF-κB response to TLR stimulation. Altogether, our results demonstrated a role of TLRs in the modulation of Pyy expression and the importance of butyrate, a product of bacterial fermentation in regulation of microbial TLR-dependent sensing.

Numerical tool for estimating the dielectric constant, the thickness, and the coverage of immobilized inhomogeneous protein films on gold in aqueous solution.

A numerical simulation tool is reported for nanometer thin and inhomogeneous immobilized protein films on gold in aqueous solution. It allows for the first time, to the best of our knowledge, the simultaneous assessment of refractive index, film thickness, and surface coverage. The model relies on and combines the convective diffusion equation, the Langmuir adsorption isotherm, and the Helmholtz equation, with appropriate boundary conditions. These three differential equations were jointly solved using a multiphysics software. The physical film parameters were extracted employing an optimization procedure for immobilized bovine serum albumin, hemoglobin, and neutravidin films. The relatively good agreement between the extracted values for the refractive index, film thickness, and surface coverage and the corresponding values reported in the open literature show the correctness of the proposed methodology.

Energy balance and obesity: what are the main drivers?

PURPOSE: The aim of this paper is to review the evidence of the association between energy balance and obesity. METHODS: In December 2015, the International Agency for Research on Cancer (IARC), Lyon, France convened a Working Group of international experts to review the evidence regarding energy balance and obesity, with a focus on Low and Middle Income Countries (LMIC). RESULTS: The global epidemic of obesity and the double burden, in LMICs, of malnutrition (coexistence of undernutrition and overnutrition) are both related to poor quality diet and unbalanced energy intake. Dietary patterns consistent with a traditional Mediterranean diet and other measures of diet quality can contribute to long-term weight control. Limiting consumption of sugar-sweetened beverages has a particularly important role in weight control. Genetic factors alone cannot explain the global epidemic of obesity. However, genetic, epigenetic factors and the microbiota could influence individual responses to diet and physical activity. CONCLUSION: Energy intake that exceeds energy expenditure is the main driver of weight gain. The quality of the diet may exert its effect on energy balance through complex hormonal and neurological pathways that influence satiety and possibly through other mechanisms. The food environment, marketing of unhealthy foods and urbanization, and reduction in sedentary behaviors and physical activity play important roles. Most of the evidence comes from High Income Countries and more research is needed in LMICs.

Enterotypes of the human gut microbiome.

Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.

The gut bacterium and pathobiont Bacteroides vulgatus activates NF-κB in a human gut epithelial cell line in a strain and growth phase dependent manner.

The gut microbiota is increasingly implicated in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) although the identity of the bacteria that underpin these diseases has remained elusive. The pathobiont Bacteroides vulgatus has been associated with both diseases although relatively little is known about how its growth and functional activity might drive the host inflammatory response. We identified an ATP Binding Cassette (ABC) export system and lipoprotein in B. vulgatus ATCC 8482 and B. vulgatus PC510 that displayed significant sequence similarity to an NF-κB immunomodulatory regulon previously identified on a CD-derived metagenomic fosmid clone. Interestingly, the ABC export system was specifically enriched in CD subjects suggesting that it may be important for colonization and persistence in the CD gut environment. Both B. vulgatus ATCC 8482 and PC510 activated NF-κB in a strain and growth phase specific manner in a HT-29/kb-seap-25 enterocyte like cell line. B. vulgatus ATCC 8482 also activated NF-κB in a Caco-2-NF-κBluc enterocyte like and an LS174T-NF-κBluc goblet cell like cell lines, and induced NF-κB-p65 subunit nuclear translocation and IL-6, IL-8, CXCL-10 and MCP-1 gene expression. Despite this, NF-κB activation was not coincident with maximal expression of the ABC exporter or lipoprotein in B. vulgatus PC510 suggesting that the regulon may be necessary but not sufficient for the immunomodulatory effects.

Single and multiple resistance QTL delay symptom appearance and slow down root colonization by Aphanomyces euteiches in pea near isogenic lines.

BACKGROUND: Understanding the effects of resistance QTL on pathogen development cycle is an important issue for the creation of QTL combination strategies to durably increase disease resistance in plants. The oomycete pathogen Aphanomyces euteiches, causing root rot disease, is one of the major factors limiting the pea crop in the main producing countries. No commercial resistant varieties are currently available in Europe. Resistance alleles at seven main QTL were recently identified and introgressed into pea agronomic lines, resulting in the creation of Near Isogenic Lines (NILs) at the QTL. This study aimed to determine the effect of main A. euteiches resistance QTL in NILs on different steps of the pathogen life cycle. RESULTS: NILs carrying resistance alleles at main QTL in susceptible genetic backgrounds were evaluated in a destructive test under controlled conditions. The development of root rot disease severity and pathogen DNA levels in the roots was measured during ten days after inoculation. Significant effects of several resistance alleles at the two major QTL Ae-Ps7.6 and Ae-Ps4.5 were observed on symptom appearance and root colonization by A. euteiches. Some resistance alleles at three other minor-effect QTL (Ae-Ps2.2, Ae-Ps3.1 and Ae-Ps5.1) significantly decreased root colonization. The combination of resistance alleles at two or three QTL including the major QTL Ae-Ps7.6 (Ae-Ps5.1/Ae-Ps7.6 or Ae-Ps2.2/Ae-Ps3.1/Ae-Ps7.6) had an increased effect on delaying symptom appearance and/or slowing down root colonization by A. euteiches and on plant resistance levels, compared to the effects of individual or no resistance alleles. CONCLUSIONS: This study demonstrated the effects of single or multiple resistance QTL on delaying symptom appearance and/or slowing down colonization by A. euteiches in pea roots, using original plant material and a precise pathogen quantification method. Our findings suggest that single resistance QTL can act on multiple or specific steps of the disease development cycle and that their actions could be pyramided to increase partial resistance in future pea varieties. Further studies are needed to investigate QTL effects on different steps of the pathogen life cycle, as well as the efficiency and durability of pyramiding strategies using QTL which appear to act on the same stage of the pathogen cycle.