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1.
Sci Rep ; 14(1): 15292, 2024 07 03.
Article in English | MEDLINE | ID: mdl-38961134

ABSTRACT

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2 production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K2, and SCFAs are associated with progression, warranting future functional validation and mechanistic study.


Subject(s)
Disease Progression , Gastrointestinal Microbiome , Multiple Sclerosis , Humans , Gastrointestinal Microbiome/genetics , Multiple Sclerosis/microbiology , Multiple Sclerosis/pathology , Male , Female , Adult , Longitudinal Studies , Feces/microbiology , Middle Aged , Severity of Illness Index , RNA, Ribosomal, 16S/genetics
2.
Immunol Rev ; 2024 May 08.
Article in English | MEDLINE | ID: mdl-38717158

ABSTRACT

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, affecting nearly 2 million people worldwide. The etiology of MS is multifactorial: Approximately 30% of the MS risk is genetic, which implies that the remaining ~70% is environmental, with a number of factors proposed. One recently implicated risk factor for MS is the composition of the gut microbiome. Numerous case-control studies have identified changes in gut microbiota composition of people with MS (pwMS) compared with healthy control individuals, and more recent studies in animal models have begun to identify the causative microbes and underlying mechanisms. Here, we review some of these mechanisms, with a specific focus on the role of host genetic variation, dietary inputs, and gut microbial metabolism, with a particular emphasis on short-chain fatty acid and tryptophan metabolism. We put forward a model where, in an individual genetically susceptible to MS, the gut microbiota and diet can synergize as potent environmental modifiers of disease risk and possibly progression, with diet-dependent gut microbial metabolites serving as a key mechanism. We also propose that specific microbial taxa may have divergent effects in individuals carrying distinct variants of MS risk alleles or other polymorphisms, as a consequence of host gene-by-gut microbiota interactions. Finally, we also propose that the effects of specific microbial taxa, especially those that exert their effects through metabolites, are highly dependent on the host dietary intake. What emerges is a complex multifaceted interaction that has been challenging to disentangle in human studies, contributing to the divergence of findings across heterogeneous cohorts with differing geography, dietary preferences, and genetics. Nonetheless, this provides a complex and individualized, yet tractable, model of how the gut microbiota regulate susceptibility to MS, and potentially progression of this disease. Thus, we conclude that prophylactic or therapeutic modulation of the gut microbiome to prevent or treat MS will require a careful and personalized consideration of host genetics, baseline gut microbiota composition, and dietary inputs.

3.
medRxiv ; 2023 Jun 29.
Article in English | MEDLINE | ID: mdl-37425956

ABSTRACT

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. Methods: In a longitudinal study, disability status and associated clinical features in 60 MS patients were tracked over 4.2 ± 0.97 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. Results: We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 45 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia , Lachnospiraceae, and Oscillospiraceae , with an expansion of Alloprevotella , Prevotella-9 , and Rhodospirillales . Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed a significant enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K 2 production (linked to Akkermansia ), and a depletion in SCFA metabolism (linked to Lachnospiraceae and Oscillospiraceae ). Further, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to robustly predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. Conclusions: These results demonstrate the utility of the gut microbiome for predicting disease progression in MS. Further, analysis of the inferred metagenome revealed that oxidative stress, vitamin K 2 and SCFAs are associated with progression.

4.
Microbiome ; 10(1): 198, 2022 11 23.
Article in English | MEDLINE | ID: mdl-36419205

ABSTRACT

BACKGROUND: Dysregulation of gut microbiota-associated tryptophan metabolism has been observed in patients with multiple sclerosis. However, defining direct mechanistic links between this apparent metabolic rewiring and individual constituents of the gut microbiota remains challenging. We and others have previously shown that colonization with the gut commensal and putative probiotic species, Lactobacillus reuteri, unexpectedly enhances host susceptibility to experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. To identify underlying mechanisms, we characterized the genome of commensal L. reuteri isolates, coupled with in vitro and in vivo metabolomic profiling, modulation of dietary substrates, and gut microbiota manipulation. RESULTS: The enzymes necessary to metabolize dietary tryptophan into immunomodulatory indole derivatives were enriched in the L. reuteri genomes, including araT, fldH, and amiE. Moreover, metabolite profiling of L. reuteri monocultures and serum of L. reuteri-colonized mice revealed a depletion of kynurenines and production of a wide array of known and novel tryptophan-derived aryl hydrocarbon receptor (AhR) agonists and antagonists, including indole acetate, indole-3-glyoxylic acid, tryptamine, p-cresol, and diverse imidazole derivatives. Functionally, dietary tryptophan was required for L. reuteri-dependent EAE exacerbation, while depletion of dietary tryptophan suppressed disease activity and inflammatory T cell responses in the CNS. Mechanistically, L. reuteri tryptophan-derived metabolites activated the AhR and enhanced T cell production of IL-17. CONCLUSIONS: Our data suggests that tryptophan metabolism by gut commensals, such as the putative probiotic species L. reuteri, can unexpectedly enhance autoimmunity, inducing broad shifts in the metabolome and immunological repertoire. Video Abstract.


Subject(s)
Limosilactobacillus reuteri , Multiple Sclerosis , Mice , Animals , Limosilactobacillus reuteri/genetics , Limosilactobacillus reuteri/metabolism , Autoimmunity , Tryptophan/metabolism , Indoles
5.
Front Immunol ; 12: 715311, 2021.
Article in English | MEDLINE | ID: mdl-34707603

ABSTRACT

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, representing the leading cause of non-traumatic neurologic disease in young adults. This disease is three times more common in women, yet more severe in men, but the mechanisms underlying these sex differences remain largely unknown. MS is initiated by autoreactive T helper cells, but CNS-resident and CNS-infiltrating myeloid cells are the key proximal effector cells regulating disease pathology. We have previously shown that genetic ablation of p38α MAP kinase broadly in the myeloid lineage is protective in the autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), but only in females, and not males. To precisely define the mechanisms responsible, we used multiple genetic approaches and bone marrow chimeras to ablate p38α in microglial cells, peripheral myeloid cells, or both. Deletion of p38α in both cell types recapitulated the previous sex difference, with reduced EAE severity in females. Unexpectedly, deletion of p38α in the periphery was protective in both sexes. In contrast, deletion of p38α in microglia exacerbated EAE in males only, revealing opposing roles of p38α in microglia vs. periphery. Bulk transcriptional profiling revealed that p38α regulated the expression of distinct gene modules in male vs. female microglia. Single-cell transcriptional analysis of WT and p38α-deficient microglia isolated from the inflamed CNS revealed a diversity of complex microglial states, connected by distinct convergent transcriptional trajectories. In males, microglial p38α deficiency resulted in enhanced transition from homeostatic to disease-associated microglial states, with the downregulation of regulatory genes such as Atf3, Rgs1, Socs3, and Btg2, and increased expression of inflammatory genes such as Cd74, Trem2, and MHC class I and II genes. In females, the effect of p38α deficiency was divergent, exhibiting a unique transcriptional profile that included an upregulation of tissue protective genes, and a small subset of inflammatory genes that were also upregulated in males. Taken together, these results reveal a p38α-dependent sex-specific molecular pathway in microglia that is protective in CNS autoimmunity in males, suggesting that autoimmunity in males and females is driven by distinct cellular and molecular pathways, thus suggesting design of future sex-specific therapeutic approaches.


Subject(s)
Autoimmunity , Central Nervous System/immunology , Central Nervous System/metabolism , Microglia/immunology , Microglia/metabolism , Transcription, Genetic , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Disease Models, Animal , Disease Susceptibility , Encephalomyelitis, Autoimmune, Experimental/etiology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Gene Expression Profiling , Gene Expression Regulation , High-Throughput Nucleotide Sequencing , Immunophenotyping , Male , Mice , Mice, Transgenic , Multiple Sclerosis/etiology , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Sequence Deletion , Sex Factors , Single-Cell Analysis , p38 Mitogen-Activated Protein Kinases/genetics
6.
Gut Microbes ; 13(1): 1943289, 2021.
Article in English | MEDLINE | ID: mdl-34264791

ABSTRACT

The need for alternative treatments for multiple sclerosis (MS) has triggered copious amounts of research into microbial therapies focused on manipulating the microbiota-gut-brain axis. This comprehensive review was intended to present and systematically evaluate the current clinical and preclinical evidence for various probiotic and commensal gut microbial therapies as treatments for MS, using the Bradford Hill criteria (BHC) as a multi-parameter assessment rubric. Literature searches were performed to identify a total of 37 relevant studies (6 human, 31 animal), including 28 probiotic therapy and 9 commensal therapy studies. In addition to presenting qualitative summaries of these findings, therapeutic evidence for each bacterial formulation was assessed using the BHC to generate summative scores. These scores, which encompassed study quality, replication, and other considerations, were used to rank the most promising therapies and highlight deficiencies. Several therapeutic formulations, including VSL#3, Lactobacillus paracasei, Bifidobacterium animalis, E. coli Nissle 1917, and Prevotella histicola, emerged as the most promising. In contrast, a number of other therapies were hindered by limited evidence of replicable findings and other criteria, which need to be addressed by future studies in order to harness gut microbial therapies to ultimately provide cheaper, safer, and more durable treatments for MS.


Subject(s)
Gastrointestinal Microbiome/drug effects , Multiple Sclerosis/drug therapy , Multiple Sclerosis/microbiology , Probiotics/administration & dosage , Probiotics/therapeutic use , Symbiosis/drug effects , Animals , Disease Models, Animal , Humans , Treatment Outcome
8.
Proc Natl Acad Sci U S A ; 117(44): 27516-27527, 2020 11 03.
Article in English | MEDLINE | ID: mdl-33077601

ABSTRACT

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The etiology of MS is multifactorial, with disease risk determined by genetics and environmental factors. An emerging risk factor for immune-mediated diseases is an imbalance in the gut microbiome. However, the identity of gut microbes associated with disease risk, their mechanisms of action, and the interactions with host genetics remain obscure. To address these questions, we utilized the principal autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), together with a genetically diverse mouse model representing 29 unique host genotypes, interrogated by microbiome sequencing and targeted microbiome manipulation. We identified specific gut bacteria and their metabolic functions associated with EAE susceptibility, implicating short-chain fatty acid metabolism as a key element conserved across multiple host genotypes. In parallel, we used a reductionist approach focused on two of the most disparate phenotypes identified in our screen. Manipulation of the gut microbiome by transplantation and cohousing demonstrated that transfer of these microbiomes into genetically identical hosts was sufficient to modulate EAE susceptibility and systemic metabolite profiles. Parallel bioinformatic approaches identified Lactobacillus reuteri as a commensal species unexpectedly associated with exacerbation of EAE in a genetically susceptible host, which was functionally confirmed by bacterial isolation and commensal colonization studies. These results reveal complex interactions between host genetics and gut microbiota modulating susceptibility to CNS autoimmunity, providing insights into microbiome-directed strategies aimed at lowering the risk for autoimmune disease and underscoring the need to consider host genetics and baseline gut microbiome composition.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/genetics , Gastrointestinal Microbiome/immunology , Genetic Predisposition to Disease , Host Microbial Interactions/immunology , Multiple Sclerosis/genetics , Animals , Autoimmunity/genetics , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/microbiology , Female , Genetic Variation , Host Microbial Interactions/genetics , Humans , Limosilactobacillus reuteri/immunology , Male , Mice , Multiple Sclerosis/immunology , Multiple Sclerosis/microbiology
9.
Sci Signal ; 9(456): ra115, 2016 11 29.
Article in English | MEDLINE | ID: mdl-27899525

ABSTRACT

The increased expression of genes induced by type I interferon (IFN) is characteristic of viral infections and systemic lupus erythematosus (SLE). We showed that mitochondrial antiviral signaling (MAVS) protein, which normally forms a complex with retinoic acid gene I (RIG-I)-like helicases during viral infection, was activated by oxidative stress independently of RIG-I helicases. We found that chemically generated oxidative stress stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased adenosine triphosphate production and spare respiratory capacity, responses that were not observed in similarly treated cells lacking MAVS. Peripheral blood lymphocytes of SLE patients also showed spontaneous MAVS oligomerization that correlated with the increased secretion of type I IFN and mitochondrial oxidative stress. Furthermore, inhibition of mitochondrial reactive oxygen species (ROS) by the mitochondria-targeted antioxidant MitoQ prevented MAVS oligomerization and type I IFN production. ROS-dependent MAVS oligomerization and type I IFN production were reduced in cells expressing the MAVS-C79F variant, which occurs in 30% of sub-Saharan Africans and is linked with reduced type I IFN secretion and milder disease in SLE patients. Patients expressing the MAVS-C79F variant also had reduced amounts of oligomerized MAVS in their plasma compared to healthy controls. Together, our findings suggest that oxidative stress-induced MAVS oligomerization in SLE patients may contribute to the type I IFN signature that is characteristic of this syndrome.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Lupus Erythematosus, Systemic/metabolism , Lymphocytes/metabolism , Mitochondria/metabolism , Protein Multimerization , Reactive Oxygen Species/metabolism , Adaptor Proteins, Signal Transducing/genetics , Amino Acid Substitution , Animals , Humans , Lupus Erythematosus, Systemic/genetics , Mice , Mitochondria/genetics , Mutation, Missense
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