Biology subjects

Davidovic, L.

Publications and source records attributed to Davidovic, L..

4 recordsLinked to original sources

bioRxiv2026

Microbial metabolite p-cresol associates with constipation in adults with high-functioning autism spectrum disorder and induces constipation-like symptoms in mice

Gastrointestinal (GI) symptoms are prevalent in Autism Spectrum Disorder (ASD), yet their biological correlates remain poorly understood. The gut microbial metabolite p-cresol is reported to be elevated in ASD, but its link to specific GI symptoms in adult high-functioning adults remains unexplored. We examined the relationship between serum levels of p-cresol and its conjugates (p-cresol sulfate, p-cresol glucuronide) with five common GI symptoms (diarrhea, constipation, abnormal stool aspect, bloating, abdominal pain) in 272 adults with high-functioning ASD. Clinical and dietary assessments were performed, and serum metabolites were measured using targeted metabolomics in 177 patients. Females with ASD had higher rates of GI symptoms and elevated p-cresol compared to males. Multivariable regression analysis showed that serum p-cresol, but not its conjugates, was selectively associated with constipation frequency, independent of sex, age, and diet. No associations were observed with the other GI symptoms. In mice, chronic p-cresol exposure induced constipation-like GI dysfunction, supporting a causal link. These findings identify p-cresol as a possible mediator of constipation in ASD. This work supports the development of tailored interventions for GI symptoms in adults with ASD. LAY SUMMARYPeople with autism spectrum disorder (ASD) often experience gastrointestinal (GI) symptoms, but the role of the gut microbiota remains unclear. Elevated levels of p-cresol, a gut microbiota-derived molecule, have been reported in ASD, though its link to specific GI symptoms, particularly in adults, remains unknown. We studied 272 adults with high-functioning ASD and we found that women with ASD reported more frequently GI symptoms and had higher levels of p-cresol than men. Higher p-cresol levels were associated with more frequent constipation, but not with other GI symptoms. In mice, p-cresol treatment induced signs of constipation, suggesting a causal role. Overall, our findings indicate that p-cresol may contribute to constipation in adults with ASD and support the need personalized medical approaches to digestive health in adults with ASD.

microbiology↗

bioRxiv2020

An Integrated Workflow for Enhanced Taxonomic and Functional Coverage of the Mouse Faecal Metaproteome

Intestinal microbiota plays a key role in shaping host homeostasis by regulating metabolism, immune responses and behaviour. Its dysregulation has been associated with metabolic, immune and neuropsychiatric disorders and is accompanied by changes in bacterial metabolic regulation. Although proteomics is well suited for analysis of individual microbes, metaproteomics of faecal samples is challenging due to the physical structure of the sample, presence of contaminating host proteins and coexistence of hundreds of microorganisms. Furthermore, there is a lack of consensus regarding preparation of faecal samples, as well as downstream bioinformatic analyses following metaproteomics data acquisition. Here we assess sample preparation and data analysis strategies applied to mouse faeces in a typical mass spectrometry-based metaproteomic experiment. We show that subtle changes in sample preparation protocols may influence interpretation of biological findings. Two-step database search strategies led to significant underestimation of false positive protein identifications. Unipept software provided the highest sensitivity and specificity in taxonomic annotation of the identified peptides of unknown origin. Comparison of matching metaproteome and metagenome data revealed a positive correlation between protein and gene abundances. Notably, nearly all functional categories of detected protein groups were differentially abundant in the metaproteome compared to what would be expected from the metagenome, highlighting the need to perform metaproteomics when studying complex microbiome samples.

microbiology↗

bioRxiv2020

Gut microbial metabolite p-Cresol promotes autistic-like behaviors in mice through remodeling of the microbiota

BackgroundAutism Spectrum Disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis resulting in changes in microbiota composition as well as fecal, serum and urine levels of microbial metabolites. Yet, a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. ResultsMice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol levels compared to mice transplanted with the microbiota of control mice and identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. ConclusionsThe microbial metabolite p-Cresol induces ASD core behavioral symptoms in mice via a gut microbiota-dependent mechanism. Our study paves the way for therapeutic interventions targeting the microbiota to treat patients with ASD.

neuroscience↗

bioRxiv2020

Integration of behavioral and biological variables using penalized regression: an application to the maternal immune activation model of autism

Maternal immune activation (MIA) during pregnancy increases the odds of developing neuropsychiatric disorders such as autism spectrum disorder (ASD) later in life. In pregnant mice, MIA can be induced by injecting the viral mimic polyinosinic:polycytidylic acid (poly(I:C) to pregnant dams resulting in altered fetal neurodevelopmental and behavioral changes in their progeny. Although the murine MIA model has been extensively studied worldwide, the underlying mechanisms have only been partially elucidated. Furthermore, the murine MIA model suffers from lack of reproducibility, at least in part because it is highly influenced by subtle changes in environmental conditions. In human studies, multivariable (MV) statistical analysis is widely used to control for covariates including sex, age, exposure to environmental factors and many others. We reasoned that animal studies in general, and studies on the MIA model in particular, could therefore benefit from MV analyzes to account for complex phenotype interactions and high inter-individual variability. Here, we used a dataset consisting of 26 variables collected on 67 male pups during the course of several independent experiments on the MIA model. We then analyzed this dataset using penalized regression to identify variables associated with in utero exposure to MIA. In addition to confirming the association between some previously described biological variables and MIA, we identified new variables that could play a role in neurodevelopment alterations. Aside from providing new insights into variable interactions in the MIA model, this study highlights the importance of extending the use of MV statistics to animal studies.

neuroscience↗