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Gut Microbiota and Systemic Autoimmunity: Ameliorating Systemic Lupus Erythematosus through Diet, Microbiota, and Host Immune System Interactions.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Gut Microbiota and Systemic Autoimmunity: Ameliorating Systemic Lupus Erythematosus through Diet, Microbiota, and Host Immune System Interactions./
作者:	Zegarra Ruiz, Daniel Fernando.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	184 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-02, Section: B.
Contained By:	Dissertations Abstracts International80-02B.
標題:	Microbiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10957220
ISBN:	9780438269613

Gut Microbiota and Systemic Autoimmunity: Ameliorating Systemic Lupus Erythematosus through Diet, Microbiota, and Host Immune System Interactions.
Zegarra Ruiz, Daniel Fernando.

Gut Microbiota and Systemic Autoimmunity: Ameliorating Systemic Lupus Erythematosus through Diet, Microbiota, and Host Immune System Interactions. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 184 p.

Source: Dissertations Abstracts International, Volume: 80-02, Section: B.

Thesis (Ph.D.)--Yale University, 2018.

This item must not be added to any third party search indexes.

Autoimmune diseases are a major health problem affecting over 200 million people worldwide and represent one of the leading causes of death for women under 65 years old. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that leads to chronic inflammation in various organs due to immune responses to self-antigens. However, current treatments for SLE are merely aimed at suppressing the immune system without treating the cause, which leads to serious side effects. Therefore, finding safer approaches is key to effectively control these chronic and debilitating disorders. Alterations in the gut microbiota composition have been associated to autoimmune diseases, but it is largely unknown which specific bacterial communities are responsible for these effects. Interestingly, diet has been demonstrated to shape the gut microbial composition and thus, affect immune responses. Resistant starch (RS) is a dietary component that is resistant to digestion in the small intestine but is fermented by the microbiota in the lower gastrointestinal tract producing short-chain fatty acids (SCFAs) that dampen immune responses and modulate the microbial landscape in the gut. Therefore, a better understanding of the effects of RS on the gut microbiota composition and how these alterations influence the immune response in models of autoimmunity will represent an entirely novel approach to treat autoimmune diseases at the root cause. I utilized a spontaneous and inducible lupus model to dissect the role that diet, gut microbiota, and their interactions play in SLE. For the spontaneous model, I worked with toll-like receptor 7 transgenic (TLR7.1 Tg) mice that develop SLE-like disease as they age due to an overexpression of TLR7. For the inducible model, I applied a TLR7 agonist (Imiquimod, IMQ) to C57B1/6 wild type mice and induced SLE-like disease due to an over-activation of the TLR7 pathway. In chapter I, I introduce the literature describing what is currently known about diet-gut microbiota interactions in a homeostatic background and in autoimmunity. In chapter II, I demonstrate the role that gut microbiota plays on SLE. Fecal 16S rDNA sequencing was performed and I identified that murine SLE models developed intestinal dysbiosis. Depletion of the gut microbiota reduced mortality and pathogenesis in both SLE models, mainly by reducing hepatosplenomegaly, modulating pDCs and type I interferons. Interestingly, the gut microbiota was an active component of SLE progression, since cecal microbiota transfers from SLEprone mice exacerbated lupus pathogenesis. In chapter III, I identify a key bacterial strain that exacerbates SLE. Through culture of internal organs I revealed that L. reuteri (LR) translocated outside the gut in SLE-prone mice and in cohoused wild type littermates. In addition, 16S rDNA sequencing of fecal samples showed a longitudinal increase of LR abundance in TLR7-dependent SLE models. Furthermore, LR gavages worsened pathogenesis in SLE-prone and induced mice and in monocolonized germ-free (GF) mice in the IMQinducible model by increasing pDCs infiltration and type I interferon pathways. Finally, in chapter IV, I fed a RS enriched diet to our lupus mouse models before onset of disease to assess if diet can ameliorate systemic autoimmunity through modulation of the gut microbiome and LR outgrowth inhibition. Fecal 16S rDNA sequencing and culture of internal organs revealed that RS modulated the gut microbiome and suppressed LR abundance and translocation in SLE-prone mice, while reducing mortality, hepatosplenomegaly, gut leakiness, pDCs accumulation, type I interferons, and glomerulonephritis in both SLE models. Furthermore, RS prevented LR-dependent worsening of SLE in the IMQ-inducible model through SCFAs generation by the gut microbiota. In conclusion, the research outline in this thesis contributes to a better understanding of the effects of RS on lupus pathogenesis through modulation of the gut microbiome and suppression of pathobionts, representing a safer approach to ameliorate SLE at the root cause. Furthermore, diet-gut microbiota modulation of type I interferons may lead to novel methodologies and development of functional foods to treat systemic autoimmune diseases in an effective and more specific manner, further advancing the knowledge in gut microbiota and host dynamics.

ISBN: 9780438269613Subjects--Topical Terms:

536250
Microbiology.

Gut Microbiota and Systemic Autoimmunity: Ameliorating Systemic Lupus Erythematosus through Diet, Microbiota, and Host Immune System Interactions.
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520 $a Autoimmune diseases are a major health problem affecting over 200 million people worldwide and represent one of the leading causes of death for women under 65 years old. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that leads to chronic inflammation in various organs due to immune responses to self-antigens. However, current treatments for SLE are merely aimed at suppressing the immune system without treating the cause, which leads to serious side effects. Therefore, finding safer approaches is key to effectively control these chronic and debilitating disorders. Alterations in the gut microbiota composition have been associated to autoimmune diseases, but it is largely unknown which specific bacterial communities are responsible for these effects. Interestingly, diet has been demonstrated to shape the gut microbial composition and thus, affect immune responses. Resistant starch (RS) is a dietary component that is resistant to digestion in the small intestine but is fermented by the microbiota in the lower gastrointestinal tract producing short-chain fatty acids (SCFAs) that dampen immune responses and modulate the microbial landscape in the gut. Therefore, a better understanding of the effects of RS on the gut microbiota composition and how these alterations influence the immune response in models of autoimmunity will represent an entirely novel approach to treat autoimmune diseases at the root cause. I utilized a spontaneous and inducible lupus model to dissect the role that diet, gut microbiota, and their interactions play in SLE. For the spontaneous model, I worked with toll-like receptor 7 transgenic (TLR7.1 Tg) mice that develop SLE-like disease as they age due to an overexpression of TLR7. For the inducible model, I applied a TLR7 agonist (Imiquimod, IMQ) to C57B1/6 wild type mice and induced SLE-like disease due to an over-activation of the TLR7 pathway. In chapter I, I introduce the literature describing what is currently known about diet-gut microbiota interactions in a homeostatic background and in autoimmunity. In chapter II, I demonstrate the role that gut microbiota plays on SLE. Fecal 16S rDNA sequencing was performed and I identified that murine SLE models developed intestinal dysbiosis. Depletion of the gut microbiota reduced mortality and pathogenesis in both SLE models, mainly by reducing hepatosplenomegaly, modulating pDCs and type I interferons. Interestingly, the gut microbiota was an active component of SLE progression, since cecal microbiota transfers from SLEprone mice exacerbated lupus pathogenesis. In chapter III, I identify a key bacterial strain that exacerbates SLE. Through culture of internal organs I revealed that L. reuteri (LR) translocated outside the gut in SLE-prone mice and in cohoused wild type littermates. In addition, 16S rDNA sequencing of fecal samples showed a longitudinal increase of LR abundance in TLR7-dependent SLE models. Furthermore, LR gavages worsened pathogenesis in SLE-prone and induced mice and in monocolonized germ-free (GF) mice in the IMQinducible model by increasing pDCs infiltration and type I interferon pathways. Finally, in chapter IV, I fed a RS enriched diet to our lupus mouse models before onset of disease to assess if diet can ameliorate systemic autoimmunity through modulation of the gut microbiome and LR outgrowth inhibition. Fecal 16S rDNA sequencing and culture of internal organs revealed that RS modulated the gut microbiome and suppressed LR abundance and translocation in SLE-prone mice, while reducing mortality, hepatosplenomegaly, gut leakiness, pDCs accumulation, type I interferons, and glomerulonephritis in both SLE models. Furthermore, RS prevented LR-dependent worsening of SLE in the IMQ-inducible model through SCFAs generation by the gut microbiota. In conclusion, the research outline in this thesis contributes to a better understanding of the effects of RS on lupus pathogenesis through modulation of the gut microbiome and suppression of pathobionts, representing a safer approach to ameliorate SLE at the root cause. Furthermore, diet-gut microbiota modulation of type I interferons may lead to novel methodologies and development of functional foods to treat systemic autoimmune diseases in an effective and more specific manner, further advancing the knowledge in gut microbiota and host dynamics.
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