Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes.

For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.

Bifidobacterium Against COVID-19: A Mother and Her Newborn's Gut Microbiome.

Several treatments and preventive measures for SARS-CoV-2 were studied during the pandemic, but few focused on the neonatal gut microbiome and its role in the setting of COVID-19. This case report is unique because it describes the gut microbiomes of a mother and her newborn, who both contracted COVID-19 shortly after the baby's birth. In this prospective study, on day 11 postpartum, both the newborn and mother (38 years old), of white race/ethnicity, were exposed to a COVID-19-positive person. After exposure, the mother received a 40,000 IU bolus of vitamin D orally and started a five-day course of high-dose vitamin C (10,000 mg daily), after which she continued her daily combination of vitamins C, D, and zinc pill with probiotic skyr yogurt and manuka honey. Stool specimens and DNA were extracted, quantitated, and normalized from the mother and the newborn for downstream library fabrication utilizing shotgun methodology. Baseline Bifidobacteria level for the mother was 1.5% which increased to 19% on day 15 postpartum after testing positive for COVID-19 and taking vitamin C. Neonatal Bifidobacteriasteadily increased regardless of COVID-19 infection. We propose that the disease course was altered by maternal supplementation of vitamins C and D and zinc, which may have increased Bifidobacterium levels and led to improved outcomes for both patients.

Correction to: Improvements in Gut Microbiome Composition and Clinical Symptoms Following Familial Fecal Microbiota Transplantation in a Nineteen-Year-Old Adolescent With Severe Autism.

[This corrects the article DOI: 10.14740/jmc4209.].

Improvements in Gut Microbiome Composition and Clinical Symptoms Following Familial Fecal Microbiota Transplantation in a Nineteen-Year-Old Adolescent With Severe Autism.

This case report describes a novel therapy for patients with severe autism spectrum disorder (ASD) that is worth further investigation. A 19-year-old male adolescent with ASD, who was not responding to standard treatment received fecal microbiota transplant (FMT) using donor material from his typically developing female sibling. The patient's ASD symptoms were assessed by assessors who were blind to the patient's past ASD symptomatology. Assessors used the Childhood Autism Rating Scale (CARS), an observation-based rating scale to assess developmental delay in children with autism (range of CARS scores is 15 - 60; a score > 28 is indicative of autism; higher score is positively correlated with degree of severity), at baseline and again at six timepoints post-FMT. The patient experienced marked improvements in microbiome diversity and composition over the year and a half period that followed the FMT procedure. Additionally, the patient who was previously nonverbal said his first two words and experienced a reduction in aggression 1-month post-FMT. To the authors' knowledge, this is the first report to demonstrate the use of familial FMT in an adolescent patient with ASD. Given that ASD symptom improvements post-FMT tend to occur in younger patients, the authors hypothesize that the use of a familial donor may be an important factor that contributed to the improved outcomes experienced by this older child.

Microbiota-derived psychedelics: Lessons from COVID-19.

Emil Kraepelin believed that dementia praecox, the disorder we now call schizophrenia, was caused by the brain being poisoned with toxins generated in other parts of the body, especially the mouth, intestine or genitals. In this regard, Kraepelin hinted at the microbiome and conceptualized microbial molecules as drivers of severe psychiatric illness. However, it was not until the coronavirus disease (COVID-19) pandemic that Kraepelin's paradigm gained traction, particularly because this virus was associated with both gut barrier disruption and new-onset psychosis.Likewise, despite numerous studies linking severe psychiatric illness to genomic damage and dysfunctional DNA repair, this pathogenetic mechanism was underappreciated before the COVID-19 pandemic. The use of the psychotomimetic anesthetic, ketamine, for treatment-resistant depression has reawakened the interest in endogenous serotonergic hallucinogens, especially tryptamine and N,N-dimethyltryptamine (DMT), which are beneficial for depression but associated with psychosis.In this editorial, we take a closer look at the role of the microbiome in psychopathology, attempting to answer 2 questions:1. Why may psychosis-predisposing serotonergic hallucinogens alleviate depression?2. Are microbiota-derived psychedelics part of an inbuilt antidepressant system similar to endogenous opioids?

Vitamin C improves gut Bifidobacteria in humans.

Aims: Numerous beneficial effects of vitamin C (ascorbic acid) supplementation have been reported in the literature. However, data on its effects toward the gut microbiome are limited. We assessed the effect of vitamin C supplementation on the abundance of beneficial bacterial species in the gut microbiome. Materials and methods: Stool samples were analyzed for relative abundance of gut microbiome bacteria using next-generation sequencing-based profiling and metagenomic shotgun analysis. Results: Supplementation with vitamin C increased the abundance of bacteria of the genus Bifidobacterium (p = 0.0001) and affected various species. Conclusion: The beneficial effects of vitamin C supplementation may be attributed to modulation of the gut microbiome and the consequent health benefits thereof.

Vitamin C, also known as ascorbic acid, is used as a supplement for fighting infectious disorders. Many disorders, including COVID-19 and cancer, harmfully disrupt the levels of bacteria that naturally reside in the gut, which may contribute to symptoms. The aim of the study was to understand whether high-dose vitamin C could improve the types of bacteria in the human gut. To do this we characterized the gut bacteria before and after 23 individuals took vitamin C, as prescribed by their respective physicians. We observed that vitamin C increased levels of a gut bacterium called Bifidobacterium which has positive health benefits, including fighting infection. This study suggests the possibility that vitamin C could be successful for improving infection outcomes, possibly even COVID-19, partially because it improves the gut bacteria present.

Psychotropic drugs interaction with the lipid nanoparticle of COVID-19 mRNA therapeutics.

The messenger RNA (mRNA) vaccines for COVID-19, Pfizer-BioNTech and Moderna, were authorized in the US on an emergency basis in December of 2020. The rapid distribution of these therapeutics around the country and the world led to millions of people being vaccinated in a short time span, an action that decreased hospitalization and death but also heightened the concerns about adverse effects and drug-vaccine interactions. The COVID-19 mRNA vaccines are of particular interest as they form the vanguard of a range of other mRNA therapeutics that are currently in the development pipeline, focusing both on infectious diseases as well as oncological applications. The Vaccine Adverse Event Reporting System (VAERS) has gained additional attention during the COVID-19 pandemic, specifically regarding the rollout of mRNA therapeutics. However, for VAERS, absence of a reporting platform for drug-vaccine interactions left these events poorly defined. For example, chemotherapy, anticonvulsants, and antimalarials were documented to interfere with the mRNA vaccines, but much less is known about the other drugs that could interact with these therapeutics, causing adverse events or decreased efficacy. In addition, SARS-CoV-2 exploitation of host cytochrome P450 enzymes, reported in COVID-19 critical illness, highlights viral interference with drug metabolism. For example, patients with severe psychiatric illness (SPI) in treatment with clozapine often displayed elevated drug levels, emphasizing drug-vaccine interaction.

Microbiome-Based Hypothesis on Ivermectin's Mechanism in COVID-19: Ivermectin Feeds Bifidobacteria to Boost Immunity.

Ivermectin is an anti-parasitic agent that has gained attention as a potential COVID-19 therapeutic. It is a compound of the type Avermectin, which is a fermented by-product of Streptomyces avermitilis. Bifidobacterium is a member of the same phylum as Streptomyces spp., suggesting it may have a symbiotic relation with Streptomyces. Decreased Bifidobacterium levels are observed in COVID-19 susceptibility states, including old age, autoimmune disorder, and obesity. We hypothesize that Ivermectin, as a by-product of Streptomyces fermentation, is capable of feeding Bifidobacterium, thereby possibly preventing against COVID-19 susceptibilities. Moreover, Bifidobacterium may be capable of boosting natural immunity, offering more direct COVID-19 protection. These data concord with our study, as well as others, that show Ivermectin protects against COVID-19.

Lost microbes of COVID-19: Bifidobacterium, Faecalibacterium depletion and decreased microbiome diversity associated with SARS-CoV-2 infection severity.

OBJECTIVE: The study objective was to compare gut microbiome diversity and composition in SARS-CoV-2 PCR-positive patients whose symptoms ranged from asymptomatic to severe versus PCR-negative exposed controls. DESIGN: Using a cross-sectional design, we performed shotgun next-generation sequencing on stool samples to evaluate gut microbiome composition and diversity in both patients with SARS-CoV-2 PCR-confirmed infections, which had presented to Ventura Clinical Trials for care from March 2020 through October 2021 and SARS-CoV-2 PCR-negative exposed controls. Patients were classified as being asymptomatic or having mild, moderate or severe symptoms based on National Institute of Health criteria. Exposed controls were individuals with prolonged or repeated close contact with patients with SARS-CoV-2 infection or their samples, for example, household members of patients or frontline healthcare workers. Microbiome diversity and composition were compared between patients and exposed controls at all taxonomic levels. RESULTS: Compared with controls (n=20), severely symptomatic SARS-CoV-2-infected patients (n=28) had significantly less bacterial diversity (Shannon Index, p=0.0499; Simpson Index, p=0.0581), and positive patients overall had lower relative abundances of Bifidobacterium (p<0.0001), Faecalibacterium (p=0.0077) and Roseburium (p=0.0327), while having increased Bacteroides (p=0.0075). Interestingly, there was an inverse association between disease severity and abundance of the same bacteria. CONCLUSION: We hypothesise that low bacterial diversity and depletion of Bifidobacterium genera either before or after infection led to reduced proimmune function, thereby allowing SARS-CoV-2 infection to become symptomatic. This particular dysbiosis pattern may be a susceptibility marker for symptomatic severity from SARS-CoV-2 infection and may be amenable to preinfection, intrainfection or postinfection intervention. TRIAL REGISTRATION NUMBER: NCT04031469 (PCR-) and 04359836 (PCR+).

Pre-Existing Microbiome Signature in a SARS-CoV-2 Discordant Family.

Our index patient is a 19-year-old man with Crohn's disease. After developing symptoms consistent with COVID-19, he, his 62-year-old father, and 14-year-old sister tested positive for SARS-CoV-2 in May 2020. Despite a shared household, his 50-year-old mother with a history of asthma and his healthy brother and sister-in-law (a married couple) remained negative. The index patient and his mother had undergone microbiome analysis in May 2019, following his brother and his sister-in-law in November 2020. We observed significant differences between the fecal microbiota of the SARS-CoV-2-positive son and those of his healthy family. There were differences in the bacterial phylum, class, order, family, and genus level with the increased relative abundance of Bacteroidetes and reductions or deletions in bacterial diversity, particularly of the Bifidobacterium family. This unique study may signal a new exploratory avenue for the prevention or treatment of SARS-CoV-2 infections.

Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients.

Aims: Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ random, controlled trials. Having developed combination therapies for Helicobacter pylori, the authors present a highly effective COVID-19 therapeutic combination, stemming from clinical observations. Patients & methods: In 24 COVID-19 subjects refusing hospitalization with high-risk features, hypoxia and untreated moderate to severe symptoms averaging 9 days, the authors administered this novel combination of ivermectin, doxycycline, zinc and vitamins D and C. Results & conclusions: All subjects resolved symptoms (in 11 days on average), and oxygen saturation improved in 24 h (87.4% to 93.1%; p = 0.001). There were no hospitalizations or deaths, less than (p < 0.002 or 0.05, respectively) background-matched CDC database controls. Triple combination therapy is safe and effective even when used in outpatients with moderate to severe symptoms. Clinical Trial Registration: NCT04482686 (ClinicalTrial.gov).

Successful Bacterial Engraftment Identified by Next-Generation Sequencing Predicts Success of Fecal Microbiota Transplant for Clostridioides difficile.

BACKGROUND: The effectiveness of fecal microbiota transplantation (FMT), a treatment for Clostridioides difficile infection (CDI), is dependent on successful engraftment (incorporation) of donor stool. We present a method for evaluating engraftment success based on next-generation sequencing (NGS)-based profiling of bacterial strains present in donor and recipient stool, and we suggest its potential to guide treatment decisions. METHODS: Bacterial strains in stool samples from three patients from the clinic and one donor were analyzed via NGS and metagenomic sequencing, before and 1 month after FMT for CDI. The similarity of strains present was assessed via relative abundance, principal component analysis, Shannon and Simpson diversity indexes, and Bray-Curtis dissimilarity matrix. A positive outcome was successful engraftment, where the post-FMT sample closely resembled that of the donor and CDI was cured. RESULTS: Patients (Pts.) 1 and 2, but not Pt. 3's stool samples closely resembled the donor specimen post-FMT. Noteworthy, Pt. 3 pre-FMT sample was less similar to the donor than that of Pts. 1 and 2. All methods of assessing similarity and dissimilarity used yielded virtually identical conclusions. Pts. 1 and 2 which closely resembled donor specimen, eradicated CDI giving a surrogate objective measure of engraftment. CONCLUSIONS: Success of engraftment in FMT can be assessed using NGS and metagenomic analysis and parallels success in curing CDI of the microbiome. The statistical methods we present here are reliable and consistent for such purposes. The dissimilarity of Pt. 3 to the donor combined with the failure of engraftment and failure to cure CDI in Pt. 3 suggests that FMT success may be predictable by comparing pre-FMT samples to donor. There is no clinical trial registry listing this study.

n-6 High Fat Diet Induces Gut Microbiome Dysbiosis and Colonic Inflammation.

Background: Concerns are emerging that a high-fat diet rich in n-6 PUFA (n-6HFD) may alter gut microbiome and increase the risk of intestinal disorders. Research is needed to model the relationships between consumption of an n-6HFD starting at weaning and development of gut dysbiosis and colonic inflammation in adulthood. We used a C57BL/6J mouse model to compare the effects of exposure to a typical American Western diet (WD) providing 58.4%, 27.8%, and 13.7% energy (%E) from carbohydrates, fat, and protein, respectively, with those of an isocaloric and isoproteic soybean oil-rich n-6HFD providing 50%E and 35.9%E from total fat and carbohydrates, respectively on gut inflammation and microbiome profile. Methods: At weaning, male offspring were assigned to either the WD or n-6HFD through 10-16 weeks of age. The WD included fat exclusively from palm oil whereas the n-6HFD contained fat exclusively from soybean oil. We recorded changes in body weight, cyclooxygenase-2 (COX-2) expression, colon histopathology, and gut microbiome profile. Results: Compared to the WD, the n-6HFD increased plasma levels of n-6 fatty acids; colonic expression of COX-2; and the number of colonic inflammatory and hyperplastic lesions. At 16 weeks of age, the n-6HFD caused a marked reduction in the gut presence of Firmicutes, Clostridia, and Lachnospiraceae, and induced growth of Bacteroidetes and Deferribacteraceae. At the species level, the n-6HFD sustains the gut growth of proinflammatory Mucispirillum schaedleri and Lactobacillus murinus. Conclusions: An n-6HFD consumed from weaning to adulthood induces a shift in gut bacterial profile associated with colonic inflammation.

Detection of SARS-CoV-2 from patient fecal samples by whole genome sequencing.

BACKGROUND: SARS-CoV-2 has been detected not only in respiratory secretions, but also in stool collections. Here were sought to identify SARS-CoV-2 by enrichment next-generation sequencing (NGS) from fecal samples, and to utilize whole genome analysis to characterize SARS-CoV-2 mutational variations in COVID-19 patients. RESULTS: Study participants underwent testing for SARS-CoV-2 from fecal samples by whole genome enrichment NGS (n = 14), and RT-PCR nasopharyngeal swab analysis (n = 12). The concordance of SARS-CoV-2 detection by enrichment NGS from stools with RT-PCR nasopharyngeal analysis was 100%. Unique variants were identified in four patients, with a total of 33 different mutations among those in which SARS-CoV-2 was detected by whole genome enrichment NGS. CONCLUSION: These results highlight the potential viability of SARS-CoV-2 in feces, its ongoing mutational accumulation, and its possible role in fecal-oral transmission. This study also elucidates the advantages of SARS-CoV-2 enrichment NGS, which may be a key methodology to document complete viral eradication. Trial registration ClinicalTrials.gov, NCT04359836, Registered 24 April 2020, https://clinicaltrials.gov/ct2/show/NCT04359836?term=NCT04359836&draw=2&rank=1 ).

Shotgun Metagenomic Sequencing Identifies Dysbiosis in Triplet Sibling with Gastrointestinal Symptoms and ASD.

The gut microbiome profile of a child with autism spectrum disorder (ASD) and co-occurring gastrointestinal (GI) symptoms was compared to that of her healthy triplet siblings to determine if she exhibited intestinal dysbiosis. Shotgun metagenomic sequencing was performed in individual fecal samples, and relative microbial abundance and diversity was determined. Microbial diversity was lower in sibling #3, coupled with a higher Bacteroidetes/Firmicutes ratio, a lower relative abundance of Actinobacteria, and an increased relative abundance of Proteobacteria. Our findings are suggestive of gut dysbiosis in a child with ASD and co-occurring GI symptoms, compared to her two healthy triplet siblings.

Anti-Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis.

BACKGROUND: Eosinophilic gastritis and duodenitis are characterized by gastrointestinal mucosal eosinophilia, chronic symptoms, impaired quality of life, and a lack of adequate treatments. Mast-cell activity may contribute to the pathogenesis of the conditions. AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells and that has shown potential in animal models as a treatment for eosinophilic gastritis and duodenitis. METHODS: In this phase 2 trial, we randomly assigned adults who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo. The primary end point was the change in gastrointestinal eosinophil count from baseline to 2 weeks after the final dose; to maximize statistical power, we evaluated this end point in the placebo group as compared with the combined AK002 group. Secondary end points were treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) and the change in total symptom score. RESULTS: Of the 65 patients who underwent randomization, 43 were assigned to receive AK002 and 22 were assigned to receive placebo. The mean percentage change in gastrointestinal eosinophil count was -86% in the combined AK002 group, as compared with 9% in the placebo group (least-squares mean difference, -98 percentage points; 95% confidence interval [CI], -121 to -76; P<0.001). Treatment response occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo (difference, 58 percentage points; 95% CI, 36 to 74; P<0.001). The mean change in total symptom score was -48% with AK002 and -22% with placebo (least-squares mean difference, -26 percentage points; 95% CI, -44 to -9; P = 0.004). Adverse events associated with AK002 were similar to those with placebo, with the exception of higher percentages of patients having mild-to-moderate infusion-related reactions with AK002 (60% in the combined AK002 group and 23% in the placebo group). CONCLUSIONS: In patients with eosinophilic gastritis or duodenitis, AK002 reduced gastrointestinal eosinophils and symptoms. Infusion-related reactions were more common with AK002 than with placebo. (Funded by Allakos; ENIGMA ClinicalTrials.gov number, NCT03496571.).

Rapid improvement in Alzheimer's disease symptoms following fecal microbiota transplantation: a case report.

Alzheimer's disease (AD), the most common form of dementia, is a leading cause of death and a major cause of morbidity in older people. The disease is characterized by progressive memory loss, cognitive impairment, and the cerebral accumulation of amyloid-ß peptide. Given the health and economic impacts of AD, treatments that target the underlying etiology of AD or modify the course of the disease are of significant interest. The gut microbiome has been increasingly implicated in the pathogenesis of several neurological diseases, including multiple sclerosis and Parkinson's disease. Furthermore, emerging evidence has demonstrated that there are alterations in gut microbiome composition in patients with AD, suggesting involvement of the microbiome-gut-brain axis. We present symptom improvement in a patient with AD following fecal microbiota transplantation for a Clostridioides difficile infection.

Correction to: Thinking Outside the Box: Visualization of an Ectopic Stomach via Surgically Advanced Endoscopy at Site of Intussusception.

[This corrects the article on p. e00236 in vol. 6, PMID: 31832463.].