Microbiota-gut-brain axis in health and disease: Is NLRP3 inflammasome at the crossroads of microbiota-gut-brain communications?

Growing evidence highlights the relevance of microbiota-gut-brain axis in the maintenance of brain homeostasis as well as in the pathophysiology of major neurological and psychiatric disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), autism spectrum disorder (ASD) and major depressive disorder (MDD). In particular, changes in gut microbiota can promote enteric and peripheral neurogenic/inflammatory responses, which, in turn, could contribute to neuroinflammation and neurodegeneration in the central nervous system (CNS). Of note, the nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome acts as a key player in both coordinating the host physiology and shaping the peripheral and central immune/inflammatory responses in CNS diseases. In this context, there is pioneering evidence supporting the existence of a microbiota-gut-inflammasome-brain axis, in which enteric bacteria modulate, via NLRP3 signaling, inflammatory pathways that, in turn, contribute to influence brain homeostasis. The present review provides an overview of current knowledge on the role of microbiota-gut-inflammasome-brain axis in the major CNS diseases, including PD, AD, MS, ASD and MDD. In particular, though no direct and causal correlation among altered gut microbiota, NLRP3 activation and brain pathology has been demonstrated and in-depth studies are needed in this setting, our purpose was to pave the way to a novel and pioneering perspective on the pathophysiology of CNS disorders. Our intent was also to highlight and discuss whether alterations of microbiota-gut-inflammasome-brain axis support a holistic view of the pathophysiology of CNS diseases, even though each disorder displays a different clinical picture.

High-dose Dexamethasone in a Child With Enteric Encephalopathy Caused by Salmonella enterica serovar Typhi.

Increased antimicrobial resistance to Salmonella species threatens successful treatment of typhoid and other infectious diseases. Consequently, rare complications arising from incompletely treated typhoid could increase in frequency. We describe a case of enteric encephalopathy caused by Salmonella enterica serovar Typhi and the utility of adjunct treatment with corticosteroids.

Tryptophan Metabolism and Related Pathways in Psychoneuroimmunology: The Impact of Nutrition and Lifestyle.

In the past, accelerated tryptophan breakdown was considered to be a feature of clinical conditions, such as infection, inflammation, and malignant disease. More recently, however, the focus has changed to include the additional modulation of tryptophan metabolism by changes in nutrition and microbiota composition. The regulation of tryptophan concentration is critical for the maintenance of systemic homeostasis because it integrates essential pathways involved in nutrient sensing, metabolic stress response, and immunity. In addition to tryptophan being important as a precursor for the synthesis of the neurotransmitter serotonin, several catabolites along the kynurenine axis are neuroactive. This emphasizes the importance of the immunometabolic fate of this amino acid for processes relevant to neuropsychiatric symptoms. In humans, besides hepatic catabolism, there is usually a strong relationship between immune activation-associated tryptophan breakdown and increased levels of biomarkers, such as neopterin, which has particular relevance for both acute and chronic diseases. A shift towards neopterin synthesis during oxidative stress may indicate a corresponding decrease in tetrahydrobiopterin, a cofactor of several mono-oxygenases, providing a further link between tryptophan metabolism and serotonergic and catecholaminergic neurotransmission. The psychoneuroimmunological consequences of tryptophan metabolism and the susceptibility of this pathway to modulation by a variety of nutritional and lifestyle-related factors have important implications for the development of both diagnostic and treatment options.

Use of standard enteral formula versus enteric formula with prebiotic content in nutrition therapy: A randomized controlled study among neuro-critical care patients.

OBJECTIVE: To compare use of standard enteral formula versus enteric formula with prebiotic content in terms of nutrition therapy related outcomes among neurocritical care patients. METHODS: A total of 46 adult neurocritical care patients who received nutrition therapy with standard enteral formula (SEF group; n = 23) or enteral formula with prebiotic content (EFPC group; n = 23) during their hospitalization in intensive care unit (ICU) were included in this prospective randomized controlled study. Data on patient demographics (age, gender), diagnosis, co-morbid diseases, anthropometrics, length of stay (LOS) in hospital and ICU, Nutritional Risk Screening (NRS-2002) score, and Acute Physiology and Chronic Health (APACHE-II) score were recorded at enrollment. Data on daily nutritional intake [total energy (kcal/day), carbohydrate (g/day), protein (g/day), lipid (g/day), FOS (g/day), enteral volume (ml/day), fluid in enteral product (ml/day) and fluid intake (ml/day)], achievement of target dose [total fluid intake in enteral product (ml)/20 h], laboratory findings (blood biochemistry and complete blood count), complications and drug treatments were recorded on Day 1, Day 4, Day 7, Day 14 and Day 21 of nutrition therapy in SEF and EFPC groups. RESULTS: Use of EFPC compared to SEF was associated with significantly higher total energy, carbohydrate, protein, lipid, enteral volume and fluid intake (p values ranged from <0.05 to <0.001) on each day of nutrition therapy. Target dose was achieved by majority of patients (86.9%) and at day 4 of nutrition therapy in most of patients (71.7%) in the overall study population. Patients in the EFPC group had a non-significant tendency for higher rate (95.7% vs. 78.3%) and earlier (87.0% vs. 56.5% on day 4) achievement of target dose, lower rate (8.7% vs. 56.5%) and faster amelioration (none vs. 52.2% were diarrheic on day 7) of diarrhea and lesser need for insulin (56.5% vs. 13.0%, p = 0.002). Nutrition therapy was associated with significant decrease in prealbumin (Day 14 vs. Day 1, p < 0.05 for both), albumin (Day 14 vs. day 1, p < 0.01 for SEF, p < 0.05 for PEF), hemoglobin (Day 14 and Day 21 vs. Day 1and Day 14 vs. Day 4, p < 0.001 for each for SEF, Day 7, Day 14 and Day 21 vs. Day 1, p < 0.01 for each for PEF) and hematocrit (Day 14 and Day 21 vs. Day 1, p < 0.001 for each for both) levels in both SEF and EFPC groups. CONCLUSIONS: In conclusion, our findings revealed achievement of target nutritional intake in majority of neurocritical care patients via nutrition therapy, whereas EFPC was associated with a non-significant tendency for more frequent and earlier achievement of target dose along with significantly lower rate and faster amelioration of diarrhea as compared with SEF group. Prealbumin and albumin levels remained below the normal range, whereas C reactive protein (CRP) and white blood cell (WBC) were over the normal range throughout the nutrition period in both groups, while creatinine and urea levels were higher in EFPC than in SEF group. Hence, our findings seem to emphasize the importance of avoiding protein debt in provision of nutrition therapy and the likelihood of deterioration of nutritional status in elderly neurocritical care patients despite provision of early enteral nutrition support due to complex and deleterious inflammatory and metabolic changes during critical illness.

Multimodal Treatment of Rhinocerebral Mucormycosis in a Pediatric Patient With Relapsed Pre-B Acute Lymphoblastic Leukemia.

A 17-year-old girl developed invasive rhinocerebral mucormycosis during intensive re-induction chemotherapy for relapsed pre-B acute lymphoblastic leukemia. Due to the high case fatality rate for invasive mucormycosis in profoundly immunosuppressed patients, an aggressive treatment regimen was pursued. In addition to the standard of care treatments with intravenous amphotericin and aggressive surgical debridements, she received intraventricular amphotericin to the brain via an Ommaya reservoir, hyperbaric oxygen treatments, filgrastim, intravenous immunoglobulin and antifungal in vitro synergy testing to allow for more targeted antifungal therapy with the addition of micafungin. After a 3-month treatment course, it was determined that her mucormycosis was under appropriate control, allowing her to continue treatment for her leukemia with hematopoietic stem cell transplant with a plan for continued intravenous antifungal therapy through engraftment.

To exenterate or not? An unusual case of pediatric rhinocerebral mucormycosis.

Rhinocerebral mucormycosis (RM) is a rare, potentially lethal fungal infection. Traditional teaching encourages aggressive surgical resection until viable bleeding tissue is encountered, often leading to orbital exenteration, skull base resection, and cerebral debridement, in addition to systemic antifungal therapy. We present a 2-year-old male with acute lymphocytic leukemia undergoing chemotherapy presenting with RM and unilateral orbital and intracranial involvement. After aggressive sinonasal debridement, systemic antifungal and hyperbaric oxygen therapies, he recovered without need for further aggressive tissue resection. We report the successful management of invasive orbital and intracranial RM without orbital exenteration or cerebral debridement.

Rapid eradication of Listeria monocytogenes by moxifloxacin in a murine model of central nervous system listeriosis.

Listeriosis is a rare but life-threatening infection. A favorable outcome is greatly aided by early administration of antibiotics with rapid bactericidal activity against Listeria monocytogenes. Moxifloxacin, a new-generation fluoroquinolone with extended activity against gram-positive bacteria, has proved its effectiveness in vitro against intracellular reservoirs of bacteria. The efficacies of moxifloxacin and amoxicillin were compared in vivo by survival curve assays and by studying the kinetics of bacterial growth in blood and organs in a murine model of central nervous system (CNS) listeriosis. We combined pharmacokinetic and pharmacodynamic approaches to correlate the observed efficacy in vivo with plasma and tissue moxifloxacin concentrations. Death was significantly delayed for animals treated with a single dose of moxifloxacin compared to a single dose of amoxicillin. We observed rapid bacterial clearance from blood and organs of animals treated with moxifloxacin. The decrease in the bacterial counts in blood and brain correlated with plasma and cerebral concentrations of antibiotic. Moxifloxacin peaked in the brain at 1.92 +/- 0.32 microg/g 1 hour after intraperitoneal injection. This suggests that moxifloxacin rapidly crosses the blood-brain barrier and diffuses into the cerebral parenchyma. Moreover, no resistant strains were selected during in vivo experiments. Our results indicate that moxifloxacin combines useful pharmacokinetic properties and rapid bactericidal activity and that it may be a valuable alternative for the treatment of CNS listeriosis.

Mucormycosis--early diagnosis and treatment.

OBJECTIVE: The aim of this retrospective study was to analyse the data of patients with rhino-orbital-cerebral mucormycosis for predisposing factors, diagnosis, treatment and survival rate. The role of frozen section in early diagnosis and use of nasal endoscopy in diagnosis, treatment and follow-up of patients has also been examined. DESIGN: Retrospective case series. SETTING: University Teaching Hospital. METHODS: The case notes of 9 patients with diagnosis of mucormycosis who presented from 1973 to 2001 were examined. The data for predisposing factors, signs/symptoms, histological diagnosis, radiological intervention, medical and surgical treatment and final outcome was analysed. RESULTS: There were 9 patients with mucormycoses. Early diagnosis was made by endoscopic examination and frozen section in 5 patients, which was later confirmed by histology. Treatment included parental and/or local amphotericin, hyperbaric oxygen and debridement either by endoscopic or external approach, with or without orbital exenteration. This resulted in an overall survival of 5 patients. CONCLUSION: Frozen section diagnosis allows for early therapy since successful treatment depends on systemic amphotericin, surgical debridement and treatment of underlying predisposing factors. Nasal endoscopy is useful in diagnosis, endoscopic debridement and follow up of patients.

Whipple's disease with destructive arthritis, abdominal lymphadenopathy, and central nervous system involvement.

We describe a patient with Whipple's disease who had an unusual erosive and destructive polyarthritis, massive abdominal lymphadenopathy, asymptomatic central nervous system involvement, and rare manifestations of orbital pseudotumor and orchitis with epididymitis. Taking oral therapy with trimethoprim-sulfamethoxazole he had recurrent flares of orbital pseudotumor, an episode of orchitis with epididymitis, and persistent polymerase chain reaction T. whipplei-positive cerebrospinal fluid. Resolution was achieved with a one month course of intravenous ceftriaxone and a 6 month course of azithromycin, and no relapse occurred during 24 months of followup.

Systemic and intracerebral infections of mice with Listeria monocytogenes successfully treated with linezolid.

Linezolid is an oxazolidinone derivative which is active mostly against Gram-positive bacteria. In this work its activity against the facultatively intracellular bacterium Listeria monocytogenes was examined in vitro, in tissue culture and in animal models of systemic and intracerebral infection and compared with ampicillin which is the antibiotic of choice for treatment of listeriosis. All strains of L. monocytogenes were susceptible to the substance, with minimal inhibitory concentrations (MICs) determined by E-test ranging from 0.38 to 1.5 mg/l which is below the preliminary breakpoint of this substance. Linezolid was bacteriostatic against L. monocytogenes since up to 64 times the MIC did not kill the bacteria in 24 hours. Linezolid was also bacteriostatic on L monocytogenes in infected tissue culture cells. In animal models of systemic and intracerebral infection, linezolid was able to inhibit bacterial growth but was clearly less effective than ampicillin. In conclusion, linezolid might be useful for the treatment of infections with L monocytogenes in humans when ampicillin may not be used.

The ketolide antibiotic HMR 3647, a candidate substance for the treatment of systemic and intracerebral infections with Listeria monocytogenes.

HMR 3647 is a novel macrolide derivative with a broad spectrum of activity against grampositive bacteria and some fastiduous gramnegative bacteria, anaerobes and Toxoplasma gondii. In this work, its activity against the facultatively intracellular bacterium, Listeria monocytogenes, was examined in vitro, in tissue culture and in animal models of systemic and intracerebral infection and compared with that of erythromycin. All strains of L. monocytogenes were susceptible to the substance, with minimal inhibitory concentrations (MICs) that were consistently lower than the MICs of erythromycin. HMR 3647 was bacteriostatic against L. monocytogenes since concentrations of up to 64 times the MIC did not kill the bacteria within 24 hours. HMR 3647 produced a pronounced postantibiotic effect (PAE) and was bacteriostatic in tissue culture cells infected with L. monocytogenes. In animal models of systemic and intracerebral infection, HMR 3647 was slightly more effective than erythromycin in the livers and spleens and comparably effective in the brains when given in the same dosage. In conclusion, HMR 3647 is a candidate substance for the treatment of infections with L. monocytogenes in immunocompetent subjects.

Efficacy of ER-30346, a novel oral triazole antifungal agent, in experimental models of aspergillosis, candidiasis, and cryptococcosis.

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. In the present study, we investigated the therapeutic effects of oral ER-30346 on experimental local infections caused by Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans and compared them with those of itraconazole and fluconazole. In experimental murine models of pulmonary aspergillosis, candidiasis, and cryptococcosis, ER-30346 reduced the numbers of CFU in the lungs significantly compared with the numbers of CFU in the lungs of the controls (P < 0.05). ER-30346 was as effective as or more effective than itraconazole against pulmonary aspergillosis. Against pulmonary candidiasis and cryptococcosis, ER-30346 was more effective than itraconazole and was as effective as fluconazole. ER-30346 was also effective against pulmonary candidiasis caused by fluconazole-resistant C. albicans. In mice with intracranial cryptococcosis, ER-30346 reduced the numbers of CFU in the brains significantly compared with the numbers of CFU in the brains of the controls (P < 0.05) and was more effective than itraconazole and as effective as fluconazole. In an experimental model of oral candidiasis in rats, ER-30346 reduced the numbers of CFU in oral swabs significantly compared with the numbers of CFU in oral swabs from the controls (P < 0.05) and was more effective than itraconazole and as effective as fluconazole. Thus, ER-30346 shows efficacy in murine aspergillosis, candidiasis, and cryptococcosis models. Further studies are needed to determine the potential of ER-30346 for use in the treatment of these infections.

Survival factors in rhino-orbital-cerebral mucormycosis.

Mucormycosis is a highly aggressive fungal infection affecting diabetic, immunocompromised, and, occasionally, healthy patients. This infection is associated with significant mortality. We have reviewed 208 cases in the literature since 1970, 139 of which were presented in sufficient detail to assess prognostic factors, and added data from six of our patients. The histories of these 145 patients were analyzed for the following variables: 1) underlying conditions associated with mucormycotic infections; 2) incidence of ocular and orbital signs and symptoms; 3) incidence of nonocular signs and symptoms; 4) interval from symptom onset to treatment; and 5) the pattern of sinus involvement seen on imaging studies and noted at the time of surgery. Factors related to a lower survival rate include: 1) delayed diagnosis and treatment; 2) hemiparesis or hemiplegia; 3) bilateral sinus involvement; 4) leukemia; 5) renal disease; and 6) treatment with deferoxamine. The association of facial necrosis with a poor prognosis fell just short of statistical significance, but appears clinically important. This is the first review that documents the heretofore intuitive claim that early diagnosis is necessary to cure this disease. Standard treatment with amphotericin B and aggressive surgery are reviewed and adjunctive therapeutic modalities are discussed, including local amphotericin B irrigation, hyperbaric oxygen, and optimizing the immunosuppressive regimen in transplant patients. Hyperbaric oxygen was found to have a favorable effect on prognosis. In addition, possible treatment options for patients with declining renal function are reviewed.

Adjunctive hyperbaric oxygen in the treatment of bilateral cerebro-rhino-orbital mucormycosis.

Survival is uncommon in bilateral cerebro-rhino-orbital mucormycosis treated surgically and medically. A 66-year-old man in previously good health had bilateral cerebro-rhino-orbital mucormycosis and newly diagnosed nonketotic diabetes mellitus at initial examination. Total loss of vision, proptosis, and ophthalmoplegia of both eyes were present. The patient was treated with aggressive surgical and medical therapies that included bilateral orbital exenteration, intravenous and local amphotericin B, hyperbaric oxygen, and control of the diabetes mellitus. One and one-half years after onset of the illness, the patient is alert and clinically stable. The importance of prompt diagnosis and aggressive treatment of this disease is emphasized by this case. Additionally, we suggest that adjunctive hyperbaric oxygen is a reasonable modality in the treatment of this often fatal disease.

Antimicrobial synergism in the therapy of experimental cerebral nocardiosis.

A mouse model of cerebral nocardiosis was used to determine the efficacy of synergistic antimicrobial combinations in reducing bacterial colony counts per gram of brain tissue. The combinations of imipenem-cefotaxime and imipenem-trimethoprim/sulphamethoxazole (TMP/SMP) were compared with each other and with each agent used alone. A saline treated control group was also included. At the completion of 72 h of therapy the combinations of imipenem-cefotaxime and imipenem-TMP/SMX were the most effective in reducing bacterial colony counts. These were statistically superior to cefotaxime and TMP/SMX used alone but not statistically superior to imipenem alone. TMP/SMX was not effective in this model and was inferior to all other antibiotic treatments.

Intracerebral infection of mice with ovine strains of Chlamydia psittaci: an animal screening test for the assay of vaccines.

Intracerebral inoculation of mice with the A22 strain of ovine C. psittaci gave a reproducible non-lethal infection; multiplication of the inoculum could be quantitated by titration of mouse brain extracts in tissue culture. Mice which had recovered from infection, or which had been inoculated subcutaneously with living organisms of A22 strain, showed solid resistance to intracerebral challenge infection. However, subcutaneous inoculation of formalin-inactivated chlamydia showed little protective effect unless given in very high dosage. Inactivated vaccines of the heterologous ZC113 strain gave better, but still incomplete, protection against A22 challenge infection than did the homologous inactivated vaccine. The implication of these findings is discussed. The mouse intracerebral protection test appears to be a suitable laboratory procedure for assessing the potency of vaccines against enzootic ewe abortion and for comparing the immunological cross-protection between the various strains of C. psittaci currently found in the natural disease in sheep.