Gut microbiota manipulation during the prepubertal period shapes behavioral abnormalities in a mouse neurodevelopmental disorder model.

Previous studies demonstrate an association between activation of the maternal immune system during pregnancy and increased risk of neurodevelopmental psychiatric conditions, such as schizophrenia and autism, in the offspring. Relatively recent findings also suggest that the gut microbiota plays an important role in shaping brain development and behavior. Here we show that maternal immune activation (MIA) accomplished by infection with a mouse-adapted influenza virus during pregnancy induced up-regulation of frontal cortex serotonin 5-HT2A receptor (5-HT2AR) density in the adult offspring, a phenotype previously observed in postmortem frontal cortex of schizophrenic subjects. 5-HT2AR agonist-induced head-twitch behavior was also augmented in this preclinical mouse model. Using the novel object recognition (NOR) test to evaluate cognitive performance, we demonstrate that MIA induced NOR deficits in adult offspring. Oral antibiotic treatment of prepubertal mice prevented this cognitive impairment, but not increased frontal cortex 5-HT2AR density or psychedelic-induced head-twitch behavior in adult MIA offspring. Additionally, gut microbiota transplantation from MIA mice produced behavioral deficits in antibiotic-treated mock mice. Adult MIA offspring displayed altered gut microbiota, and relative abundance of specific components of the gut microbiota, including Ruminococcaceae, correlated with frontal cortex 5-HT2AR density. Together, these findings provide a better understanding of basic mechanisms by which prenatal insults impact offspring brain function, and suggest gut-brain axis manipulation as a potential therapeutic approach for neurodevelopmental psychiatric conditions.

Periodontal therapy favorably modulates the oral-gut-hepatic axis in cirrhosis.

Cirrhosis is associated with a systemic proinflammatory milieu, endotoxemia, and gut dysbiosis. The oral cavity could be an additional source of inflammation. We aimed to determine the effect of periodontal therapy in cirrhosis through evaluating endotoxemia, inflammation, cognition, and quality of life (QOL). Age-matched cirrhotic and noncirrhotic subjects exhibiting chronic gingivitis and/or mild or moderate periodontitis underwent periodontal therapy with follow-up at 30 days. Saliva/stool for microbial composition and serum for Model for End-stage Liver Disease (MELD) score, endotoxin and lipopolysaccharide binding protein (LBP) and immune-inflammatory markers (IL-1ß; IL-6; histatins 1, 3, 5; and lysozyme) were collected at baseline and day 30. The cognitive function and QOL were also evaluated similarly. A separate group of cirrhotic patients were followed for the same duration without periodontal therapy. Cirrhotics, especially those with hepatic encephalopathy (HE), demonstrated improved dysbiosis in stool and saliva, and improved endotoxin, LBP, and salivary and serum inflammatory mediators following periodontal therapy. These parameters, which were higher in HE at baseline, became statistically similar posttherapy. Pretherapy vs. posttherapy QOL and cognition also improved in HE patients following oral interventions. On the other hand, LBP and endotoxin increased over time in cirrhotic patients not receiving therapy, but the rest of the parameters, including microbiota remained similar over time in the no-therapy group. This proof-of-concept study demonstrates that periodontal therapy in cirrhosis, especially in those with HE, is associated with improved oral and gut dysbiosis, systemic inflammation, MELD score, and cognitive function, which was not observed in those who did not receive therapy over the same time period. NEW & NOTEWORTHY Systematic periodontal therapy in cirrhotic outpatients improved endotoxemia, as well as systemic and local inflammation, and modulated salivary and stool microbial dysbiosis over 30 days. This was associated with improved quality of life and cognition in patients with prior hepatic encephalopathy. In a cirrhotic group that was not provided periodontal therapy, there was an increase in endotoxin and lipopolysaccharide binding protein in the same duration. The oral cavity could be an important underdefined source of inflammation in cirrhosis.

Gut microbial RNA and DNA analysis predicts hospitalizations in cirrhosis.

BACKGROUND: Cirrhosis is associated with gut microbial changes, but current 16S rDNA techniques sequence both dead and live bacteria. We aimed to determine the rRNA content compared with DNA from the same stool sample to evaluate cirrhosis progression and predict hospitalizations. METHODS: Cirrhotics and controls provided stool for RNA and DNA analysis. Comparisons were made between cirrhotics/controls and within cirrhosis (compensated/decompensated, infected/uninfected, renal dysfunction/not, rifaximin use/not) with respect to DNA and RNA bacterial content using linear discriminant analysis. A separate group was treated with omeprazole for 14 days with longitudinal microbiota evaluation. Patients were followed for 90 days for hospitalizations. Multivariable models for hospitalizations with clinical data with and without DNA and RNA microbial data were created. RESULTS: Twenty-six controls and 154 cirrhotics (54 infected, 62 decompensated, 20 renal dysfunction, 18 rifaximin) were included. RNA and DNA analysis showed differing potentially pathogenic taxa but similar autochthonous taxa composition. Thirty subjects underwent the omeprazole study, which demonstrated differences between RNA and DNA changes. Thirty-six patients were hospitalized within 90 days. In the RNA model, MELD score and Enterococcus were independently predictive of hospitalizations, while in the DNA model MELD was predictive and Roseburia protective. In both models, adding microbiota significantly added to the MELD score in predicting hospitalizations. CONCLUSION: DNA and RNA analysis of the same stool sample demonstrated differing microbiota composition, which independently predicts the hospitalization risk in cirrhosis. RNA and DNA content of gut microbiota in cirrhosis are modulated differentially with disease severity, infections, and omeprazole use. TRIAL REGISTRATION: NCT01458990. FUNDING: VA Merit I0CX001076.

Correction: Almeida-Dalmet, S.; et al. Differential Gene Expression in Response to Salinity and Temperature in a Haloarcula Strain from Great Salt Lake, Utah. Genes 2017, 9, 52.

The authors wish to make the following changes to their paper [1].[...].

Differential Gene Expression in Response to Salinity and Temperature in a Haloarcula Strain from Great Salt Lake, Utah.

Haloarchaea that inhabit Great Salt Lake (GSL), a thalassohaline terminal lake, must respond to the fluctuating climate conditions of the elevated desert of Utah. We investigated how shifting environmental factors, specifically salinity and temperature, affected gene expression in the GSL haloarchaea, NA6-27, which we isolated from the hypersaline north arm of the lake. Combined data from cultivation, microscopy, lipid analysis, antibiotic sensitivity, and 16S rRNA gene alignment, suggest that NA6-27 is a member of the Haloarcula genus. Our prior study demonstrated that archaea in the Haloarcula genus were stable in the GSL microbial community over seasons and years. In this study, RNA arbitrarily primed PCR (RAP-PCR) was used to determine the transcriptional responses of NA6-27 grown under suboptimal salinity and temperature conditions. We observed alteration of the expression of genes related to general stress responses, such as transcription, translation, replication, signal transduction, and energy metabolism. Of the ten genes that were expressed differentially under stress, eight of these genes responded in both conditions, highlighting this general response. We also noted gene regulation specific to salinity and temperature conditions, such as osmoregulation and transport. Taken together, these data indicate that the GSL Haloarcula strain, NA6-27, demonstrates both general and specific responses to salinity and/or temperature stress, and suggest a mechanistic model for homeostasis that may explain the stable presence of this genus in the community as environmental conditions shift.

Gut Microbiota Alterations can predict Hospitalizations in Cirrhosis Independent of Diabetes Mellitus.

Diabetes (DM) is prevalent in cirrhosis and may modulate the risk of hospitalization through gut dysbiosis. We aimed to define the role of gut microbiota on 90-day hospitalizations and of concomitant DM on microbiota. Cirrhotic outpatients with/without DM underwent stool and sigmoid mucosal microbial analysis and were followed for 90 days. Microbial composition was compared between those with/without DM, and those who were hospitalized/not. Regression/ROC analyses for hospitalizations were performed using clinical and microbial features. 278 cirrhotics [39% hepatic encephalopathy (HE), 31%DM] underwent stool while 72 underwent mucosal analyses. Ultimately, 94 were hospitalized and they had higher MELD, proton pump inhibitor (PPI) use and HE without difference in DM. Stool/mucosal microbiota were significantly altered in those who were hospitalized (UNIFRAC p < = 1.0e-02). Specifically, lower stool Bacteroidaceae, Clostridiales XIV, Lachnospiraceae, Ruminococcacae and higher Enterococcaceae and Enterobacteriaceae were seen in hospitalized patients. Concomitant DM impacted microbiota UNIFRAC (stool, p = 0.003, mucosa, p = 0.04) with higher stool Bacteroidaceae and lower Ruminococcaeae. Stool Bacteroidaceaeae and Clostridiales XIV predicted 90-day hospitalizations independent of clinical predictors (MELD, HE, PPI). Stool and colonic mucosal microbiome are altered in cirrhotics who get hospitalized with independent prediction using stool Bacteroidaceae and Clostridiales XIV. Concomitant DM distinctly impacts gut microbiota without affecting hospitalizations.

Temporal Study of the Microbial Diversity of the North Arm of Great Salt Lake, Utah, U.S.

We employed a temporal sampling approach to understand how the microbial diversity may shift in the north arm of Great Salt Lake, Utah, U.S. To determine how variations in seasonal environmental factors affect microbial communities, length heterogeneity PCR fingerprinting was performed using consensus primers for the domain Bacteria, and the haloarchaea. The archaeal fingerprints showed similarities during 2003 and 2004, but this diversity changed during the remaining two years of the study, 2005 and 2006. We also performed molecular phylogenetic analysis of the 16S rRNA genes of the whole microbial community to characterize the taxa in the samples. Our results indicated that in the domain, Bacteria, the Salinibacter group dominated the populations in all samplings. However, in the case of Archaea, as noted by LIBSHUFF for phylogenetic relatedness analysis, many of the temporal communities were distinct from each other, and changes in community composition did not track with environmental parameters. Around 20-23 different phylotypes, as revealed by rarefaction, predominated at different periods of the year. Some phylotypes, such as Haloquadradum, were present year-round although they changed in their abundance in different samplings, which may indicate that these species are affected by biotic factors, such as nutrients or viruses, that are independent of seasonal temperature dynamics.