The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

Abstract Background Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the 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. Results Mice 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 excretion, compared to mice transplanted with the microbiota of control mice. In addition, we 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. Conclusions The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.

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The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

10.1101/2020.05.18.101147 ◽

2020 ◽

Cited By ~ 2

Author(s):

P. Bermudez-Martin ◽

J. A. J. Becker ◽

S. P. Fernandez ◽

R. Costa-Campos ◽

S. Barbosa ◽

...

Keyword(s):

Social Behavior ◽

Gut Microbiota ◽

Autism Spectrum ◽

Dopamine Neurons ◽

Therapeutic Interventions ◽

Microbiota Composition ◽

Microbial Metabolites ◽

Fecal Matter ◽

Microbial Metabolite ◽

Central Dopamine Neurons

ABSTRACTBrain development and behavioral responses are influenced by gut microbiota. Perturbations of the microbiota-gut-brain axis have been identified in autism spectrum disorders (ASD), suggesting that the microbiota could be involved in abnormal social and stereotyped behaviors in ASD patients. Notably, changes in microbiota composition and fecal, serum or urine levels of microbial metabolites are associated with ASD. Yet, a causal relationship between abnormal microbiota composition, altered microbial metabolite production, and ASD remains to be demonstrated. We hypothesized that p-Cresol (also known as 4-Cresol), a microbial metabolite that was described as more abundant in ASD patients, contributes to ASD core behavioral symptoms. Here we show that mice 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 modified the relative abundance of specific bacterial taxa which correlated with social behavior. In addition, social behavior deficits were transferrable from p-Cresol-treated mice to control mice by fecal matter transplantation. In contrast, the microbiota from control mice restored both social interactions and dopamine neurons excitability when transplanted to p-Cresol-treated mice. Altogether, our results suggest that microbial metabolites p-Cresol could be involved in the development of core autistic behaviors via a gut microbiota-dependent mechanism. Further, this study paves the way for therapeutic interventions targeting the production of p-Cresol by gut bacteria to treat patients with ASD.

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Gut microbiota determines the social behavior of mice and induces metabolic and inflammatory changes in their adipose tissue

npj Biofilms and Microbiomes ◽

10.1038/s41522-021-00193-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Oryan Agranyoni ◽

Sapir Meninger-Mordechay ◽

Atara Uzan ◽

Oren Ziv ◽

Mali Salmon-Divon ◽

...

Keyword(s):

Adipose Tissue ◽

Social Behavior ◽

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Critical Role ◽

Fecal Microbiota ◽

Rrna Gene ◽

Microbiota Composition ◽

The Social ◽

Inflammatory Profile

AbstractThe link between the gut microbiota and social behavior has been demonstrated, however the translational impact of a certain microbiota composition on stable behavioral patterns is yet to be elucidated. Here we employed an established social behavior mouse model of dominance (Dom) or submissiveness (Sub). A comprehensive 16S rRNA gene sequence analysis of Dom and Sub mice revealed a significantly different gut microbiota composition that clearly distinguishes between the two behavioral modes. Sub mice gut microbiota is significantly less diverse than that of Dom mice, and their taxa composition uniquely comprised the genera Mycoplasma and Anaeroplasma of the Tenericutes phylum, in addition to the Rikenellaceae and Clostridiaceae families. Conversely, the gut microbiota of Dom mice includes the genus Prevotella of the Bacteriodetes phylum, significantly less abundant in Sub mice. In addition, Sub mice show lower body weight from the age of 2 weeks and throughout their life span, accompanied with lower epididymis white adipose tissue (eWAT) mass and smaller adipocytes together with substantially elevated expression of inflammation and metabolic-related eWAT adipokines. Finally, fecal microbiota transplantation into germ-free mice show that Sub-transplanted mice acquired Sub microbiota and adopted their behavioral and physiological features, including depressive-like and anti-social behaviors alongside reduced eWAT mass, smaller adipocytes, and a Sub-like eWAT adipokine profile. Our findings demonstrate the critical role of the gut microbiome in determining dominance vs. submissiveness and suggest an association between gut microbiota, the eWAT metabolic and inflammatory profile, and the social behavior mode.

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Interplay between the Gut Microbiota and Inflammatory Mediators in the Development of Colorectal Cancer

Cancers ◽

10.3390/cancers13040734 ◽

2021 ◽

Vol 13 (4) ◽

pp. 734

Author(s):

Gwangbeom Heo ◽

Yunna Lee ◽

Eunok Im

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Inflammatory Mediators ◽

Tumor Metastasis ◽

Intestinal Tract ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Therapeutic Interventions ◽

Potential Therapeutic Target ◽

Necrosis Factor

Inflammatory mediators modulate inflammatory pathways during the development of colorectal cancer. Inflammatory mediators secreted by both immune and tumor cells can influence carcinogenesis, progression, and tumor metastasis. The gut microbiota, which colonize the entire intestinal tract, especially the colon, are closely linked to colorectal cancer through an association with inflammatory mediators such as tumor necrosis factor, nuclear factor kappa B, interleukins, and interferons. This association may be a potential therapeutic target, since therapeutic interventions targeting the gut microbiota have been actively investigated in both the laboratory and in clinics and include fecal microbiota transplantation and probiotics.

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Fecal microbiota transplantation alleviates myocardial damage in myocarditis by restoring the microbiota composition

Pharmacological Research ◽

10.1016/j.phrs.2018.11.042 ◽

2019 ◽

Vol 139 ◽

pp. 412-421 ◽

Cited By ~ 12

Author(s):

Xiao-Fan Hu ◽

Wen-Yong Zhang ◽

Qiang Wen ◽

Wei-Jun Chen ◽

Zhi-Min Wang ◽

...

Keyword(s):

Fecal Microbiota Transplantation ◽

Myocardial Damage ◽

Fecal Microbiota ◽

Microbiota Composition

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Future Directions in Reducing Gastrointestinal Disorders in Children With ASD Using Fecal Microbiota Transplantation

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.630052 ◽

2021 ◽

Vol 11 ◽

Author(s):

Paulina Żebrowska ◽

Izabela Łaczmańska ◽

Łukasz Łaczmański

Keyword(s):

Pediatric Patients ◽

Fecal Microbiota Transplantation ◽

Neurodevelopmental Disorder ◽

Fecal Microbiota ◽

Autism Spectrum ◽

Long Term Effects ◽

Gi Symptoms ◽

Inflammatory Bowel ◽

Age Range

Research on the use of fecal microbiota transplantation (FMT) in the treatment of disorders related to digestive system ailments in children with autism spectrum disorders (ASDs) is a new attempt in a therapeutic approach. There are very little scientific evidences available on this emerging alternative method. However, it appears to be interesting not only because of its primary outcome, relieving the gastrointestinal (GI) symptoms, but also secondary therapeutic effect of alleviating autistic behavioral symptoms. FMT seems to be also promising method in the treatment of another group of pediatric patients, children with inflammatory bowel disease (IBD). The aim of this study is to discuss the potential use of FMT and modified protocols (MTT, microbiota transfer therapy) in the treatment of GI disorders in ASD children supported by reports on another disease, IBD concerning pediatric patients. Due to the few reports of the use of FMT in the treatment of children, these two patients groups were selected, although suffering from distant health conditions: neurodevelopmental disorder and gastrointestinal tract diseases, because of the the fact that they seem related in aspects of the presence of GI symptoms, disturbed intestinal microbiota, unexplained etiology of the condition and age range of patients. Although the outcomes for all are promising, this type of therapy is still an under-researched topic, studies in the group of pediatric patients are sparse, also there is a high risk of transmission of infectious and noninfectious elements during the procedure and no long-term effects on global health are known. For those reasons all obtained results should be taken with a great caution. However, in the context of future therapeutic directions for GI observed in neurodevelopmental disorders and neurodegenerative diseases, the topic seems worthy of attention.

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Fecal microbiota transplantation from high caloric-fed donors alters glucose metabolism in recipient mice, independently of adiposity or exercise status

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00037.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. E203-E216

Author(s):

Jereon Zoll ◽

Mark N. Read ◽

Sarah E. Heywood ◽

Emma Estevez ◽

Jessica P. S. Marshall ◽

...

Keyword(s):

Body Composition ◽

Glucose Metabolism ◽

Glucose Intolerance ◽

Fecal Microbiota Transplantation ◽

High Energy ◽

Fecal Microbiota ◽

Metabolic Effects ◽

Microbiota Composition ◽

No Donor ◽

Glucose Levels

Studies suggest the gut microbiota contributes to the development of obesity and metabolic syndrome. Exercise alters microbiota composition and diversity and is protective of these maladies. We tested whether the protective metabolic effects of exercise are mediated through fecal components through assessment of body composition and metabolism in recipients of fecal microbiota transplantation (FMT) from exercise-trained (ET) mice fed normal or high-energy diets. Donor C57BL/6J mice were fed a chow or high-fat, high-sucrose diet (HFHS) for 4 wk to induce obesity and glucose intolerance. Mice were divided into sedentary (Sed) or ET groups (6 wk treadmill-based ET) while maintaining their diets, resulting in four donor groups: chow sedentary (NC-Sed) or ET (NC-ET) and HFHS sedentary (HFHS-Sed) or ET (HFHS-ET). Chow-fed recipient mice were gavaged with feces from the respective donor groups weekly, creating four groups (NC-Sed-R, NC-ET-R, HFHS-Sed-R, HFHS-ET-R), and body composition and metabolism were assessed. The HFHS diet led to glucose intolerance and obesity in the donors, whereas exercise training (ET) restrained adiposity and improved glucose tolerance. No donor group FMT altered recipient body composition. Despite unaltered adiposity, glucose levels were disrupted when challenged in mice receiving feces from HFHS-fed donors, irrespective of donor-ET status, with a decrease in insulin-stimulated glucose clearance into white adipose tissue and large intestine and specific changes in the recipient’s microbiota composition observed. FMT can transmit HFHS-induced disrupted glucose metabolism to recipient mice independently of any change in adiposity. However, the protective metabolic effect of ET on glucose metabolism is not mediated through fecal factors.

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Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition

Cells ◽

10.3390/cells8060517 ◽

2019 ◽

Vol 8 (6) ◽

pp. 517 ◽

Cited By ~ 12

Author(s):

Claudia Burrello ◽

Maria Rita Giuffrè ◽

Angeli Dominique Macandog ◽

Angelica Diaz-Basabe ◽

Fulvia Milena Cribiù ◽

...

Keyword(s):

Ulcerative Colitis ◽

Gut Microbiota ◽

Immune Cells ◽

Intestinal Inflammation ◽

Fecal Microbiota Transplantation ◽

Experimental Colitis ◽

Fecal Microbiota ◽

Microbiota Composition ◽

Chronic Intestinal Inflammation ◽

Gut Microbiota Composition

Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently showed that therapeutic effects of FMT during acute experimental colitis are linked to functional modulation of the mucosal immune system and of the gut microbiota composition. Here we analysed the effects of therapeutic FMT administration during chronic experimental colitis, a condition more similar to that of IBD patients, on immune-mediated mucosal inflammatory pathways. Mucus and feces from normobiotic donors were orally administered to mice with established chronic Dextran Sodium Sulphate (DSS)-induced colitis. Immunophenotypes and functions of infiltrating colonic immune cells were evaluated by cytofluorimetric analysis. Compositional differences in the intestinal microbiome were analyzed by 16S rRNA sequencing. Therapeutic FMT in mice undergoing chronic intestinal inflammation was capable to decrease colonic inflammation by modulating the expression of pro-inflammatory genes, antimicrobial peptides, and mucins. Innate and adaptive mucosal immune cells manifested a reduced pro-inflammatory profile in FMT-treated mice. Finally, restoration of a normobiotic core ecology contributed to the resolution of inflammation. Thus, FMT is capable of controlling chronic intestinal experimental colitis by inducing a concerted activation of anti-inflammatory immune pathways, mechanistically supporting the positive results of FMT treatment reported in ulcerative colitis patients.

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Daily, Oral FMT for Long-Term Maintenance Therapy in Ulcerative Colitis: Results of a Single-Center, Prospective, Randomized Pilot Study.

10.21203/rs.3.rs-62372/v1 ◽

2020 ◽

Author(s):

Jessica Wood Crothers ◽

Nathaniel D. Chu ◽

Le Thanh Tu Nguyen ◽

Magen Phillips ◽

Cheryl Collins ◽

...

Keyword(s):

Fecal Microbiota Transplantation ◽

Oral Treatment ◽

Randomized Study ◽

Treatment Strategies ◽

Chronic Administration ◽

Fecal Microbiota ◽

Longterm Treatment ◽

Induced Changes ◽

Mait Cell

Abstract This randomized study was designed to assess the safety and feasibility of long-term fecal microbiota transplantation (FMT) in subjects with mild to moderate UC using frozen, encapsulated oral FMT (cFMT). FMT induction was implemented by colonoscopy, followed by 12 weeks of daily oral administration of frozen encapsulated cFMT. Ribosomal 16S bacterial sequencing was used to assess donor-induced changes in the gut microbiota. Changes in T regulatory (Treg) and mucosal associated invariant T (MAIT) cell populations were evaluated as an exploratory endpoint. Twelve subjects with active UC were randomized: 6 subjects completed the full 12-week course of FMT plus cFMT, and 6 subjects received sham treatment by colonic installation and longitudinal oral treatment. Chronic administration of cFMT was found to be safe and well-tolerated. Protocol adherence was high, and none of the study subjects experienced FMT-associated treatment emergent adverse events. While n-values were too small to draw firm conclusions, 3/6 subjects that received cFMT exhibited multiple signs of clinical improvement. These pilot data suggest that daily encapsulated cFMT may extend the durability of index FMT-induced changes in gut bacterial community structure and that an association between MAIT cell cytokine production and clinical response to FMT may exist in UC populations. Oral frozen encapsulated cFMT is a promising FMT delivery system and may be preferred for longterm treatment strategies in UC and other chronic diseases but further evaluations will have to address home storage concerns. Larger trials should be done to explore the benefits of cFMT and to determine its long-term impacts on the colonic microbiome. Trial registration: ClinicalTrials.gov (NCT02390726). Registered 17 March 2015, https://clinicaltrials.gov/ct2/show/NCT02390726?term=NCT02390726&draw=2&rank=1.

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Fecal Supernatant from Adult with Autism Spectrum Disorder Alters Digestive Functions, Intestinal Epithelial Barrier, and Enteric Nervous System

Microorganisms ◽

10.3390/microorganisms9081723 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1723

Author(s):

Jacques Gonzales ◽

Justine Marchix ◽

Laetitia Aymeric ◽

Catherine Le Berre-Scoul ◽

Johanna Zoppi ◽

...

Keyword(s):

Nervous System ◽

Gut Microbiota ◽

Enteric Nervous System ◽

Fecal Microbiota ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Rrna Gene ◽

Intestinal Epithelial ◽

Microbiota Composition ◽

Α Diversity

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders defined by impaired social interactions and communication with repetitive behaviors, activities, or interests. Gastrointestinal (GI) disturbances and gut microbiota dysbiosis are frequently associated with ASD in childhood. However, it is not known whether microbiota dysbiosis in ASD patients also occurs in adulthood. Further, the consequences of altered gut microbiota on digestive functions and the enteric nervous system (ENS) remain unexplored. Therefore, we studied, in mice, the ability offecal supernatant (FS) from adult ASD patients to induce GI dysfunctions and ENS remodeling. First, the analyses of the fecal microbiota composition in adult ASD patients indicated a reduced α-diversity and increased abundance of three bacterial 16S rRNA gene amplicon sequence variants compared to healthy controls (HC). The transfer of FS from ASD patients (FS–ASD) to mice decreased colonic barrier permeability by 29% and 58% compared to FS–HC for paracellular and transcellular permeability, respectively. These effects are associated with the reduced expression of the tight junction proteins JAM-A, ZO-2, cingulin, and proinflammatory cytokines TNFα and IL1β. In addition, the expression of glial and neuronal molecules was reduced by FS–ASD as compared to FS-HC in particular for those involved in neuronal connectivity (βIII-tubulin and synapsin decreased by 31% and 67%, respectively). Our data suggest that changes in microbiota composition in ASD may contribute to GI alterations, and in part, via ENS remodeling.

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