Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic, relapsing immune-mediated disease with a varying and sometimes severe disease course. IBD is often diagnosed in early adulthood and can lead to a substantial decline in quality of life. It has been suggested that patients with IBD are at increased risk of depression and anxiety, but it is still unclear to what extent these diseases co-occur and in what sequence they arise. This Review summarizes the literature on the degree of co-occurrence of IBD with depression and anxiety and the temporal relationship between these diseases. We also discuss the effect of psychological stress on the onset and course of IBD. In addition, we outline the possible mechanisms underlying the co-occurrence of IBD and depression and anxiety, which include changes in brain signalling and morphology, increases in peripheral and intracerebral pro-inflammatory cytokines, impairment of the nitric oxide pathway, changes in vagal nerve signalling, gut dysbiosis and genetics. Finally, we examine the possible effects of treatment of depression and anxiety on the risk and course of IBD, the influence of psychological interventions on IBD, and the effects of IBD treatment on psychiatric comorbidity.© 2022. Springer Nature Limited.

During the past decade, research has revealed that the vast community of micro-organisms that inhabit the gut - known as the gut microbiota - is intricately linked to human health and disease, partly as a result of its influence on systemic immune responses. Accumulating evidence demonstrates that these effects on immune function are important in neuroinflammatory diseases, such as multiple sclerosis (MS), and that modulation of the microbiome could be therapeutically beneficial in these conditions. In this Review, we examine the influence that the gut microbiota have on immune function via modulation of serotonin production in the gut and through complex interactions with components of the immune system, such as T cells and B cells. We then present evidence from studies in mice and humans that these effects of the gut microbiota on the immune system are important in the development and course of MS. We also consider how strategies for manipulating the composition of the gut microbiota could be used to influence disease-related immune dysfunction and form the basis of a new class of therapeutics. The strategies discussed include the use of probiotics, supplementation with bacterial metabolites, transplantation of faecal matter or defined microbial communities, and dietary intervention. Carefully designed studies with large human cohorts will be required to gain a full understanding of the microbiome changes involved in MS and to develop therapeutic strategies that target these changes.© 2022. Springer Nature Limited.

Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease. Emerging evidence indicates that these disorders are characterized by alterations in the intestinal microbiota composition and its metabolites, which translocate from the gut across a disrupted intestinal barrier to affect various metabolic organs, such as the liver and adipose tissue, thereby contributing to metabolic inflammation. Here, we discuss some of the recently identified mechanisms that showcase the role of the intestinal microbiota and barrier dysfunction in metabolic inflammation. We propose a concept by which the gut microbiota fuels metabolic inflammation and dysregulation.

Gut-associated lymphoid tissues (GALT) are the key antigen sampling and adaptive immune inductive sites within the intestinal wall. Human GALT includes the multi-follicular Peyer's patches of the ileum, the vermiform appendix, and the numerous isolated lymphoid follicles (ILF) which are distributed along the length of the intestine. Our current understanding of GALT diversity and function derives primarily from studies in mice, and the relevance of many of these findings to human GALT remains unclear. Here we review our current understanding of human GALT diversity, structure, and composition as well as their potential for regulating intestinal immune responses during homeostasis and inflammatory bowel disease (IBD). Finally, we outline some key remaining questions regarding human GALT, the answers to which will advance our understanding of intestinal immune responses and provide potential opportunities to improve the treatment of intestinal diseases.

Intestinal T cells and group 3 innate lymphoid cells (ILC3 cells) control the composition of the microbiota and gut immune responses. Within the gut, ILC3 subsets coexist that either express or lack the natural cytoxicity receptor (NCR) NKp46. We identified here the transcriptional signature associated with the transcription factor T-bet-dependent differentiation of NCR(-) ILC3 cells into NCR(+) ILC3 cells. Contrary to the prevailing view, we found by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR(+) ILC3 cells were redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells. However, NCR(+) ILC3 cells were essential for cecal homeostasis. Our data show that interplay between intestinal ILC3 cells and adaptive lymphocytes results in robust complementary failsafe mechanisms that ensure gut homeostasis.

The human vermiform ("worm-like") appendix is a 5-10cm long and 0.5-1cm wide pouch that extends from the cecum of the large bowel. The architecture of the human appendix is unique among mammals, and few mammals other than humans have an appendix at all. The function of the human appendix has long been a matter of debate, with the structure often considered to be a vestige of evolutionary development despite evidence to the contrary based on comparative primate anatomy. The appendix is thought to have some immune function based on its association with substantial lymphatic tissue, although the specific nature of that putative function is unknown. Based (a) on a recently acquired understanding of immune-mediated biofilm formation by commensal bacteria in the mammalian gut, (b) on biofilm distribution in the large bowel, (c) the association of lymphoid tissue with the appendix, (d) the potential for biofilms to protect and support colonization by commensal bacteria, and (e) on the architecture of the human bowel, we propose that the human appendix is well suited as a "safe house" for commensal bacteria, providing support for bacterial growth and potentially facilitating re-inoculation of the colon in the event that the contents of the intestinal tract are purged following exposure to a pathogen.

The gut contains our largest collection of resident microorganisms. One obvious question is how microbial communities establish and maintain themselves within a perfused intestine. The answers, which may come in part from observations made by environmental engineers and glycobiologists, have important implications for immunologists who wish to understand how indigenous microbial communities are accommodated. Here we propose that the mucus gel layer overlying the intestinal epithelium is a key contributor to the structural and functional stability of this microbiota and its tolerance by the host.

The inflammatory bowel diseases (IBDs) are contemporary conditions of industrialized societies. The prevalence of IBD continues to increase steadily in Western countries, and newly industrialized countries have a rapidly increasing incidence. The global spread of IBD appears to associate with Westernization of diets and environments, which affects the intestinal microbiome and increases the risk of IBD in genetically susceptible individuals. It is important to increase our understanding of these events to slow progression of IBD. We present a long-term plan to develop interventions that slow or stop the global increase in the incidence of IBD.Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well established, but whether this reflects a shared genetic aetiology, and whether consistent genetic relationships exist between MS and the two predominant IBD subtypes, ulcerative colitis (UC) and Crohn's disease (CD), remains unclear. Here, we use large-scale genome-wide association study summary data to investigate the shared genetic architecture between MS and IBD overall and UC and CD independently. We find a significantly greater genetic correlation between MS and UC than between MS and CD, and identify three SNPs shared between MS and IBD (rs13428812), UC (rs116555563) and CD (rs13428812, rs9977672) in cross-trait meta-analyses. We find suggestive evidence for a causal effect of MS on UC and IBD using Mendelian randomization, but no or weak and inconsistent evidence for a causal effect of IBD or UC on MS. We observe largely consistent patterns of tissue-specific heritability enrichment for MS and IBDs in lung, spleen, whole blood and small intestine, and identify cell-type-specific enrichment for MS and IBDs in CD4 T cells in lung and CD8 cytotoxic T cells in lung and spleen. Our study sheds light on the biological basis of comorbidity between MS and IBD.© 2021. The Author(s).

Increasing evidence supports reciprocal communication between the enteric and the central nervous system in disease, termed the 'gut-brain axis'. Recent findings suggest a connection between IBD and development of Parkinson's disease. The role of IBD in dementia, another insidious neurodegenerative disorder, has not been explored.Using the Taiwanese National Health Insurance Research Database, we performed comparative analysis of 1742 patients with IBD ≥45 years old against 17 420 controls to assess dementia risk following IBD diagnosis. Controls were matched on bases of sex, access to healthcare, income and dementia-related comorbidities. All individuals were followed for dementia diagnosis for up to 16 years. Subanalyses included the relationship between sex, ulcerative colitis (UC) and Crohn's disease (CD), and dementia risk.Overall incidence of dementia among patients with IBD was significantly elevated (5.5% vs 1.4% among controls). Patients with IBD were diagnosed with dementia at 76.24 years old on average, compared with 83.45 among controls. The HR of developing dementia among patients with IBD was 2.54 (95% CI 1.91 to 3.37). Among dementia types, the risk of developing Alzheimer's dementia demonstrated the greatest increase. Dementia risk did not differ between sex differences nor UC versus CD.This population-based cohort study demonstrates significant association between IBD and subsequent development of dementia. Dementia was diagnosed at an earlier age among patients with IBD, and disease risk appeared to increase with IBD chronicity. These findings highlight the need for future research to elucidate the relationship between IBD and dementia.© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

The human appendix has long been considered as a vestigial organ, an organ that has lost its function during evolution. In recent years, however, reports have emerged that link the appendix to numerous immunological functions in humans. Evidence has been presented for an important role of the appendix in maintaining intestinal health. This theory suggests that the appendix may be a reservoir or 'safe house' from which the commensal gut flora can rapidly be reestablished if it is eradicated from the colon. However, the appendix may also have a role in the development of inflammatory bowel disease (IBD). Several large epidemiological cohort studies have demonstrated the preventive effect of appendectomy on the development of ulcerative colitis, a finding that has been confirmed in murine colitis models. In addition, current studies are examining the possible therapeutic effect of an appendectomy to modulate disease course in patients with ulcerative colitis. This literature review assesses the current knowledge about the clinical and immunological aspects of the vermiform appendix in IBD and suggests that the idea of the appendix as a vestigial remnant should be discarded.

Appendicectomy may reduce relapses and need for medication in patients with ulcerative colitis, but long-term prospective data are lacking. This study aimed to analyse the effect of appendicectomy in patients with refractory ulcerative colitis.In this prospective multicentre cohort series, all consecutive patients with refractory ulcerative colitis referred for proctocolectomy between November 2012 and June 2015 were counselled to undergo laparoscopic appendicectomy instead. The primary endpoint was clinical response (reduction of at least 3 points in the partial Mayo score) at 12 months and long-term follow-up. Secondary endpoints included endoscopic remission (endoscopic Mayo score of 1 or less), failure (colectomy or start of experimental medication), and changes in Inflammatory Bowel Disease Questionnaire (IBDQ) (range 32-224), EQ-5D™ and EORTC-QLQ-C30-QL scores.A total of 28 patients (13 women; median age 40·5 years) underwent appendicectomy. The mean baseline IBDQ score was 127·0, the EQ-5D™ score was 0·65, and the EORTC-QLQ-C30-QL score was 41·1. At 12 months, 13 patients had a clinical response, five were in endoscopic remission, and nine required a colectomy (6 patients) or started new experimental medical therapy (3). IBDQ, EQ-5D™ and EORTC-QLQ-C30-QL scores improved to 167·1 (P < 0·001), 0·80 (P = 0·003) and 61·0 (P < 0·001) respectively. After a median of 3·7 (range 2·3-5·2) years, a further four patients required a colectomy (2) or new experimental medical therapy (2). Thirteen patients had a clinical response and seven were in endoscopic remission. The improvement in IBDQ, EQ-5D™ and the EORTC-QLQ-C30-QL scores remained stable over time.Appendicectomy resulted in a clinical response in nearly half of patients with refractory ulcerative colitis and a substantial proportion were in endoscopic remission. Elective appendicectomy should be considered before proctocolectomy in patients with therapy-refractory ulcerative colitis.© 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.

Ulcerative colitis (UC) is a chronic inflammatory disease usually responding well to anti-inflammatory drugs but many patients will still need colectomy. Appendectomy is associated with a lower risk of later developing UC. We aimed to assess the longitudinal relationship between appendectomy, appendicitis, and disease course in UC patients.A national cohort of UC patients with a diagnosis in 1964-2010 was identified from the Swedish National Patient Register that also provided information regarding appendicitis and/or appendectomy before or after the UC diagnosis. The risk for colectomy and UC-related hospital admissions was evaluated.Among 63,711 UC patients, 2,143 had appendectomy and 7,690 underwent colectomy. Appendectomy for appendicitis before 20 years of age and for non-appendicitis at all ages before UC diagnosis was associated with a lower risk of colectomy (hazard ratio (HR) 0.44, 0.27-0.72 and HR 0.62, 0.43-0.90, respectively), and fewer hospital admissions (incidence rate ratio (IRR) 0.68, 95% confidence interval (CI) 0.64-0.73 and IRR 0.54, 0.47-0.63, respectively). Appendectomy for appendicitis after the UC diagnosis was associated with a higher risk of colectomy (HR 1.56, 1.20-2.03), whereas no such association was found for other pathology (HR 1.40, 0.79-2.47).Appendectomy early in life and before developing UC is associated with a lower risk of colectomy as well as UC-related hospital admissions. Appendectomy for appendicitis after established UC appears associated with a worse disease course, with an increased rate of subsequent colectomy.

Synucleinopathies are a group of clinically and neuropathologically distinct protein misfolding diseases caused by unique α-synuclein conformations, or strains. While multiple atomic resolution cryo-electron microscopy structures of α-synuclein fibrils are now deposited in Protein Data Bank, significant gaps in the biological consequences arising from each conformation have yet to be unraveled. Mutations in the α-synuclein gene (SNCA), cofactors, and the solvation environment contribute to the formation and maintenance of each disease-causing strain. This review highlights the impact of each of these factors on α-synuclein misfolding and discusses the implications of the resulting structural variability on therapeutic development.© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Cell-to-cell transmission and subsequent amplification of pathological proteins promote neurodegenerative disease progression. Most research on this has focused on pathological protein seeds, but how their normal counterparts, which are converted to pathological forms during transmission, regulate transmission is less understood. Here we show in cultured cells that phosphorylation of soluble, nonpathological α-synuclein (α-Syn) at previously identified sites dramatically affects the amplification of pathological α-Syn, which underlies Parkinson's disease and other α-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC-MS/MS analyses on soluble α-Syn purified from Parkinson's disease and other α-synucleinopathies, identifying many new α-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble α-Syn also modified pathological α-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble α-Syn could modulate the seeding properties of pathological α-Syn. Our study represents the first systematic analysis how of soluble α-Syn PTMs affect the spreading and amplification of pathological α-Syn, which may affect disease progression.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Aggregation of alpha-synuclein (α-Syn) drives Parkinson's disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)-derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.© 2022. The Author(s).

Parkinson's disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson's disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson's disease into this case-control PET study. Patients with Parkinson's disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA). When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson's disease.© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Host microbial cross-talk is essential to maintain intestinal homeostasis. However, maladaptation of this response through microbial dysbiosis or defective host defense toward invasive intestinal bacteria can result in chronic inflammation. We have shown that macrophages differentiated in the presence of the bacterial metabolite butyrate display enhanced antimicrobial activity. Butyrate-induced antimicrobial activity was associated with a shift in macrophage metabolism, a reduction in mTOR kinase activity, increased LC3-associated host defense and anti-microbial peptide production in the absence of an increased inflammatory cytokine response. Butyrate drove this monocyte to macrophage differentiation program through histone deacetylase 3 (HDAC3) inhibition. Administration of butyrate induced antimicrobial activity in intestinal macrophages in vivo and increased resistance to enteropathogens. Our data suggest that (1) increased intestinal butyrate might represent a strategy to bolster host defense without tissue damaging inflammation and (2) that pharmacological HDAC3 inhibition might drive selective macrophage functions toward antimicrobial host defense.Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Multiple sclerosis continues to be a challenging and disabling condition but there is now greater understanding of the underlying genetic and environmental factors that drive the condition, including low vitamin D levels, cigarette smoking, and obesity. Early and accurate diagnosis is crucial and is supported by diagnostic criteria, incorporating imaging and spinal fluid abnormalities for those presenting with a clinically isolated syndrome. Importantly, there is an extensive therapeutic armamentarium, both oral and by infusion, for those with the relapsing remitting form of the disease. Careful consideration is required when choosing the correct treatment, balancing the side-effect profile with efficacy and escalating as clinically appropriate. This move towards more personalised medicine is supported by a clinical guideline published in 2018. Finally, a comprehensive management programme is strongly recommended for all patients with multiple sclerosis, enhancing health-related quality of life through advocating wellness, addressing aggravating factors, and managing comorbidities. The greatest remaining challenge for multiple sclerosis is the development of treatments incorporating neuroprotection and remyelination to treat and ultimately prevent the disabling, progressive forms of the condition.Copyright © 2018 Elsevier Ltd. All rights reserved.

The gut microbiome plays an important role in autoimmunity including multiple sclerosis and its mouse model called experimental autoimmune encephalomyelitis (EAE). Prior studies have demonstrated that the multiple sclerosis gut microbiota can contribute to disease, hence making it a potential therapeutic target. In addition, antibiotic treatment has been shown to ameliorate disease in the EAE mouse model of multiple sclerosis. Yet, to this date, the mechanisms mediating these antibiotic effects are not understood. Furthermore, there is no consensus on the gut-derived bacterial strains that drive neuroinflammation in multiple sclerosis.Here, we characterized the gut microbiome of untreated and vancomycin-treated EAE mice over time to identify bacteria with neuroimmunomodulatory potential. We observed alterations in the gut microbiota composition following EAE induction. We found that vancomycin treatment ameliorates EAE, and that this protective effect is mediated via the microbiota. Notably, we observed increased abundance of bacteria known to be strong inducers of regulatory T cells, including members of Clostridium clusters XIVa and XVIII in vancomycin-treated mice during the presymptomatic phase of EAE, as well as at disease peak. We identified 50 bacterial taxa that correlate with EAE severity. Interestingly, several of these taxa exist in the human gut, and some of them have been implicated in multiple sclerosis including Anaerotruncus colihominis, a butyrate producer, which had a positive correlation with disease severity. We found that Anaerotruncus colihominis ameliorates EAE, and this is associated with induction of RORγt regulatory T cells in the mesenteric lymph nodes.We identified vancomycin as a potent modulator of the gut-brain axis by promoting the proliferation of bacterial species that induce regulatory T cells. In addition, our findings reveal 50 gut commensals as regulator of the gut-brain axis that can be used to further characterize pathogenic and beneficial host-microbiota interactions in multiple sclerosis patients. Our findings suggest that elevated Anaerotruncus colihominis in multiple sclerosis patients may represent a protective mechanism associated with recovery from the disease. Video Abstract.© 2022. The Author(s).

Changes in gut microbiota have been associated with several diseases. Here, the International Multiple Sclerosis Microbiome Study (iMSMS) studied the gut microbiome of 576 MS patients (36% untreated) and genetically unrelated household healthy controls (1,152 total subjects). We observed a significantly increased proportion of Akkermansia muciniphila, Ruthenibacterium lactatiformans, Hungatella hathewayi, and Eisenbergiella tayi and decreased Faecalibacterium prausnitzii and Blautia species. The phytate degradation pathway was over-represented in untreated MS, while pyruvate-producing carbohydrate metabolism pathways were significantly reduced. Microbiome composition, function, and derived metabolites also differed in response to disease-modifying treatments. The therapeutic activity of interferon-β may in part be associated with upregulation of short-chain fatty acid transporters. Distinct microbial networks were observed in untreated MS and healthy controls. These results strongly support specific gut microbiome associations with MS risk, course and progression, and functional changes in response to treatment.Copyright © 2022 Elsevier Inc. All rights reserved.

Multiple sclerosis is a chronic immune-mediated disease of the brain and spinal cord resulting in physical and cognitive impairment in young adults. It is hypothesized that a disrupted bacterial and viral gut microbiota is a part of the pathogenesis mediating disease impact through an altered gut microbiota-brain axis. The aim of this study is to explore the characteristics of gut microbiota in multiple sclerosis and to associate it with disease variables, as the etiology of the disease remains only partially known.Here, in a case-control setting involving 148 Danish cases with multiple sclerosis and 148 matched healthy control subjects, we performed shotgun sequencing of fecal microbial DNA and associated bacterial and viral microbiota findings with plasma cytokines, blood cell gene expression profiles, and disease activity.We found 61 bacterial species that were differentially abundant when comparing all multiple sclerosis cases with healthy controls, among which 31 species were enriched in cases. A cluster of inflammation markers composed of blood leukocytes, CRP, and blood cell gene expression of IL17A and IL6 was positively associated with a cluster of multiple sclerosis-related species. Bacterial species that were more abundant in cases with disease-active treatment-naïve multiple sclerosis were positively linked to a group of plasma cytokines including IL-22, IL-17A, IFN-β, IL-33, and TNF-α. The bacterial species richness of treatment-naïve multiple sclerosis cases was associated with number of relapses over a follow-up period of 2 years. However, in non-disease-active cases, we identified two bacterial species, Faecalibacterium prausnitzii and Gordonibacter urolithinfaciens, whose absolute abundance was enriched. These bacteria are known to produce anti-inflammatory metabolites including butyrate and urolithin. In addition, cases with multiple sclerosis had a higher viral species diversity and a higher abundance of Caudovirales bacteriophages.Considerable aberrations are present in the gut microbiota of patients with multiple sclerosis that are directly associated with blood biomarkers of inflammation, and in treatment-naïve cases bacterial richness is positively associated with disease activity. Yet, the finding of two symbiotic bacterial species in non-disease-active cases that produce favorable immune-modulating compounds provides a rationale for testing these bacteria as adjunct therapeutics in future clinical trials.© 2022. The Author(s).

The appendix is thought to have a role in the pathogenesis of ulcerative colitis, but the nature and basis of this association remains unclear. In this Perspective, we consider the biology of the appendix with respect to its immunological function and the microbiome, and how this relates to evidence that supports the involvement of the appendix in ulcerative colitis. In experimental models, removal of the inflamed appendix prevents colitis, and in human observational studies, appendectomy is associated with protection against ulcerative colitis. Further, among people who develop ulcerative colitis, appendectomy before diagnosis might influence the course and outcomes of the disease - some evidence suggests that it protects against colectomy but could increase the risk of colorectal cancer. Appendectomy after onset of ulcerative colitis seems to have disparate consequences. Clinical trials to understand whether appendectomy has a role in the treatment of ulcerative colitis are ongoing. Major questions about the role of the appendix in the pathogenesis of ulcerative colitis remain unanswered, and further research is needed to establish whether the connection is clinically relevant.© 2023. Springer Nature Limited.