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Autoimmune diseases are complex, multifactorial diseases with a polygenic trait and diverse environmental factors that contribute to triggering and exacerbating each disorder. The human microbiome is increasingly implicated in the multistep pathogenesis of autoimmune diseases. We summarize here the latest developments in the field of how the microbiota interacts with the host on a cellular and molecular level. We review how pathobionts evolve within the gut of autoimmune-prone hosts to translocate to secondary lymphoid tissues. On mucosal sites and in non-gut tissues, pathobionts trigger autoimmune pathways through various mechanisms, including cross-reactivity with autoantigens and secretion of metabolites that alter immune functions. A better understanding of these mechanisms will hasten the development of unconventional therapeutic approaches for autoimmune diseases.

Introduction

The microbiota colonizing host surfaces such as the gastrointestinal tract co-evolved in many multicellular organisms. A bidirectional cross-talk exists between commensals and numerous physiologic host circuits, including immunity, to reinforce a symbiotic relationship. Environmental influences disturb this cross-talk, contributing to the rise of immune-mediated diseases. Accumulating evidence supports that the gut microbiota is an important mediator of non-gut autoimmune disorders in animal models [1], which is also suggested by various associations between dysbiotic states and human immunologic diseases. However, the interindividual heterogeneity of the microbial communities in humans makes interpretations of associations difficult. Environmental factors and host characteristics such as alcohol intake bias associations between microbial community structures and disease states [2]. Medications such as proton-pump inhibitors also strongly influence microbiome signatures [3]. In addition, early life events may influence the development of immune-mediated diseases later in life, which makes it difficult to identify all potential microbiota triggers in an established disease. The first years of life are crucial for the development of microbiota, as suggested by the link between childhood living environments and exposome with adulthood microbiomes [3]. The early shaping of human microbiomes might thus be an additional factor in the host predisposition to autoimmunity such as type-1 diabetes (T1D) [4].

In mice, the intestinal colonization with certain commensal bacteria at weaning was found to expand thymic antigen-specific T cells via trafficking of microbial antigens by intestinal dendritic cells [5]. Thymic microbiota-specific T cells exhibited a pathogenic potential for colitis and protected the host against pathogens through cross-reactivity. Cross-reactivity with autoantigens is one of several molecular mechanisms of how the adult microbiota is known to contribute to pathogenesis in several autoimmune diseases (see also a recent issue on structural aspects of host-microbiota interactions [6]). This review will summarize the most recent findings (from 2020 to 2022) on cellular and molecular mechanisms including cross-reactivity. The studies highlighted here extend prior reviews 1, 7 that already introduced general concepts of how the gut, oral and skin microbiota impinges on autoimmunity. The recently described lung–brain axis in autoimmunity [8] is not covered as well as other recent advances in nonbacterial microbiota in inflammatory diseases 9, 10.

Section snippetsBarrier dysfunction and microbiota translocation in systemic autoimmunity

Environmental factors influence the gut and skin epithelial barrier function and subsequently allergic and autoimmune diseases as recently discussed 11, 12, 13. An imbalanced gut microbiota can promote intestinal barrier leakiness and systemic inflammation as demonstrated in arthritis and diabetes models 14•, 15. Early rheumatoid arthritis (RA) in both mice and humans showed increased barrier permeability and fecal zonulin [14], a marker of disturbed intestinal tight junctions [16]. Early

Dietary and microbiota-derived metabolites involved in autoimmunity

Microbiota may influence systemic immune responses via release of metabolites in the gut or systemic tissues. Microbially produced indoles derived from a tryptophan-rich diet are ligands for the transcription factor aryl hydrocarbon receptor (AhR), which is intricately involved in tissue homeostasis and inflammation [26]. For instance, the expansion of MLN Th17 and autoantibody production induced by translocating E. gallinarum is abrogated by pharmacologic blockade of AhR in vivo [17]. A more

Microbiota cross-reactivity involved in chronic autoimmune pathology

Transient autoimmune diseases are well-known to be triggered in some cases by cross-reactive infectious agents [1]. Once the infectious trigger is removed, the autoimmune response eventually wanes. Instead, chronic colonization or repeated translocation with microbiota could sustain chronic autoimmune diseases and possibly also explain via within-host evolution the waxing and waning course of these disorders (Figure 1). One of the molecular mechanisms of how autoimmune responses are sustained

Conclusions and implications for emerging therapeutic interventions

The processes of how gut pathobionts evolve to translocate across the gut barrier and instigate systemic autoimmune reactions are increasingly better understood. The ‘within-host evolution’ involves increased capsular thickness of the pathobionts with subsequent immune evasion that allows for dysregulated inflammatory processes in transiently colonized non-gut tissues [23]. Gut barrier leakiness is increasingly recognized as a pathophysiologic state in various autoimmune diseases and first

Conflict of interest statement

M.A.K. received salary, consulting fees, honoraria, or research funds from Eligo Biosciences, Novartis, Roche, Bristol-Meyers Squibb, AbbVie, and Cell Applications, and holds a patent on the use of microbiota manipulations to treat immune-mediated diseases. M.P. declares no competing interests.

Acknowledgements

The authors would like to thank Noah W. Palm and Yi Yang for insightful discussions on this topic. Work discussed in this paper was supported by grants from the National Institutes of Health, USA (R01AI118855, T32AI07019;) Arthritis National Research Foundation, USA; Arthritis Foundation, Lupus Research Alliance (Lupus Insight Prize and Global Team Science Award), USA; and the Maren Foundation, USA.

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