Treatment of Hyperammonemia by Transplanting a Symbiotic Pair of Intestinal Microbes

Hyperammonemia is a deleterious and inevitable consequence of liver failure. However, no adequate therapeutic agent is available for hyperammonemia. Although recent studies showed that the pharmabiotic approach could be a therapeutic option for hyperammonemia, its development is clogged with poor identification of etiological microbes and low transplantation efficiency of candidate microbes. In this study, we developed a pharmabiotic treatment for hyperammonemia that employs a symbiotic pair of intestinal microbes that are both able to remove ammonia from the surrounding environment. By a radioactive tracing experiment in mice, we elucidated how the removal of ammonia by probiotics in the intestinal lumen leads to lower blood ammonia levels. After determination of the therapeutic mechanism, ammonia-removing probiotic strains were identified by high-throughput screening of gut microbes. The symbiotic partners of ammonia-removing probiotic strains were identified by screening intestinal microbes of a human gut, and the pairs were administrated to hyperammonemic mice to evaluate therapeutic efficacy. Blood ammonia was in a chemical equilibrium relationship with intestinal ammonia. Lactobacillus reuteri JBD400 removed intestinal ammonia to shift the chemical equilibrium to lower the blood ammonia level. L. reuteri JBD400 was successfully transplanted with a symbiotic partner, Streptococcus rubneri JBD420, improving transplantation efficiency 2.3×103 times more compared to the sole transplantation while lowering blood ammonia levels significantly. This work provides new pharmabiotics for the treatment of hyperammonemia as well as explains its therapeutic mechanism. Also, this approach provides a concept of symbiotic pairs approach in the emerging field of pharmabiotics.

Влияние курсового приема L-орнитин- L-аспартата на фиброз и стеатоз печени у больных ассоциированной с нарушениями метаболизма жировой болезнью печени (неалкогольной жировой болезнью печени), имеющих гипераммониемию

Introduction. Hyperammonaemia develops both in cirrhosis and earlier fibrotic stages during metabolic-associated fatty liver disease (MAFLD). Besides neurotropic, ammonia exerts the hepatotoxic and profibrotic effects. L-ornithine-L-aspartate (LOLA) has been proved effective in treatment for hyperammonaemia in cirrhosis patients.Aim. An impact study of the LOLA course therapy on inflammation, steatosis and liver fibrosis biomarkers in MAFLD.Materials and methods. A total of 90 patients were divided between two cohorts. The control cohort included patients with liver steatosis S0–S1, absent liver fibrosis, normal liver function tests, clean history of liver disease, while MAFLD cohort gathered liver steatosis S2–S3 and METAVIR fibrosis F1. Steatosis and fibrosis were assessed with a Fibroscan 502 unit with CAP measurement. All patients had ammonia estimated from whole blood. At high ammonia, LOLA was ordered at 9 g/day for 8 weeks, with control of blood ammonia, AST, ALT, GGT, CRP and ferritin, as well as fibrosis and steatosis post-therapy.Results. The study enrolled 45 patients of the MAFLD and 45 — of control cohort. Hyperammonaemia was revealed in 26 (58 %) MAFLD and 3 (7 %) control patients (p <0.001). MAFLD-hyperammonaemic patients also had the significantly higher male ratio, type 2 diabetes and severer hepatic steatosis rates vs. hyperammonaemia-negative MAFLD individuals. In 8 weeks of LOLA therapy, the ALT, AST, GGT, ferritin and CRP levels decreased significantly, and blood ammonia attained normal range (p <0.001). Elastometry liver stiffness decreased in 22 (85 %) patients, reaching F0 values in 6 cases (p <0.001). The steatosis grade reduced in 18 (69 %) individuals.Conclusion. LOLA normalises blood ammonia levels and reduces the severity of inflammation, steatosis and liver fibrosis.

Risk Factors of Elevated Blood Ammonia Level in Epilepsy Patients Treated With Lamotrigine

Background The aim of this study was to explore the effect of lamotrigine (LTG) on blood ammonia level in patients with epilepsy and identify risk factors affecting blood ammonia level. Methods This study included 91 epilepsy patients who were treated with LTG at Department of Neurology, Zhongshan Hospital, Xiamen University from January 2011 to April 2016, and were followed up for three years. Blood samples were taken during the interictal state and analyzed for blood LTG and ammonia levels. Results Total 46.1% of the samples exceeded the median blood ammonia level, and 2.1% of patients had hyperammonemia. Blood ammonia level was positively correlated with LTG blood concentration. LTG combined with valproic acid (VPA) therapy, seizure within one year, and elevated neutrophils affected blood ammonia level. Conclusion Blood ammonia level was significantly correlated with plasma concentration of LTG. LTG combined with VPA therapy, seizure within one year, and elevated neutrophils may be risk factors for elevated blood ammonia level in epilepsy patients treated with LTG.

Two Japanese siblings with arginase-1 deficiency identified using a novel frameshift mutation of ARG1 (p.Lys41Thrfs∗2)

We described two Japanese siblings with arginase-1 (ARG1) deficiency. A 10-year-old girl (the proband and elder sister) was referred to our hospital complaining about her short stature. We diagnosed her with ARG1 deficiency, possibly with elevated levels of blood ammonia and plasma arginine. Her younger sister was found to have spastic paraparesis in her lower extremities and short stature at the age of 4 years. The younger sister also had high levels of plasma arginine, instead of normal levels of blood ammonia. Interestingly, they also prefer to avoid protein-rich foods such as meat, soybeans, cow milk, and dairy products. Genetic testing identified compound heterozygous mutations (c.121_122insCTT [p.Lys41Thrfs∗2] and c.298G>A [p.Asp100Asn]) in the ARG1 gene. The ARG1 mutation of p.Lys41Thrfs∗2 is a novel pathogenic mutation according to open databases and literature.

Influence of Different Antiepileptic Drugs on Blood Ammonia and Homocysteine Levels in Children with Epilepsy

In this study, we performed a study on 106 children with epilepsy who were treated with sodium valproate (the VPA group, n = 37), oxcarbazepine (the OXC group, n = 34), or levetiracetam (the LEV group, n = 35). In addition, the clinical data of epileptic children who were newly diagnosed in the same period without antiepileptic drug (AED) treatment (the untreated group, n = 35) and normal children who received physical examination in our hospital (the healthy group, n = 35) were selected as controls. We analyzed the efficacy and safety of different AEDs, used blood ammonia and homocysteine levels as the observation indicators, and calculated the incidence of hyperammonemia (VAH) and hyperhomocysteinemia (HHcy) treated with different AEDs. And, based on the effect of epilepsy status on the cognitive function of patients, we also analyzed the effect of different AED treatments on children’s cognitive function. Our results show that sodium valproate, oxcarbazepine, and levetiracetam are all effective in the treatment of children with epilepsy and can be used as the first-line choice of antiepileptic treatment for children with epilepsy. However, compared with sodium valproate, levetiracetam and oxcarbazepine have a lower incidence of adverse drug reactions and do not cause an increase in blood ammonia and Hcy levels, so they have higher safety of drug treatment. In addition, compared with sodium valproate, levetiracetam and oxcarbazepine have better recovery of cognitive function in children with epilepsy and so they have better application value.

The Role of Helicobacter Pylori Eradication on the Pathogenesis of Minimal Hepatic Encephalopathy in Egyptian Patients with Liver Cirrhosis

Background Hepatic Encephalopathy (HE) is defined as alteration of mental state in the absence of other causes of encephalopathy due to liver failure and/or abnormal shunting of blood from portal to systemic circulation often accompanied by elevated blood ammonia. Objectives The aim of this study was to determine the relation between the Helicobacter pylori infectionand minimal hepatic encephalopathy (MHE) in cirrhotic patients and to assess the outcome after treatment of H. pylori. Patients and Methods This study was can•ied out at Egyptian Railway Medical Centre at the in-patients section at Gastroenterology and Hepatology Medicine Department with chronic liver disease who agreed to participate in the study. After performing the psychometric tests the patients were allocated in one of the two groups according to test results: Group I: consisted of 30 consecutive patients who have chronic liver disease and presented with evidence of Minimal hepatic encephalopathy (MHE), as recognized by positive psychometric tests, Group Il: included 30 consecutive patients who presented with chronic liver disease and did not have Minimal hepatic encephalopathy, as confirmed by negative psychometric test. Results In this study a significant reduction was found in blood ammonia levels in MHE and non- MHE after triple-drug anti-H. pylori treatment (p &lt; 0.001). This reduction was more marked in patients with MHE group compared to non-MHE group with % improvement in ammonia level 26.1 ± 8.36 umol/L and 17.79 ± 7.308 for MHE and non-MHE respectively. This finding indicates that H. pylori may contribute to the development of hyperammonemia in patients with liver disease and MHE. The role of H. pylori in the pathogenesis of hyperammonemia has been shown in previous studies which showed a reduction in blood ammonia levels after eradication of H.pylori infection. Conclusion Helicobacter Pylori infection was more prevalent in patients with MHE than without MHE. Serum arnrnonia levels were significantly higher in MHE patients than without MHE and even higher in H.pylori positive patients than without H.pylori infection. Helicobacter Pylori eradication treatment significantly improves ammonia levels, results of psychometric tests and improves manifestations of MHE.

Clinical and Hematological Characteristics of Patients with COVID-19 Co-infected with Bacteria

Objectives: To provide suggestions and treatment opinions by analyzing laboratory data of COVID-19 patients co-infected with bacteria. Methods: We analyzed 63 patients with COVID-19 admitted to the isolation ward of the First Affiliated Hospital of Wenzhou Medical University. COVID-19 was detected using PCR, and bacteria were identified using culture. Patients were divided into two groups, including those with and those without bacterial infections, and differences in hematologic indices between the groups were analyzed. Results: There were 63 patients with median age of 55.82 years. The average hospital stay was 22.56 days. Seven patients (11.11%) had coincident bacterial infections. Detection rates in sputum/alveolar lavage and blood were the highest, 60.52% and 21.05%, respectively. Klebsiella pneumoniae, Acinetobacter, and Stenotrophomonas maltophilia were the most common found in 31.58%, 18.42%, and 15.79%, respectively. Interleukin 6 (IL-6) levels were elevated in 84.13% of patients, while IL-10 levels were elevated in 69.84%, blood ammonia levels were elevated in 82.05%, lactate levels were elevated in 75.41%, and LDH levels were elevated in 69.84%. There were significant differences between the groups in terms of expression levels of IgG, C4, AST, LDH, IL-6, IL-10, percentage of neutrophils, percentage of lymphocytes, and platelets. Conclusions: For patients with COVID-19 suspected of having bacterial infections, empiric antibiotics should be given to cover K. pneumoniae, Acinetobacter, and S. maltophilia.

Transitional Care for Patients with Portal Hypertension:A multicenter study of intervention for patients post-TIPS

Background:To explore the application effect of multicenter transitional nursing in patients post-TIPS.Methods:A total of 368 patients who underwent TIPS were randomly allocated to the control or intervention group. Patients in the control group received conventional care, and patients in the intervention group received conventional care combined with transitional care. The Child-Pugh scores, blood ammonia levels, compliance behavior, medication compliance, and adverse event incidence rates in the two groups were compared at 1, 3, 6, 9 and 12 months post-TIPS.Results:Repeated measures analysis of variance showed significant group effects 1, 3, 6, 9 and 12 months post-TIPS in the compliance behavior scores of the two groups. The intervention group had significantly higher compliance behavior scores than the control group 1, 3, 6, 9 and 12 months post-TIPS. The incidence of postoperative adverse events in the intervention group was significantly lower than that in the control group 12 months after TIPS. The group effects, time effects and group*time interaction revealed significant differences in the Child-Pugh scores 1, 3, 6, 9 and 12 months post-TIPS between the two groups and significant differences in blood ammonia levels 9 months after TIPS.Conclusions:Post-TIPS transitional care interventions increased patients’access to scientifically informed nursing, significantly improved patients’compliance behavior and health, and decreased the incidence of postoperative adverse events.

The Effect of Carnitine Supplementation on Blood Ammonia Level in Epilepsy Children Treated with Valproic Acid: A Randomized Controlled Trial

Background: Long-term use of valproic acid is associated with a high level of blood ammonia related to carnitine deficiency. This study investigates the effect of carnitine supplementation on blood ammonia levels in children with epilepsy who have been treated with valproic acid for more than six months.Materials and Methods: This was a randomized, double-blind, placebo-controlled trial study where children with epilepsy who were treated with valproic acid were randomly allocated to the carnitine supplementation and control group. All children were followed for month, and then measured for blood ammonia level. Blood ammonia levels of both groups were compared using an Independent t-test with a significant of p<0.05.Results: Total of 32 children with epilepsy were enrolled as subjects in this study, with 16 children in carnitine group, and 16 children in control group. Among the subjects, 50% were male and 50% were female, with a mean age of 6.5 years old. The average duration of epilepsy in the carnitine and control group were 41.7 months and 36.9 months, respectively (p=0.419). The duration of valproic acid therapy in the carnitine and control group were 33.1 months and 27.6 months, respectively (p=0.483). The level of blood ammonia in carnitine and control group were 44.6 mg/dL and 81.4 mg/dL, respectively (p=0.007).Conclusion: The level of blood ammonia in a carnitine group was significantly lower than in a control group. It is recommended to give carnitine supplementation in epileptic children treating with long-term valproic acid.Keywords: ammonia, carnitine, epilepsy, seizure, valproic acid