Preclinical and clinical evidence of the association of colibactin-producing Escherichia coli with anxiety and depression in colon cancer.

BACKGROUND: The association between the intestinal microbiota and psychiatric disorders is becoming increasingly apparent. The gut microbiota contributes to colorectal carcinogenesis (CRC), as demonstrated with colibactin-producing Escherichia coli (CoPEC). AIM: To evaluate the association between CoPEC prevalence and anxiety- and depressive-like behaviors with both preclinical and clinical approaches. METHODS: Patients followed after a CRC surgery and for whom the prevalence of CoPEC has been investigated underwent a psychiatric interview. Results were compared according to the CoPEC colonization. In parallel C57BL6/J wild type mice and mice with a CRC susceptibility were chronically infected with a CoPEC strain. Their behavior was assessed using the Elevated Plus Maze test, the Forced Swimming Test and the Behavior recognition system PhenoTyper®. RESULTS: In a limited cohort, all patients with CoPEC colonization presented with psychiatric disorders several years before cancer diagnosis, whereas only one patient (17%) without CoPEC did. This result was confirmed in C57BL6/J wild-type mice and in a CRC susceptibility mouse model (adenomatous polyposis colimultiple intestinal neoplasia/+). Mice exhibited a significant increase in anxiety- and depressive-like behaviors after chronic infection with a CoPEC strain. CONCLUSION: This finding provides the first evidence that CoPEC infection can induce microbiota-gut-brain axis disturbances in addition to its procarcinogenic properties.

Acyloxyacyl hydrolase modulates pelvic pain severity.

Chronic pelvic pain causes significant patient morbidity and is a challenge to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia in BALB/c mice relative to C57BL/6 mice. Here, we report that a quantitative trait locus (QTL) analysis of PRV-induced allodynia in F2CxB progeny identified a polymorphism on chromosome 13, rs6314295 , significantly associated with allodynia (logarithm of odds = 3.11). The nearby gene encoding acyloxyacyl hydrolase ( Aoah) was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited increased vesicomotor reflex in response to bladder distension, consistent with spontaneous bladder hypersensitivity, and increased pelvic allodynia in neurogenic cystitis and postbacterial chronic pain models. AOAH deficiency resulted in greater bladder pathology and tumor necrosis factor production in PRV neurogenic cystitis, markers of increased bladder mast cell activation. AOAH immunoreactivity was detectable along the bladder-brain axis, including in brain sites previously correlated with human chronic pelvic pain. Finally, AOAH-deficient mice had significantly higher levels of bladder vascular endothelial growth factor, an emerging marker of chronic pelvic pain in humans. These findings indicate that AOAH modulates pelvic pain severity, suggesting that allelic variation in Aoah influences pelvic pain in IC.

Link between cutaneous infection, stress and depression.

Depression and mood disorders often develop after dermatological conditions which could be primary or secondary to dermatological pathology. The oxidative and psychological stress cause physiological changes in the body. Shift in the methylation pathway, elevated cortisol, lowered neurotransmitter levels and lowered immune system allow infection to penetrate the body and lead to anxiety and depression. Here, a case report of a 20 year old male patient is presented to show how infectious skin lesions, unresponsive to the usual treatment plan, were treated after using a multipronged approach of addressing systemic infection of Escherichia coli, elevated cortisol levels and nutritional imbalances.

PKR deficiency alters E. coli-induced sickness behaviors but does not exacerbate neuroimmune responses or bacterial load.

BACKGROUND: Systemic inflammation induces neuroimmune activation, ultimately leading to sickness (e.g., fever, anorexia, motor impairments, exploratory deficits, and social withdrawal). In this study, we evaluated the role of protein kinase R (PKR), a serine-threonine kinase that can control systemic inflammation, on neuroimmune responses and sickness. METHODS: Wild-type (WT) PKR+/+ mice and PKR-/- mice were subcutaneously injected with live Escherichia coli (E. coli) or vehicle. Food consumption, rotarod test performance, burrowing, open field activity, object investigation, and social interaction were monitored. Plasma TNF-α and corticosterone were measured by ELISA. The percentage of neutrophils in blood was deduced from blood smears. Inflammatory gene expression (IL-1ß, TNF-α, IL-6, cyclooxygenase (COX)-2, iNOS) in the liver and the brain (hypothalamus and hippocampus) were quantified by real-time PCR. Blood and lavage fluid (injection site) were collected for microbiological plate count and for real-time PCR of bacterial 16S ribosomal DNA (rDNA). Corticotrophin-releasing hormone (CRH) expression in the hypothalamus was also determined by real-time PCR. RESULTS: Deficiency of PKR diminished peripheral inflammatory responses following E. coli challenge. However, while the core components of sickness (anorexia and motor impairments) were similar between both strains of mice, the behavioral components of sickness (reduced burrowing, exploratory activity deficits, and social withdrawal) were only observable in PKR-/- mice but not in WT mice. Such alteration of behavioral components was unlikely to be caused by exaggerated neuroimmune activation, by an impaired host defense to the infection, or due to a dysregulated corticosterone response, because both strains of mice displayed similar neuroimmune responses, bacterial titers, and plasma corticosterone profiles throughout the course of infection. Nevertheless, the induction of hypothalamic corticotrophin-releasing hormone (CRH) by E. coli was delayed in PKR-/- mice relative to WT mice, suggesting that PKR deficiency may postpone the CRH response during systemic inflammation. CONCLUSIONS: Taken together, our findings show that (1) loss of PKR could alter E. coli-induced sickness behaviors and (2) this was unlikely to be due to exacerbated neuroimmune activation, (3) elevated bacterial load, or (4) dysregulation in the corticosterone response. Further studies can address the role of PKR in the CRH response together with its consequence on sickness.

Quality of life one year post-Shiga toxin-producing Escherichia coli O104 infection--a prospective cohort study.

BACKGROUND: In 2011, a major outbreak of hemolytic-uremic syndrome (HUS) and bloody diarrhea related to infections from Shiga toxin-producing Escherichia coli O104 (STEC) occurred in Germany. While previous research has focused on the medical components of this disease, we aimed to investigate the course of health-related quality of life (HrQoL) over 12 months including somatic and psychosocial risk factors. Furthermore, the influence of chronic fatigue (CF) on HrQoL was examined. METHODS: A prospective cohort study with n = 389 patients completing self-report scales at baseline, after 6 months (participation rate: 79%) and after 12 months (participation rate: 77%). The courses of physical and mental HrQoL over the 12 month period were calculated by employing general linear mixed models. KEY RESULTS: While the physical component score of HrQoL reached a score comparable to the general population, the mental component score remained below average 12 months after STEC infection. Female gender, prior psychiatric disorder, and prior traumatic events were risk factors for a worse HrQoL course after 12 months, while social support was identified to be protective. CF was associated with low HrQoL. In addition, the somatic symptom burden remained persistently high. CONCLUSIONS & INFERENCES: Our results show high somatic and psychosocial burden in patients 12 months after STEC infection. We recommend considering the risk factors and protective factors of poor HrQoL early in the treatment of STEC or similar diseases. Patients who are suffering from persisting somatic symptoms, CF, and impaired HrQoL may require specific aftercare.

Secondary provoked vestibulodynia in sexually active women with uncomplicated recurrent urinary tract infections.

INTRODUCTION: Uncomplicated recurrent urinary tract infections (rUTIs) associated with uropathogenic Escherichia coli (UPEC) are common among healthy, reproductive-aged women. Provoked vestibulodynia (PVD) is a major reason of sexual pain in premenopausal women. AIM: The aim of this paper is to assess prevalence and predictors of secondary PVD in a cohort of Caucasian-European, heterosexual, sexually active, reproductive-aged women seeking medical help for rUTIs as their primary complaint. METHODS: Clinical and psychometric variables for 60 consecutive patients with rUTIs were considered. Patients were assessed with a thorough medical and sexual history, a number of psychometric instruments, and a specific physical examination. Urinalysis and self-collected urine cultures from the previous 12 months were also examined. MAIN OUTCOME MEASURE: Descriptive statistics and logistic regression models were used to test the associations between secondary PVD and sociodemographic and clinical variables. RESULTS: Mean age was 34.2 years (median 33 years; range 21-42). Secondary PVD was found in 36 of 60 patients (60%). Women with PVD had a higher prevalence of urinary tract infections (UTIs) over the previous 12 months (χ(2) : 4.54; P = 0.03) and suffered more frequently from UPEC-related rUTIs (χ(2) : 5.92; P = 0.01) than those without PVD. Moreover, women with PVD showed significantly lower scores on Female Sexual Function Index domains (all P ≤ 0.01), as compared with PVD-negative women. UPEC-related rUTIs (odds ratio [OR]: 3.1; P = 0.01), six or more UTIs over the previous 12 months (OR: 2.8; P = 0.01), and treatment with three or more antibiotics throughout the same period (OR: 2.1; P = 0.04) emerged as independent predictors of PVD. CONCLUSIONS: Three of five Caucasian-European, heterosexual, sexually active women of reproductive age complaining of rUTIs as their primary disorder also suffer from secondary PVD. Uncomplicated UPEC-related rUTIs are more frequently associated with secondary PVD than are UTIs caused by different uropathogens.

Analyzing consumers' reactions to news coverage of the 2011 Escherichia coli O104:H4 outbreak, using the Extended Parallel Processing Model.

This article describes and analyzes Flemish consumers' real-life reactions after reading online newspaper articles related to the enterohemorrhagic Escherichia coli (EHEC) O104:H4 outbreak associated with fresh produce in May and June 2011 in Germany. Using the Extended Parallel Processing Model (EPPM) as the theoretical framework, the present study explored the impact of Flemish (Belgian) online news coverage on consumers' perception of the risk induced by the EHEC outbreak and their behavioral intentions as consumers of fresh produce. After the consumers read a newspaper article related to the outbreak, EPPM concepts were measured, namely, perceived severity, susceptibility, self-efficacy, and affective response, combined with behavioral intentions to eat less fresh produce, to rinse fresh produce better, and to alert loved ones concerning the risk. The consumers' reactions were measured by inserting a link to an online survey below every online newspaper article on the EHEC outbreak that appeared in two substantial Flemish newspapers. The reactions of 6,312 respondents were collected within 9 days for 17 different online newspaper articles. Looking at the perceived values of the EPPM concepts, the perceived severity and the perceived susceptibility of the risk were, as expected, high. However, the consumers thought they could prevent the risk from happening, which stresses the importance of increasing consumers' knowledge of emerging food safety risks. Furthermore, analyses showed the moderating role of government trust and its influence on the way consumers perceived the risk, how worried they were, and their behavioral intentions.

Short communication: The effects of experimentally induced Escherichia coli clinical mastitis on lying behavior of dairy cows.

Clinical mastitis is a commonly occurring and economically important problem in the dairy industry. Researchers have suggested that changes in lying behavior could be useful as early indicators of cow discomfort and poor welfare. The objective of this study was to determine the associations between the onset of illness resulting from experimentally induced clinical mastitis and measures of lying behavior. Clinical mastitis was induced in 21 lactating dairy cows (parity=2.0±1.0, range=1 to 4; days in milk=61±18) by intramammary infusion of 25 or 100 µg of Escherichia coli lipopolysaccharide (LPS) into 1 uninfected mammary quarter. Lying behavior was monitored from 2 d before through 3 d after the LPS challenge by fitting each cow with a data logger. Calculated outcome measures were total lying time, lying time on the side of the intramammary infusion, number of lying bouts, and average lying bout duration. Cows spent less time lying down on the day of the challenge compared with the 2 d before (633.3 vs. 707.0 min/d; SE=29.6), particularly during the 4 to 7h following LPS infusion. However, no significant relationship was found between the mammary quarter challenged and cow preference for lying side throughout the episode of induced clinical mastitis. Given that lying is a high-priority behavior in dairy cows and that increased lying time is an adaptive sickness behavior to facilitate recovery, we infer that this reduction in lying time may present a concern for cows with clinical mastitis. Although additional studies with larger numbers of animals are needed, automated monitoring of lying behavior could be an important component of the on-farm early detection of health problems, such as mastitis, in the future.

Sickness behavior in dairy cows during Escherichia coli mastitis.

The consequences of mastitis in terms of dairy cow behavior are relatively unknown. Future assessment of dairy cow welfare during mastitis will be facilitated by knowledge about the potential of mastitis to induce sickness behavior. Our aim was to examine behavior of dairy cows in the period from 2 d before (d -2 and -1) to 3 d (d 0, 1, and 2) after experimental intramammary challenge with Escherichia coli. Effects of experimentally induced mastitis on behavior were examined in 20 primiparous Danish Holstein-Friesian cows, all 3 to 6 wk after calving and kept in tie stalls. After evening milking on d 0, each cow received an intramammary infusion with 20 to 40 cfu of E. coli in 1 healthy front quarter. Paraclinical and bacteriological examinations were conducted to confirm infection. Half of the cows were subjected to liver and udder biopsies twice during the trial. Behavior was video-recorded on 5 consecutive days, d -2 to +2 after challenge when the cows were not disturbed by humans. The behavior of the animals was compared among all days. Infection with E. coli altered the behavior of the dairy cows. Time spent feeding was lower in the initial 24 h after infection compared with that on the other days (16.6±1.1, 16.5±1.0, 13.2±1.2, 18.1±1.1, and 16.0±0.8% of time for d -2, -1, 0, 1, and 2, respectively). The duration of standing idle increased on d 0 compared with that on the control days and d 1 and 2 (29.4±2.6, 28.0±2.3, 39.1±2.6, 31.4±3.8, and 25.9±2.6% of time for d -2, -1, 0, 1 and 2, respectively). The frequency of self-grooming behavior per hour decreased in the initial 24h compared with that on d -2, -1, and 2 (4.1±0.8, 5.4±1.9, 3.2±0.6, 3.6±0.6, and 4.8±1.0 for d -2, -1, 0, 1, and 2, respectively). Likewise, duration of rumination and frequency of turning the head against the udder decreased in the first days after infection (rumination: 32.2±1.6, 34.8±1.8, 27.9±1.7, 30.0±2.6, and 34.8±1.7% of time; and frequency of turning head: 0.6±0.1, 0.6±0.1, 0.3±0.1, 0.3±0.1, and 0.6±0.1 per hour for d -2, -1, 0, 1 and 2, respectively). The cows subjected to biopsies showed an overall decreased lying time during the entire observation period (36.3±1.5 vs. 46.1±2.2% of time) but not directly related to the period after the biopsies. Dairy cows show classic signs of illness behavior in the hours after intramammary challenge with E. coli. This knowledge can be useful for the development of welfare assessment protocols, early disease detection, and for future work aimed at understanding the behavioral needs of dairy cows suffering from mastitis.

IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats.

In normal aging, a peripheral immune challenge induces a sensitized and protracted neuroinflammatory response in parallel with long-term memory (LTM) impairments. Pro-inflammatory mediators of neuroinflammation impair LTM, synaptic plasticity and LTP. The immediate early gene Arc is considered a critical protein regulating LTM and synaptic plasticity. The present investigation examined whether (1) a peripheral Escherichia coli infection suppresses hippocampal Arc expression, and (2) central pro-inflammatory cytokines (IL-1beta and IL-6) mediate the effects of peripheral E. coli infection on Arc and LTM. In 24 months F344xBN F1 rats, E. coli infection suppressed basal Arc gene expression as well as contextual fear conditioning-induced Arc expression. E. coli treatment failed to alter either basal or conditioning-induced c-Fos expression. At 24h post-infection, intra-cisterna magna (ICM) treatment with the anti-inflammatory cytokine IL-1RA blocked the E. coli-induced suppression of hippocampal Arc and increases in IL-6 protein. At 4-day post-infection, IL-1RA blocked the E. coli-induced LTM impairments and increases in IL-6 protein. The present results suggest that central pro-inflammatory cytokines play a salient role in the suppression of Arc and impairments of LTM by a peripheral immune challenge in older animals.

Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain.

Systemic infection with Escherichia coli on postnatal day (P) 4 in rats results in significantly altered brain cytokine responses and behavioral changes in adulthood, but only in response to a subsequent immune challenge with lipopolysaccharide [LPS]. The basis for these changes may be long-term changes in glial cell function. We assessed glial and neural cell genesis in the hippocampus, parietal cortex (PAR), and prefrontal cortex (PFC), in neonates just after the infection, as well as in adulthood in response to LPS. E. coli increased the number of newborn microglia within the hippocampus and PAR compared to controls. The total number of microglia was also significantly increased in E. coli-treated pups, with a concomitant decrease in total proliferation. On P33, there were large decreases in numbers of cells coexpressing BrdU and NeuN in all brain regions of E. coli rats compared to controls. In adulthood, basal neurogenesis within the dentate gyrus (DG) did not differ between groups; however, in response to LPS, there was a decrease in neurogenesis in early-infected rats, but an increase in controls to the same challenge. There were also significantly more microglia in the adult DG of early-infected rats, although microglial proliferation in response to LPS was increased in controls. Taken together, we have provided evidence that systemic infection with E. coli early in life has significant, enduring consequences for brain development and subsequent adult function. These changes include marked alterations in glia, as well as influences on neurogenesis in brain regions important for cognition.

Emotional and behavioral changes in parents of children affected by hemolytic-uremic syndrome associated with verocytotoxin-producing Escherichia coli: a qualitative analysis.

BACKGROUND: The long-term clinical outcome for children affected by hemolytic uremic syndrome associated with verocytotoxin-producing Escherichia coli (VTEC-HUS) is well documented, but the parental experience is not. OBJECTIVE: The authors investigated the effects of the critical-care hospitalization for this condition on well-being of patients' families. METHOD: A group of 30 parents completed a free-response format survey when their child presented to the hospital; 19 of this cohort completed a 1-year follow-up. RESULTS: Content analysis demonstrated that this cohort of parents experienced long-term emotional distress and substantive disruption to family and daily life. DISCUSSION: These results corroborate anecdotal clinical observations. The authors suggest future research initiatives and best practices to reduce parental distress.

Bacterial infection early in life protects against stressor-induced depressive-like symptoms in adult rats.

Both early-life stress and immune system activation in adulthood have been linked independently to depression in a number of studies. However, the relationship between early-life infection, which may be considered a "stressor", and later-life depression has not been explored. We have reported that neonatal bacterial infection in rats leads to exaggerated brain cytokine production, as well as memory impairments, to a subsequent peripheral immune challenge in adulthood, and therefore predicted that stressor-induced depressive-like symptoms would be more severe in these rats as well. Rats treated on postnatal day 4 with PBS or Escherichia coli were as adults exposed to inescapable tailshock stress (IS), and then tested for sucrose preference, social exploration with a juvenile, and overall activity, 1, 3, 5, and 7 days following the stressor. Serum corticosterone and extracellular 5-HT within the basolateral amygdala were measured in a second group of rats in response to the IS. IS resulted in profound depressive-like behaviors in adult rats, but, surprisingly, rats that suffered a bacterial infection early in life had blunted corticosterone responses to the stressor and were remarkably protected from the depressive symptoms compared to controls. These data suggest that early-life infection should be considered within a cost/benefit perspective, in which outcomes in adulthood may be differentially protected or impaired. These data also suggest that the immune system likely plays a previously unsuspected role in "homeostatic" HPA programming and brain development, which may ultimately lend insight into the often-contradictory literature on cytokines, inflammation, and depression.

Peripheral infection and aging interact to impair hippocampal memory consolidation.

We report that a peripheral injection of Escherichia coli produces both anterograde and retrograde amnesia in 24 month old, but not 3 month old rats for memories that depend on the hippocampus, that is, memory of context, contextual fear, and place learning. The anterograde effect was restricted to measures of long-term memory. Short-term memory was not affected, nor did E. coli produce amnesia for auditory-cue fear conditioning. There were no age related effects on memory in vehicle-treated rats. In addition to these age-related cognitive effects of E.coli, we report that it produced a marked increased in IL-1beta levels in the hippocampus, but not in parietal cortex or serum. These findings support the hypothesis that age is a vulnerability factor that increases the likelihood that an immune challenge will produce a cognitive impairment. It is possible that this cognitive vulnerability is mediated by age-related changes in the glial environment that results in an exaggerated brain pro-inflammatory response to infection.

Neonatal infection induces memory impairments following an immune challenge in adulthood.

Exposure to infectious agents during early postnatal life often alters glucocorticoid responses to stress and immune outcomes in adulthood. The authors examined whether neonatal infection results in memory impairments in adult animals. Rats infected with Escherichia coli (E. coli) as neonates displayed impaired memory for a recently explored context in adulthood. This impairment, however, was only observed in rats that received a peripheral immune challenge (lipopolysaccharide; LPS) immediately following context exposure. Adult rats treated neonatally with E. coli also had decreased hippocampal astrocytes compared with phosphate-buffered saline-treated rats, but displayed increased astrocyte reactivity in the hippocampus and decreased brain interleukin-1beta following lipopolysaccharide. Infection during development appears to alter glia within the hippocampus, which may contribute to altered cytokine responses and memory impairment.

Escherichia coli meningitis in the newborn: follow-up study.

Followup study of 22 cases of meningitis due to Escherichia coli (E. coli) in the newborn period showed a mortality rate of 7 out of 22 (31.88%), severe physical and mental sequelae occurred in one case and mild to moderate sequelae in two others. Most psychometric tests were within normal range in the survivors examined. There was a correlation between low birth weight and a high CSF protein with adverse prognosis.