The n e w e ng l a n d j o u r na l of m e dic i n e

Cl inic a l I m pl ic a t ions of B a sic R e se a rch

Elizabeth G. Phimister, Ph.D., Editor

The Microbiome and Systemic Lupus Erythematosus

James T. Rosenbaum, M.D., and Gregg J. Silverman, M.D.

How can it be that such a repugnant substance,
feces, is also the key to our well-being? Fecal
bacteria are essential to life, and humans are not
alone in their dependence on the microbial
world. The fruit fly requires acetic acid from
Acetobacter pomorum. The bobtail squid needs the
luminescence of Vibrio fischeri to survive. The ter-
mite can’t digest wood without trichonympha, a
genus of symbiotic gut protozoa. Humans also
depend on microbiota. The bacteria in our intes-
tine not only dispose of waste but also educate
the immune system, regulate levels of neuro­
transmitters, and synthesize essential nutrients
such as vitamin K. Disruption (or dysbiosis) of this
otherwise balanced ecosystem may result in dis-
ease; correction of dysbiosis may prevent disease.
Given the complexity of the microbiome, com-
prising trillions of bacteria, some of which can-
not currently be cultured in the laboratory, the
establishment of causal pathways between bac-
teria and disease is no easy feat. It is notable,
therefore, that Manfredo Vieira et al. recently
reported that the gram-positive bacterium Entero-
coccus gallinarum has a causative role in a mouse
model of systemic lupus erythematosus (Fig. 1).1
The authors first found that oral antibiotics,
such as vancomycin and ampicillin, extend the
lifespan of mice prone to the development of
lupus. In addition to improved survival, the anti-
biotic-treated mice had lower serum titers of
antibodies to autoantigens, such as double-
stranded DNA, than did untreated mice. Elevated
titers of these antibodies are a hallmark of sys-
temic lupus. The authors next studied the intes-
tinal permeability of the treated mice. Increased
permeability of the bowel is characteristic of
inflammatory bowel disease, but it has also been
reported in diseases such as diabetes, rheuma-
toid arthritis, and ankylosing spondylitis. Mara-
thon runners also have a transient increase in
bowel permeability. The lupus-prone mice had
increased bowel permeability and reduced levels
of proteins that make up tight junctions (inter-
cellular adhesions) in the gut epithelium. Anti-
biotics such as vancomycin, which reduce E. gal-
linarum titers, diminish the permeability of the
bowel.
The translocation of bacterial products from
the bowel into the circulation is an accepted
phenomenon.2 Bacterial endotoxins and peptido-
glycans are recognized by host receptors that are
integral to the innate immune system. Thus, the
leakage of bacterial products from the gut has
the potential to induce inflammation. Manfredo
Vieira et al. reported that live bacteria, predomi-
nantly E. gallinarum, escape the mouse intestine
and can be cultured from mesenteric veins, gut-
draining lymph nodes, and the liver. E. gallinarum
has some properties that distinguish it from
several other intestinal bacteria. The bacterium
induces an increase in levels of plasmacytoid
dendritic cells, a source of interferon-α, which
has been implicated in lupus pathogenesis.3
E. gallinarum also induces cultured liver cells to
produce more interferon-α and to synthesize
beta-2 glycoprotein 1, a protein targeted by anti-
bodies in the antiphospholipid antibody syn-
drome.
The authors were unable to culture live bacte-
ria from the mesenteric veins of healthy control
mice. However, the small intestines of healthy
mice that were colonized solely with E. gallinarum
became leaky, and these mice produced antibod-
ies to double-stranded DNA. Whereas other gut
bacteria, such as salmonella, also cause bowel
leakage and translocation to the liver, gut colo-
nization by salmonella is not associated with the
production of autoantibodies and the systemic
pathologic characteristics of lupus.
Manfredo Vieira et al. also studied a small
group of patients with lupus and a group of pa-
tients with autoimmune hepatitis. Using poly-

2236 n engl j med 378;23 nejm.org  June 7, 2018

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 Clinical Implications of Basic Research

Lupus-prone mouse Healthy

(BXSB hybrid) mouse

A B C D E F

B. thetaiotamicron Vancomycin Colonized Only with Infection with

E. gallinarum E. gallinarum
or E. faecalis or Immunization E. gallinarum Salmonella

Translocation (liver) No translocation No translocation No translocation Translocation Translocation

Increased bowel Prolonged survival Higher levels of Increased bowel

permeability antibodies against permeability
Lower levels of double-stranded DNA
Autoantibodies autoantibodies (an autoantigen) No signs of lupus

Interferon-α synthesis Higher numbers of

Th17 lymphocytes
Increased levels of
Th17 lymphocytes

Early death

Figure 1. Visceral Events in a Mouse Model of Lupus.

Manfredo Vieira et al. recently reported that Enterococcus gallinarum contributed to lupus in mice. In Panel A, in a lupus-prone mouse,
E. gallinarum translocates from the intestine to the liver. The consequences include increases in bowel permeability, in the production
of autoantibodies to double-stranded DNA, RNA, or beta-2 glycoprotein 1, in the synthesis of interferon-α, and in numbers of Th17 lympho-
cytes as well as death. In Panel B, also in a lupus-prone mouse, other bacteria, such as Bacteroides thetaiotamicron and E. faecalis, do
not translocate from the intestine to the liver. In Panel C, treatment of a lupus-prone mouse with antibiotics or immunization of the mouse
against E. gallinarum prevents translocation and limits the biologic effects. In Panel D, in a healthy mouse, E. gallinarum does not trans-
locate from the intestine to the liver. In Panel E, a healthy mouse is colonized only with E. gallinarum, translocation occurs, and the mouse
shows development of some of the changes characteristic of lupus. In Panel F, in an otherwise healthy mouse, infection with salmonella
results in translocation to the liver, but lupuslike changes do not develop.

merase chain reaction, they found that DNA
from E. gallinarum was present in the livers of
patients with lupus or autoimmune hepatitis but
not in the livers obtained from controls (cadav-
eric donors). The authors also found that human
hepatocytes, when cultured with E. gallinarum,
produce interferon-α and beta-2 glycoprotein 1.
antibiotics, prolonged survival. Would a similar
vaccine have value in the treatment or prevention
of lupus in humans? Feces are vile; some might
even say evil. Both “vile” and “evil” are anagrams
for “live.” Is this a coincidence?
Disclosure forms provided by the authors are available at
NEJM.org.

Although the work by Manfredo Vieira et al. From Oregon Health and Science University and the Legacy
is intriguing, much more research needs to be Devers Eye Institute, Portland (J.T.R.); and New York University
done. What enables E. gallinarum to induce lupus- Medical Center, New York (G.J.S.).

like effects in mice? Can other bacteria cause
similar abnormalities? Why don’t living bacteria
in the liver induce more local inflammation and
tissue injury? Do these bacteria play a role in
other mouse models of lupus, and most impor-
tant, do they contribute to lupus in patients who
do not have liver disease? In their studies, the
investigators also immunized mice against E. gal-
linarum. Early vaccination, like treatment with
1. Manfredo Vieira S, Hiltensperger M, Kumar V, et al. Trans-
location of a gut pathobiont drives autoimmunity in mice and
humans. Science 2018;359:1156-61.
2. Cirera I, Bauer TM, Navasa M, et al. Bacterial translocation of
enteric organisms in patients with cirrhosis. J Hepatol 2001;34:32-7.
3. Baechler EC, Batliwalla FM, Karypis G, et al. Interferon-
inducible gene expression signature in peripheral blood cells of
patients with severe lupus. Proc Natl Acad Sci U S A 2003;100:
2610-5.
DOI: 10.1056/NEJMcibr1804368
Copyright © 2018 Massachusetts Medical Society.

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The New England Journal of Medicine
Downloaded from nejm.org on June 6, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.