Disclosures Microbiome and Autoimmunity - Ohio Association of ...
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9/1/2021
Ohio Association of Rheumatology 16th Annual Meeting
Microbiome and Autoimmunity
August 21, 2021
Gregg J. Silverman, MD
Departments of Medicine and Pathology
NYU School of Medicine
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Disclosures
• Patent application for Lupus diagnostic test
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Learning objectives
• Discuss the implications for human immune system that co-
evolved in the presence of the gut microbiome.
• Describe the potential role of the microbiome in pathogenesis
of inflammatory and autoimmune diseases.
• Review evidence that clinical Lupus pathogenesis is linked to
gut microbiome.
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We all contain a Zoo of commensal bacteria
Our intestines are home to 1010-1014 microbial cells,
1000 or more different types of bacteria in our intestines
~ 3-10 times more microbial cells than the number of host cells
100-fold more microbial genes that human genes
- Gut microbiome may be essential for development of immune system
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Many functions of intestinal microbiome
• Nutrition
- synthesize vitamins
• Metabolism
- process complex carbohydrates and make substances like butyrate
- digest and release single chain Fatty Acids
- catabolize of Tryptophan, substrate for 2,3 IDO for tolerance
- and many other factors
• Shape the immune system
- induction of TGFb/IL-10 for active tolerance
- Induction of Th17 cells, IL-22 and TNFa-secreting cells
Is microbiome the strongest environmental influence for
development of autoimmune disease?
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inflammation
PROTECTORS
PATHOBIONTS
Pathogenic bacteria- inherently cause pathogenic tissue injury
Other commensals that are symbiotic with the host, and can initiate protective immune
responses,
but in predisposed hosts or compromised/injured tissue can contribute to inflammatory or
autoimmune disease
Palm et al. 2015 Clin Immunol
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60 × 540
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Clostridium difficile colitis- an iatrogenic disease of gut microbiome
- C. difficile-spore forming obligate anaerobe
and in health a common human bowel commensal
- Broad-spectrum antibiotics can result in C. difficile overgrowth
- C. difficile toxin contributes to development of colitis
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Clostridium difficile colitis- an iatrogenic disease of gut microbiome
-C. difficile-obligate anerobe that in health is a common human bowel commensal
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Antibiotic treatment of C. difficile colitis is often inadequate
280 × 720
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FMT for C. difficle colitis – progress and controversies
• In a metaanalysis of 1816 studies, 45 studies documented overall clinical effect by
Wk 8 following repeat FMT (24 studies, 1855 patients) was 91% (95% CI: 89–94%,
I2=53%) and 84% (80–88%, I2=86%) following single FMT (43 studies, 2937 patients).
• Delivery of FMT by lower GI endoscopy was superior to all other delivery methods,
and repeat FMT significantly the treatment effect Wk 8 (P
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Past approach
Future approach
What fecal sample is best for transplantation?
Stone L. Faecal microbiota transplantation for Clostridoides difficile infection. June 2019
www.nature.com/collections/microbiota-milestone
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Autoimmunity: The History of an Idea - Hygiene Hypothesis?
• This new appearance and rapidly rising incidence of a variety of inflammatory, immune,
allergic, and autoimmune diseases may be related to improved general hygiene and
water purification, the growth of cities, the decline of family size, and other largely 19th-
century epidemiological phenomena
• Cytokine deviation, regulatory cells?
What about changes in the food we eat? Arthritis & Rheumatology Volume 66, Issue 11, pages 2915-2920, 26 OCT 2014 DOI: 10.1002/art.38796
http://onlinelibrary.wiley.com/doi/10.1002/art.38796/full#art38796-fig-0001
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Modern gut microbiota are limited in diversity
and missing species present in isolated Hunter
and Gatherer groups
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Processed food affects the gut microbiota: The revolution has started
Inflammatory and metabolic gut and liver diseases are “modern“ diseases that appeared in West
over the past 50 yrs, and developing world in the past 25 yrs 1
Processed food now constitutes an increasing part of the world's food consumption.
The proportion of food that is ultra-processed, that is chemically modified, is 60% in the USA,
Chemicals are added to food to improve appearance, improve longevity, and enhance taste.
These include emulsifiers, preservatives, colorings, non-sugar sweeteners, and anti-oxidants.
The >300 additives permitted by regulatory authorities in US.
Approval for use of food additive has historically been based on animal toxicity studies 2
Examples that increase growth of Proteobacteria and decrease diversity-signs of dysbiosis (from Splenda).
Inhibit F. prauznitzii , an anti-inflammatory bacterium (from sodium sulfite and P-80 food emulsifier)
Increased gammaproteobacterial and decreased microbial diversity (P-80 emulsifier) 3
1. Kamm MA J Gastroenterology and Hepatology January 2020
2. Fennema OR. Food additives – an unending controversy. Am. J. Clin. Nutr. 1987; 46: 201– 203.
3. Chassaing B, Koren O, Goodrich JK et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis
and metabolic syndrome. Nature 2015; 519: 92– 96.
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"In 2000, trehalose was approved as food
Nature
additive in US for many foods from sushi and
January 2018
vegetables to ice cream," says Robert Britton,
Baylor College of Medicine in Texas.”
"About 3 years later, reports of outbreaks with
these lineages started to increase. Other
factors may also contribute, but we think that
trehalose is a key trigger."
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Do imbalances in the microbiome (dysbioses)
contribute to autoimmune disease?
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In mice, microbes can escape the gut to contribute to autoimmunity
- Enterococcus galinarum, anaerobe discovered in small intestine (ileum) of lupus-prone mouse
- Not represented in fecal microbiome
- Associated with impaired barrier function in gut (cause or effect?)
- Different Enterococcal species translocated to liver
- Found in human livers from autoimmune hepatitis and lupus liver
- with serum anti-E. gallarinum RNA
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Shifts in microbiota communities (dysbiosis) associated with
Rheumatic Diseases
Expansions of Prevotella copri in new-onset Rheumatoid Arthritis (RA)
Scher et al. eLife 2013 DOI: 10.7554/eLife.01202.001
Leaky gut and high serum zonulin, autocrine factor, controls apical intestinal epithelial tight junctions
at transition from preclinical autoimmunity to overt seropositive RA
Tajik et al. Nature Comm (2020) 11:1995 | https://doi.org/10.1038/s41467-020-15831-7
Pretreatment gut microbiota is associated with lack of response to methotrexate in New-Onset RA
Aracho et al. Arth & Rheum (2020) doi.org/10.1002/art.41622
Imbalances in nasal mucosal S. aureus vs. Corneybacterium associated with disease activity
in ANCA-associated vasculitis Rhee et al. Arth &Rheum (2021) doi.org/10.1002/art.41723
Gut microbiome in Psoriasis and Psoriatic arthritis (and relation to IBD)
review by Myers et al. Best Practice & Research Clinical Rheum 2019, 33:6
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Fecal transfer from Lupus mouse into germ-free C57/B6 mouse
Induces IgG anti-dsDNA antibodies and inflammatory milieu
Ma et al. Mol Med 2019; 25: 35. doi: 10.1186/s10020-019-0102-5 PMCID: PMC6676588
Choi et a. Sci Transl Med 2020 Jul 8; 12 (551): doi: 10.1126
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Do shifts in gut microbiome drive
Lupus pathogenesis?
Pre-disposed
SLE patients SLE SLE
and unaffected lupus
at earliest breach at disease
family members flares
tolerance onset
Increased
Inflammatory Cytokines and
Genetic predisposition Preclinical autoimmunity Tissue injury
Healthy Overt Disease
Anti-nuclear autoimmunity
Pathobiont
Pathobiont or unstable community Pathobiont Flares of lupus nephritis
Breach of tolerance Triggers Tissue injury and/or other features
Initiators of autoimmunity
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Hypothesis: Disease triggers and flares involve microbiome dysbiosis
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Clinical SLE and the gut microbiome Clinical Lupus
cohort and study design
SLE cohort Healthy controls
• Total of ~200 patients (and increasing)
• Initial cross-sectional study
• Fecal samples)
Fecal sample
Modified from XC Morgan and C. Huttenhower. PLOS Comput Biology 2012
Confidential: Do not share
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NYU Lupus cohort: Evidence of impaired gut barrier- leaky gut in clinical SLE
High fecal calprotectin
high hepatic production of acute phase reactants (sCD14 and alpha 1 acid glycoprotein)
N 11 16
Azzouz et al. Ann Rheum Dis 2019
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Bacterial diversity based on 16S rRNA estimates Clinical Lupus
61 female SLE pts
17 female controls of distinct Taxa (OTU, quasi species) shows shrinking diversity
Lupus fecal microbiota
=0.003
Alpha diversity measures =0.139
are summary statistics of 2000 =0.038 =0.108
a single community or sample
1500
Chao1 estimates
OTU
1000
500
0
HC All SLE SLE low SLE high
High disease activity have reduced diversity
Confidential: Do not share
Azzouz et al. Annals Rheum Dis (2019)
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Clinical Lupus
Beta diversity in gut microbiome correlates with Lupus disease activity
Lupus fecal microbiota Lupus communities divergence
correlates with disease activity level
Beta diversity measures
estimate similarity or dissimilarity
between populations (or samples)
Control
SLE
In patients with active SLE bacterial communities
are more different from each other than for healthy controls
Confidential: Do not share
Azzouz et al. Annals Rheum Dis (2019)
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Lupus gut microbiota community reflects the Anna Karenina Principle
Healthy gut microbiota communities are generally similar
Gut microbiota communities of Lupus
-are different from Healthy
-and different from other Lupus-affected individuals
Confidential. G. Silverman NYU
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Clinical Lupus
Candidate pathobiont- Ruminococcus blautia gnavus expansions linked flares in renal disease activity
Taxonomic abundance by SLE disease activity from fecal 16S rRNA analysis
Taxonomic level Taxonomy Healthy SLEDAIlow SLEDAIhigh p value
Family Erysipelotrichaceae 1.37% 1.44% 5.92% 0.086
Family Veillonellaceae 1.58% 3.41% 12.27% 0.008*
Family Ruminococcaceae 25.66% 11.68% 15.11% 0.045*
Genus Blautia 2.23% 4.10% 3.59% 0.077
Genus [Ruminococcus] 0.53% 1.76% 3.15% 0.007*
Species Ruminococcus gnavus 0.25% 1.19% 2.11% 0.013* Correlation or causation?
Species Bacteroides uniformis 2.11% 0.87% 0.34% 0.014*
Species Bacteroides fragilis 1.17% 2.41% 2.20% 0.081
Univariate Kruskal-Wallis ANOVA analysis of 16S rRNA abundance for all taxa for all subjects for p9/1/2021
Serum IgG anti-Ruminococccus gnavus levels
identify Lupus Nephritis in three independent cohorts
NYU Temple OSU
8000 P9/1/2021
Several microbiome pathways may contribute to Lupus
GJSilverman, NatureReviews
Silverman Nature Rev Rheum 2019
in Rheumatology January 2019
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Translational Implications
• Lupus is often relapsing –remitting disease, with cause(s) unknown.
• In health, Gut communities reflect a dynamic equilibrium--stable over time.
these gut communities are much alike in Healthy individuals.
• In Lupus patients, dysregulated gut microbiota communities (dysbiosis),
each Lupus community is largely different from other Lupus patients.
--the Anna Karenina Principle.
• Lupus patients have uniquely unstable gut microbial communities
• At NYU showed about half of Lupus Nephritis flares concurrent with blooms of R. gnavus.
• R. gnavus strains from Lupus Nephritis patients different from those in healthy adults
Confidential. G. Silverman NYU
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Translational Implications
• Are RG blooms common causes of Lupus Nephritis flares?
• Will a Cure for Lupus require treatment of the gut dysbiosis
coordinated with effective normalization of T-cell immune
abnormalities?
• Our findings open the door for trials of supervised modulation of the
gut microbiome to treat (and perhaps cure) Lupus Nephritis.
Confidential. G. Silverman NYU
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Acknowledgements
NYU School of Medicine
Doua Azzouz
Hanane El Bannoudi
Celine Anquetil
Dan Littman
Pam Rosenthal
Jill Buyon
Medical Univ South Carolina
Alexander Alekseyenko
Temple University
Roberto Caricchio
Ohio State University
Brad Rovin
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