Journal of Autoimmunity xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm

Connecting the immune system, systemic chronic inflammation and the gut
microbiome: The role of sex
Lisa Rizzettoa,∗, Francesca Favaa, Kieran M. Tuohya, Carlo Selmib,c
a
Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, San Michele all’Adige, Trento, Italy
b
Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy
c
BIOMETRA Department, University of Milan, Italy

A R T I C LE I N FO A B S T R A C T

Keywords: Unresolved low grade systemic inflammation represents the underlying pathological mechanism driving immune
Autoimmunity and metabolic pathways involved in autoimmune diseases (AID). Mechanistic studies in animal models of AID
Gut microbiota and observational studies in patients have found alterations in gut microbiota communities and their metabo-
Bile acids lites, suggesting a microbial contribution to the onset or progression of AID. The gut microbiota and its meta-
SCFA
bolites have been shown to influence immune functions and immune homeostasis both within the gut and
Microbial metabolism
systematically. Microbial derived-short chain fatty acid (SCFA) and bio-transformed bile acid (BA) have been
shown to influence the immune system acting as ligands specific cell signaling receptors like GPRCs, TGR5 and
FXR, or via epigenetic processes. Similarly, intestinal permeability (leaky gut) and bacterial translocation are
important contributors to chronic systemic inflammation and, without repair of the intestinal barrier, might
represent a continuous inflammatory stimulus capable of triggering autoimmune processes. Recent studies in-
dicate gender-specific differences in immunity, with the gut microbiota shaping and being concomitantly shaped
by the hormonal milieu governing differences between the sexes. A bi-directional cross-talk between microbiota
and the endocrine system is emerging with bacteria being able to produce hormones (e.g. serotonin, dopamine
and somatostatine), respond to host hormones (e.g. estrogens) and regulate host hormones' homeostasis (e.g by
inhibiting gene prolactin transcription or converting glucocorticoids to androgens). We review herein how gut
microbiota and its metabolites regulate immune function, intestinal permeability and possibly AID pathological
processes. Further, we describe the dysbiosis within the gut microbiota observed in different AID and speculate
how restoring gut microbiota composition and its regulatory metabolites by dietary intervention including
prebiotics and probiotics could help in preventing or ameliorating AID. Finally, we suggest that, given consistent
observations of microbiota dysbiosis associated with AID and the ability of SCFA and BA to regulate intestinal
permeability and inflammation, further mechanistic studies, examining how dietary microbiota modulation can
protect against AID, hold considerable potential to tackle increased incidence of AID at the population level.

1. Introduction an important contribution from environmental factors. A number of

The incidence of autoimmune diseases (AID) has increased sig-
nificantly in Westernized countries over the past decades, with a higher
prevalence in women (∼80% of overall incidence). The prevailing
hypothesis suggests unresolved systemic inflammation as a key factor in
disease emergence and progression. In genetically predisposed subjects
unchecked systemic inflammation leads to the formation of auto-
antibodies, physiological dysregulation and tissue damage which can
eventually manifest as specific AID.
While AID has a strong genetic basis, increasing evidence indicates
recent studies have highlighted the influence of genetics and environ-
mental factors [1], such as antibiotics [2], dietary habits [3,4] and sex
hormones [5] in AID. The host immune system plays an important role
in shaping the gut microbiota and reciprocally, host-associated micro-
organisms significantly influence the development and function of in-
nate and adaptive immunity [6,7], by establishing a “tolerant” pheno-
type and therefore facilitating the continuation of host-microbe co-
existence [8]. Similarly, the gastrointestinal microbiota has recently
been highlighted as one of the major contributors to the regulation of
immune effector cell maturation and activity, and its dysbiosis has been

∗
Corresponding author. Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, via Edmund Mach 1, 38010 San Michele all’Adige,
Trento, Italy.
E-mail address: lisa.rizzetto@fmach.it (L. Rizzetto).

https://doi.org/10.1016/j.jaut.2018.05.008
Received 3 April 2018; Received in revised form 18 May 2018; Accepted 21 May 2018
0896-8411/ © 2018 Elsevier Ltd. All rights reserved.

Please cite this article as: Rizzetto, L., Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.05.008
L. Rizzetto et al.
shown to contribute to intestinal mucosa permeability, induction of
innate defenses, and thus a candidate environmental risk factor capable
of triggering AID [3,9–11]. In addition, mucosal immune function and
susceptibility to chronic inflammation differs between sexes [12,13].
Aberrant microbiota community structure has been reported in
different AID including asthma [14], inflammatory bowel disease (IBD)
[15], type 1 diabetes (T1D) [16], rheumatoid arthritis [17], food al-
lergies [18], systemic lupus erythematosus (SLE) [11] and multiple
sclerosis (MS) [19]. The human microbiome provides key immune and
metabolic regulatory services to the host, which are set early in life and
contribute to life-long immune function. However, environmental fac-
tors like nutrition, medicines, hormonal changes and psychological
stress can disrupt the gut microbiota and determine its influence on
immune homeostasis. The contribution of diet and the relevance of
microbially-derived dietary metabolites are only just starting to be
appreciated [8,20].
This review will present evidence supporting a role for diet:microbe
interactions in the emergence of AID, with a special focus on extra-
intestinal AID, such as T1D, SLE and MS. We will highlight connections
with the gut microbiota and its cell signaling metabolites which influ-
ence inflammation systemically or provide a pathological pressure for
the onset and maintenance of AID via continuous exposure to in-
flammatory triggers by compromising the intestinal barrier. The con-
tribution of the estrogen-gut microbiota axis, the bi-directional mod-
ulation existing between gut microbiota and sex hormones, and the
gender bias in autoimmunity will be also discussed.
2. Impact of gut microbiota on gender-specific differences in
immunity and onset of autoimmunity
Males and females present some differences in the immune system
[12] and sex bias is an important aspect of many AID [12,21,22]. The
increasing number of microbiome studies is revealing a bi-directional
cross-talk between microbiota and the endocrine system is emerging
with bacteria being able to produce hormones (e.g. serotonin, dopa-
mine and somatostatine), respond to host hormones (e.g. estrogens) and
regulate host hormones' homeostasis by inhibiting gene transcription
(e.g prolactin) or converting them (e.g. glucocorticoids to androgens)
[23,24].
2.1. Sex differences in immunity and pathogen sensing
In general, normal healthy women show greater antigen presenting
activity and mitogenic responses, higher immunoglobulin levels and
more enhanced antibody production than males, being more resistant
to infection diseases and much more likely to develop AID, while
healthy male are thought to have an immune system that maintain
tolerance [25]. Generally, steroid hormones exert an opposite role on
the immune response, with estrogens promoting humoral immunity by
enhancing B cell survival and androgens and progesterone acting in
prevention or suppression of autoimmunity [26,27].
Accumulating evidence has linked Toll like receptor (TLR) function
to estrogen and estrogen receptor α (ERα) and β (ERβ), suggesting a
possible contribution of different microbial sensing and TLR activation
to sex bias in AID, likely linked to gut microbe-associated molecular
patterns (MAMPs) recognition [28]. Several immune-related genes in-
cluding TLR7/8 - involved in nucleic acid recognition - and FOXP3 – the
master transcriptional regulator of Treg expansion -, are present on X
chromosome [1] and incomplete inactivation of X chromosome in fe-
male can potentially lead to increased activation of those genes [21,29].
The balance among TLR7/8 and 9, signaling receptors detecting mi-
crobial- and self-nucleic acids, has been shown to be crucial to SLE
onset in animal models [30], as discussed below. Moreover, Jiang et al.
found that female SLE patients possess more active monocytes with
enhanced TLR4 receptiveness than male SLE patients and present in-
creased plasma levels of soluble CD14 upon in vitro LPS challenge [31].
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Journal of Autoimmunity xxx (xxxx) xxx–xxx
Through binding specific receptors in immune cells, sex hormones
such as estrogens, can influence immune function, such as enhancing
the humoral responses as in the case of 17-β-estradiol and prolactin [5].
It has been suggested that male hormones are protective in SLE or T1D
and estrogens may contribute to disease progression by promoting B
cell survival [12]. In lupus-prone mice, ERα deficiency leads to auto-
antibody production ameliorates renal damage and prolongs survival
compared to ERα-sufficient controls [32]. Knocking out ERα in both
lupus-prone and control mice resulted in impaired TLR4 activation in
immune cells, indicating that estrogen and ER signaling can influence
TLR4 responsiveness [31]. ERα deficient mice and lupus-prone ERα
deficient mice also showed a decreased TLR9-mediated inflammatory
cytokine production by DCs [33], particularly interleukin (IL)-6, MCP-
1, IL-1β and IL-23, a cytokine milieu modulating the IL-23/IL-17
pathway and the priming of the T helper (Th) 17 response. Further-
more, decreased percentages of IL-17+ RORγt+ cells were isolated from
the spleen of ERα−/−lupus prone mice [33]. The protective effects of
estrogens, particularly 17-β-estradiol, has been described in the onset
and progression of experimental autoimmune encephalomyelitis (EAE),
the prototypic animal model of MS, by enhancing regulatory B cells and
M2 macrophage activities, and prevents the dysbiosis associated to EAE
[34]. By contrast, endocrine disrupting chemicals such as bisphenol A,
have been shown to be associated with risk of T1D in non-obese dia-
betic mice, a mouse model of insulitis and leukocytic infiltration of
pancreatic islets leading to T1D [35–37] as well as with SLE patho-
genesis, as evidenced in MRL/lpr mice, the animal model of lupus ne-
phritis [38,39].
These evidences suggest a link between estrogen setting and its
impact in regulating immune function through activation of specific
microbial recognizing receptors (Fig. 1).
2.2. Sex hormones and their impact on microbiota
Host hormones can affect bacterial gene expression, bacterial viru-
lence and growth, with consequences on host physiology [24]. The sex
hormones estriol and estradiol decrease bacterial virulence by in-
hibiting quorum sensing signaling [40] while progesterone has been
shown to promote growth of oral Bacteroides species and Prevotella in-
termedius [41]. Changes in expression of ER-β ERβ affects the compo-
sition of gut microbiota of female mice and that microbiota enriched
from differential ERβ expression respond differently to changes in diet
complexity [42]. By using high-throughput sequencing, sex hormones
have been shown to modulate mammalian microbiota composition
[22,43–49] (Fig. 1). Healthy male mice have been shown to bear higher
abundance of Ruminococcus, Coprococcus and Dorea and lower abun-
dance of Porphyromonaceae and Rikenella, while female mice present
higher abundance of Allobaculum, Anaeroplasma, and Lactobacillaceae
and Veilonellaceae [22,46,49]. Mueller at al. (2006) showed that
healthy male subjects had a higher abundance of Bacteroides-Prevotella
than female while post-menopausal woman microbiota did not differed
from male one [47]. Very recently, Fransen et al. (2017) showed a
decreased relative abundance of Alistipes, Rikenella and Porphyr-
omonadaceae in female mice associated with a concomitant higher cell
content in the thymus, a bigger thymus size and an increased IFN-β
signaling than in male mice [43]. However, whether sex-dependent
immunity differences are a cause or consequence of an alteration of the
gut microbiota is still not clear. Gut microbiota analysis on 341 female
and 348 male mice from 89 inbred animals demonstrated that under a
controlled environment male and female mice show significant differ-
ences in gut microbiota composition, although genetic differences ob-
scured sex differences in examination of the entire population [22].
Furthermore, gonadectomy and hormone replacement induced a mi-
crobiota shift driven by sex hormones. Those treatments led also to
gender-specific differences in bile acid (BA) profiles between sexes
[22]. An higher rate of BA synthesis and BA pool sizes in females than in
males has been previously reported [50,51]. This is important given the
L. Rizzetto et al. Journal of Autoimmunity xxx (xxxx) xxx–xxx

Fig. 1. Schematic representation of the interconnections occurring among immune system, gut microbiota and sex hormones. Even more evidence are
indicating the establishment of a tight reciprocal regulation between immune functions, sexual hormones and gut microbiota. Gut microbiota composition contribute
to the immune homeostasis by regulating through its composition and its metabolites immune system functions and are concomitantly shaped by the immune system.
Studies in mammals have shown that sex hormones can also modulate microbiota composition and indeed could potentially contribute to the sex bias observed in
autoimmunity. Interestingly, gut microbiota metabolizes estrogens by secreted β-glucuronidase leading to estrogen activation and their translocation into the
bloodstream for reaching distal sites. The alteration of such interconnected regulation contributes to chronic inflammation and the onset of autoimmunity. Data
reported on microbial abundance are taken from mice data [22,43–47,49]. BA, bile acid; IL, interleukin; iTreg, inducible regulatory T cells; MΦ, macrophages, NK,
natural killer; regB, regulatory B cells; SCFA, short chain fatty acid; Th, T helper cells; Treg, regulatory T cells.

role of BA in immune cell signaling and the relative difference in cell
signaling potential between different BA species/chemical structure
involved in pathways responsible for regulating inflammation via TGR5
and FXR signaling (see below). A variety of tissues express estrogen
receptors, including, gut, brain, bone and adipose tissue [52]. Gut
epithelial barrier integrity can also be modified by estrogen as observed
in mice where females are more resistant to gut injury compared to
their male counterparts [53]. This indication and the observation that
gut microbiota composition differs between males and females could
potentially contribute to the sex bias observed in autoimmunity.
2.3. Microbiota regulation of sex hormones
It appears that not only is the gut microbiota influenced by estro-
gens but also the gut microbiota itself impacts on estrogen levels, and
may be an important regulator of circulating estrogen and estrogenic
molecules [54] (Fig. 1). Use of antibiotics has been shown to lower
estrogen levels and urinary estrogen levels has been correlated with a
higher abundance of Clostridia and Ruminococcaceae [55]. The gut
microbiota secretes β-glucuronidase, an enzyme that carries out de-
conjugation of estrogens. The estrogen active deconjugated forms are in
this way facilitated in entering the bloodstream and subsequently in
binding to their receptors and inducing of their physiological activities
(Fig. 1). In particular, Clostridium scindens, one of the species involved
on the bio-transformation of BA [56] has been also shown to convert
glucorticoids to androgens [57].
The important role of gut microbiota in driving a gender bias in
autoimmunity is supported by two recent studies which connect hor-
monal influences and microbiota to explain the sexual dimorphism of
autoimmunity [44,45]. Previous findings showed that germ free ani-
mals lose the sexual dimorphism of T1D, with both females and males
having a high incidence of the disease. Both studies found that puberty
affects the male microbiota composition, which becomes less diverse
than the female microbiota and that the microbiota contributed to in-
creased levels of testosterone in the blood. Importantly, post-pubescent
female and castrated male microbiota were more similar than to that of
post-pubescent males, revealing that sex hormones affected microbiota
composition. Markle et al. [44] found that T1D can be suppressed by
transferring gut microbiota from male mice into immature females and
suggested microbiome manipulations can provoke testosterone-depen-
dent protection from autoimmunity. In parallel, Yurkovetskiy et al. [45]
suggested that both hormones and microbiota were required to ensure
male protection from T1D. Despite the different interpretation of the
results, the two studies agree that the microbiota regulates the levels of

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L. Rizzetto et al.
androgens in the blood. Interestingly, in germ free mice, male protec-
tion (but not female protection) was achieved by mono-colonization
with segmented filamentous bacteria [114].
Whether microbes contribute to sexual dimorphism in other auto-
immunity models remains to be examined. Investigation of the role of
the microbiota in biasing autoimmunity in humans also needs to be
investigated, especially taking into account the possible role of micro-
bial-related signaling molecules which affect the endocrine/hormones
system, such as BA or indeed estrogenic metabolites like equol, en-
terolactone and enterodiol, produced by gut bacteria from dietary
phytoestrogens [58,59].
3. Microbial regulation of host immune responses
Microbiota can affect both innate and adaptive immunity by direct
contact to immune cells, by inducing epigenetic modification and
through the production of signaling molecules.
3.1. Immune signaling via microbial sensing
The mammalian immune system recognizes MAMPs via pathogen
recognition receptors like TLRs and NOD like receptors (NLRs) ex-
pressed on immune and non-immune cells. Dendritic cells (DCs), mac-
rophages, neutrophils and natural killer (NK) cells, important players in
the innate immunity, are necessary for the development of many types
of autoimmunity and microorganisms can influence the activity of these
cells. Macrophages isolated from gut microbiota-depleted mice release
lower levels of TNF-α and higher levels of IL-10 when stimulated with
inflammatory bacterial cell wall component lipopolysaccharide (LPS)
compared to macrophages from specific pathogen free (SPF) animals
[11]. Moreover, LPS activation of splenic DCs has been shown to de-
crease the expression of IL-15, IL-6, TNF-α and type I interferons in
germ free mice [60]. NK function is also compromised in the absence of
the gut microbiota, possibly due to the inability of DCs to produce type I
interferons in response to microbial stimuli [61]. The proper function
and activity of bone marrow-derived neutrophils is highly influenced by
exposure to commensal microorganisms and their circulating cell wall
components [62]. Inducible NK T cells, which also contribute to several
AID, are also impaired in the germ free animals and require microbial
ligands for their maturation [61,63]. Germ free mice are also reported
to have distinct alterations in their adaptive immunity including de-
creased numbers of T and B cells, decreased levels of IgA and IgG an-
tibodies, and a strong skewing towards the CD4+ T cell helper (Th) 2
population. Introduction of microorganisms restores the Th1 and Th17
subsets, normally not present in germ free mice [11]. Colonization by
the segmented filamentous bacteria (SFB) Candidatus arthromitus en-
hances the expansion of intestinal Th17 cells through adhesion to gut
epithelial cells [64–66]. Germ-free animals harboring C. arthromitus
alone develop EAE showing that gut bacteria can affect neurologic in-
flammation since SFB-induced Th17 cells in the lamina propria can
recirculate to the brain causing inflammation [67]. Therefore, an
aberrant microbiota can imbalance immune homeostasis and the in-
duced autoreactive T cell could migrate in different organs, from gut to
brain as in the case of MS or to liver as in the case of autoimmune
cholestatic liver disease [68,69], or kidney as in the case of SLE [70],
thus exacerbating specific organ inflammation.
3.2. Microbiota and epigenetic control
Epigenetic dysregulation, including histone modification, DNA
hypo- and hyper methylation, has been recently shown to play a pivotal
role in autoimmunity affecting the activity of several immune cells in
T1D [71] and SLE [72]. Sex hormones can regulate immunity and au-
toimmunity also through epigenetic mechanisms, such as regulation of
miRNA expression [73] and DNA methylation status [74–76]. Healthy
males have a tendency to bear higher methylation levels than healthy
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Journal of Autoimmunity xxx (xxxx) xxx–xxx
females [77]. Moreover, the autoimmune regulator (AIRE), a negative
regulator of autoimmunity is differentially expressed in males and fe-
males. In human and mouse thymus, females express less AIRE (mRNA
and protein) than males after puberty. AIRE expression has also been
demonstrated to be dependent on sexual hormones, as male castration
decreases AIRE thymic expression and estrogen treatment down-
regulates AIRE expression in cultured human thymic epithelial cells
[78]. Noteworthy, gut microbiota may alter host histone acetylation
and methylation in different tissue such as colon, liver and white adi-
pose tissues [79,80] and microbiota-induced chromatin changes have
been shown to be responsive to diet [80]. Moreover, AIRE expression is
reduced in germ-free mice [81]. Gut microbial metabolites, such as B
vitamins, mainly produced by bifidobacteria in human gut [82], mi-
crobial bio-transformation of dietary polyphenols [83] and short chain
fatty acids (SCFA) [80,84], have been all shown to contribute sig-
nificantly to epigenetic processes. Indeed, restoring an aberrant mi-
crobiota and microbial fermentation end products, especially SCFAs,
may be particularly important for regulation of inflammatory reactions,
as described below.
3.3. Microbial regulation of host immune responses via the synthesis of cell
signaling metabolites
Gut microbial biotransformation of exogenous and endogenous
compounds generates metabolites that play an important role in im-
mune homeostasis. Among these, microbial fermentation end-products
SCFA and microbially transformed bile acids have been demonstrated
to influence mucosal immune function, immune tolerance and regula-
tion of inflammation both within the gut and systemically [85]. In the
immune system-microbial cross-talk, these metabolites regulate the
differentiation and function of almost every cell type in the gut lym-
phoid compartments [86] and regulate intestinal permeability [87].
These metabolites can also circulate systemically to affect immune cells
in peripheral tissues [88].
3.3.1. SCFA
SCFA, primarily acetate, butyrate and propionate are the main gut
microbial end products of carbohydrate fermentation (Box 1). SCFA are
known to affect several cellular processes including gene expression,
chemotaxis, differentiation, proliferation and apoptosis, all of which
play important roles in inflammation [20,89]. SCFA represents an im-
portant energy source for intestinal epithelium (∼50% of energy re-
quirement) [90], act as ligands for activation of cellular signaling cas-
cades that carry their effects to districts other than the intestine and are
involved in the regulation of physiological functions such as lipid me-
tabolism, thermogenesis, fat storage in liver, muscle, and adipose tissue,
and blood pressure regulation [91].
The anti-inflammatory and immuno-modulatory effects of SCFAs
involve both the activation of the specific cell receptors GPR109a (also
known as HCA2), GPR41 (also referred as FFAR3) and GPR43 (FFAR2)
[92–95], and intracellular targets via inhibiting histone deacetylase
(HDACs) activity [96–99] (Box 1). Mice deficient in GPR43 develop
colitis, arthritis, and asthma, demonstrating a direct effect of SCFA on
colonic T regulatory (Treg) cells through the increased gene expression
of GPR43 [92]. Butyrate engagement of GPR109a is known to affect the
pro-inflammatory activities in colonic phagocytes, enhance Treg dif-
ferentiation and IL-10 production and reduce the colonic epithelial
secretion of IL-18, a cytokine known to regulate colonic homeostasis
[94]. SCFAs also promote inducible colonic Treg cells number and
function [96,97] through epigenetic processes by inhibiting HDAC ac-
tivity [96–99]. In particular, butyrate enhances histone H3 acetylation
in the intronic conserved non-coding sequences of the FoxP3 locus,
consequently promoting extrathymic generation of Tregs [96]. More-
over, IL-10-producing inducible Tregs develop after TGF-β cytokine
exposure in the periphery from naive CD4+ T cells [100]. Adoptive
transfer of CD4+CD45RBhi naïve T cells into Rag1−/− mice showed
L. Rizzetto et al. Journal of Autoimmunity xxx (xxxx) xxx–xxx

Box 1
SCFA pool and the gut microbiota

SCFA are produced mainly through saccharolytic fermentation of carbohydrates that escape digestion and absorption in the small intestine
and the pathways of SCFA production are relatively well understood and recently described in detail [303,304]. The major products are
acetate, propionate and butyrate. Total SCFAs in gut lumen is ∼100 mM, in blood is, portal ∼400 μM and peripheral ∼100 μM [305].
There is a strong biological gradient for each SCFA from the gut lumen to the periphery which leads to differing cell and tissue SCFA
exposure and therefore signaling potential. There is a significant reduction in butyrate, relative to acetate and propionate, across the gut
epithelium and also the significant reduction in propionate relative to acetate across the liver in humans [306–308]. Hence, SCFAs exhibit
the tissue specific physiological functions according to this concentration gradient. SCFA mainly exert their action through activation of G
protein coupled receptors (GPCRs), as well as epigenetic activities via the inhibition of histone deacetylases (HDACs), stimulation of histone
acetyltransferase activity and stabilization of the hypoxia-inducible factor (HIF) [98,309]. GPCRs show distinct patterns of expression and
they have been partially associated with the effects of the SCFAs on innate and adaptive immune cells and intestinal epithelial cells [310].
SCFA show differential abilities to activate the different signaling receptors [89]. GPR43 is mainly activated by acetate and propionate
followed by butyrate [311,312], while GPR41 si activated mainly by propionate and butyrate [311,312]. GPR109A, firstly identified as a
receptor for niacin, is also activated by β-hydroxybutryate and butyrate, but not by acetate and propionate [313]. Olfactory receptor 78
(OLFR78) was identified as SCFAs in a ligand screen for orphan GPCRs being it activated by acetate and propionate but not by butyrate
[314]. Circulating and gut SCFA pools can influence the immune system homeostasis by differently interacting with these signaling re-
ceptors at different body sites. Diverse bacteria are responsible for SCFA production. Acetate production pathways are widely distributed
among bacterial genera whereas pathways for propionate and butyrate production appear more highly conserved and substrate specific.
Overall, SCFAs, especially butyrate, seem to regulate several host functions exerting broad anti-inflammatory activities as well as affecting
cellular processes such as proliferation, activation, and apoptosis also through epigenetic effect. Butyrate has significantly greater HDAC
inhibiting potential, an important epigenetic process, compared to propionate and acetate [97,315,316]. For instance, de novo Treg cell
expansion through HDAC inhibition is promoted by butyrate and secondly by propionate, but not acetate [97]. DCs briefly exposed to
butyrate, and (to a lesser extent) propionate, but not acetate, potently induce Foxp3 expression [97]. Similarly butyrate and propionate
stimulate lipolysis, while acetate and aminobutyric acid have little or no effect [317]. Moreover, butyrate, but not propionate and acetate
are able to promote retinoic acid production via class 3 HDAC (HDAC3), but not HDAC2, inhibition [98]. Differently, it has been reported
that acetate could affect inflammation and host physiology both acting as HDAC2 inhibitor and promoting histone H3 and H4 acetylation
[318–320]. Altogether this evidence suggests that SCFAs are signaling molecules acting through different receptors and via different forms
of epigenetic regulation.

their conversion into Treg cells when mice were fed a butyrylated diet
[100]. Propionate and acetate were similarly able to enhance periph-
eral Treg generation [96]. Indeed, it is likely that commensal bacterial
species promote inducible Tregs in the gut [101] through SCFA release.
SCFA anti-inflammatory effects are not limited to adaptive immune
response. DCs exposed to butyrate suppress the conversion of naïve T
cells into IFN-γ producing cells [102]. Through GPR41 binding, pro-
pionate has also been shown to affect DCs properties in the bone
marrow by increasing their phagocytic capacity and limiting their
ability to prime a Th2 response in the airways [95]. SCFA have also
been shown to increase both intestinal IgA and systemic IgG responses
supporting plasma B cell differentiation. Mice under low dietary fiber
regimes and consequent low SCFA production, have been shown to be
defective in antibody homeostasis and to be greatly susceptible to in-
fection [103].
Animal studies have related dietary induced aberrant gut micro-
biota composition to inflammation through decreased intestinal barrier
function and increased intestinal permeability [104,105]. Increased
intestinal permeability has been previously shown to trigger low grade
chronic systemic inflammation in metabolic diseases and extra-in-
testinal inflammation [91], [106,107]. The combination of disrupted
barrier function and lack of dietary support for microbiota immuno-
modulatory metabolite production could be an important contributor to
AID risk. SCFA can dose-dependently suppress intestinal permeability
[98,108]. Butyrate in particular has been shown to suppress the per-
meability of isolated colonic mucosa epithelium [109] and in Caco-
2 cell monolayers [110], by influencing tight junction proteins (TJ)
expression (i.e increasing Claudin-5, Claudin-7, Zonulin-1 and de-
creasing Claudin-2) and increasing trans-epithelial electrical resistance
in vitro. Histological studies have shown that butyrate is also able to
alleviate intestinal injury following peritonitis induction in mice [111]
and mitigate experimental colitis [112] by improving barrier function,
thus acting as an anti-inflammatory agent. Butyrate has also been
shown to contribute to mucosal homeostasis by affecting cytokine and
chemokine secretion of intestinal epithelial cells and by increasing the
production of retinoic acid through enhancement of aldehyde dehy-
drogenase expression [98]. Butyrate also reduces levels of pro-in-
flammatory cytokines IL-6, TNF-α as well as the LPS binding receptor
TLR4, concomitantly restoring gut mucosa integrity and potentially
reducing bacterial translocation in an experimental mucositis model
[113]. Attenuation of liver injury and subsequent inflammatory re-
sponses following increased level of butyrate has also been observed
[114]. Recently, Xia et al. reported [108] that continuous oral admin-
istration of propionate during lactation, by increasing its concentration
in the proximal colon, contributes to maintenance of mucosal barrier
function by promoting the expression of Zonulin-1, Claudin-8 and 1 and
Occludin through the expression of MAPKs in rats [108].
Thus, the evidence so far indicates that SCFA can strongly impact
both the regulation of innate and adaptive immune systems, and in-
testinal permeability, all of which are commonly altered in AID. It is
noteworthy that Western-dietary habits bear about 7–10 times less
dietary fiber intake than ancient or traditional diets such as the
Mediterranean diet [115]. This lower fiber intake translates in lower
availability of substrate for microbial fermentation and therefore SCFA
production (Box 1). Diet, and especially dietary fiber has the ability to
influence both the source of inflammatory triggers through regulation
of intestinal permeability and the response to such inflammatory trig-
gers by DC and Treg maturation.
3.3.2. Bile acids
BA are cholesterol-derived molecules produced in the liver to fa-
cilitate the absorption of dietary lipids and fat-soluble vitamins and
maintain systemic cholesterol homeostasis. They also act as immune
regulators. BAs act as signaling molecules with hormone-like actions via
dedicated BA receptors such as the nuclear receptor farnesoid X re-
ceptor (FXR/NR1H4) and the membrane-bound G protein-coupled

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L. Rizzetto et al. Journal of Autoimmunity xxx (xxxx) xxx–xxx

Box 2
Microbial modulation of the BA pool

Primary bile acids (BAs) are synthesized in the liver from cholesterol and released into the small intestine in response to food intake to aid
lipid absorption and cholesterol catabolism. Newly-synthesized BAs are termed primary BAs, namely chenodeoxycholic acid and cholic
acid. Before active secretion, primary BAs are conjugated with the amino acids taurine or glycine, a fundamental amidation making BAs less
hydrophobic, less cytotoxic, and more readily secretable into bile. During the enterohepatic circulation, conjugated chenodeoxycholic acid
and cholic acid are then transformed by gut microbial enzymes through deconjugation and dihydroxylation reactions to generate un-
conjugated and secondary bile acids respectively [117]. In particular, the major microbial biotransformations include: hydrolysis of
conjugated bile acids to free bile acids and glycine or taurine by BSH activity; 7β-dehydroxylation of cholic acid and chenodexycholic acid,
leading to deoxycholic acid and litocholic acid production, respectively; bile acid 7β-dehydroxylation of ursodeoxycholic acid generating
LCA. Clostridia as well as other Gram positive gut bacteria have the most diverse bear BSH activity such as Enterococcus, Bifidobacterium,
and Lactobacillus [321]. So far, among the Gram-negative bacteria, a BSH was purified only from Bacteroides fragilis subsp. fragilis [322].
BSH activity by lactobacilli and bifidobacteria in the small intestine is particularly important in this process, making the intestinal BA pool
more available for transformation into secondary and thirtary structures by other members of the gut microbiota. The bile acid 7α/7β-
dehydroxylations involve a multistep biochemical pathway found only in the anaerobic gut bacteria, mainly Clostridia, C. perfringens and C.
scindens amongst others [56,321,323]. In addition, the gut microbiota are capable of the oxidation and epimerization of hydroxy groups at
the C3, C7 and C12 position of bile acids yielding isobile (β-hydroxy) acids.
Circulating BA pool is indeed strongly dependant on the profile of BA-converting bacteria. This dependency was firstly apparent in germ
free animals. Germ free mice show a strong increase in muricholic acid, levels compared to conventional animals, but not cholic acid.
Antibiotic treatment of conventional animals increases muricholic acid and reduces the levels of plasma secondary BAs indicating that
commensal bacteria modulate the size of the BA pool as well as its composition [324]. This bacterial activity is even more evident in disease
[117,282,325,326]. For instance, IBD patients, bearing an altered gut microbiota, often characterized by a reduction in Faecalibacterium
prausnitzii, present changes in BA profiles compared to healthy subjects [327]. Moreover, primary sclerosing cholangitis severity is ex-
acerbated in germ free mice and in conventional animals replete with intestinal microbiota correlates with decreasing level of urso-
deoxycholic acid, a microbial produced tertiary BA [328]. Transformation of conjugated primary BA cholic acid into the secondary BA
deoxycholic acid by the gut microbiota has been shown to determine the percentage of deoxycholic acid in blood [329]. Importantly, both
deoxycholic acid and ursodeoxycholic acid, produced by the gut microbiota, respond to changes in diet in animal models and are closely
linked to profiles of gut bacteria and their BSH and 7α/β-hydroxylation capabilities. Recent studies in animal models have shown that
probiotic BSH activities [330], polyphenols [331] and prebiotic fibers like oat β-glucans [332,333] can modulate the gut microbiota and
the profile of BA returning through the enterohepatic circulation. Dietary change has been shown to alter both fecal BA profiles and the
ability of the gut microbiota to generate secondary and tertiary BA [334].
Therefore, microbiota modulation through the diet might be exploited to modulate microbially-driven changes in BA pool both in terms
of BA chemical structures and in circulating concentrations of BA. Furthermore, BA themselves also have a direct modulatory affect upon
the gut microbiota [335], with taurocholate for example increasing the relative abundance of bacteria associated with inflammation in
animal models of IBD.
The importance of the composition of the BA pool is evident as BA show differential abilities to activate FXR and TGR5, as nicely
described in Refs. [336,337]. BAs are amphipatic molecules which structure characterized by a concave hydrophilic face (α face) and a
convex hydrophobic face (β face), which determined the different binding to the bile-acid receptors [336]. TGR5 showed a dose-dependent
activation by BA, with the following rank order of potency: lithocholic acid ≥ deoxycholic acid > chenodeoxycholic acid > cholic acid.
Similarly, the different BA show different affinity to FXR. The hydrophobic pocket of the FXR interacts with BAs mainly through the β
face. The α face contains several hydroxyl groups in the 3, 7 and/or 12α positions that impacts on the ability to activate FXR [338]. The 7α-
hydroxy group, conferred by gut microbiota activity, confers high capacity to chenodeoxycholic acid and synthetic ligands, such as fex-
aramine and obeticolic acid, to activate FXR. Conversely, the absence of a 7α-hydroxy group, in the case of deoxycholic acid and lithocholic
acid, compromises stable coactivator recruitment and results in partial agonistic properties. Finally, the FXR binding site cannot accom-
modate a 12α-hydroxy group and consequently, cholic acid and chenodeoxycholic acid have low affinity for FXR. Ursodeoxycholic acid has
been described as an antagonist, able to inhibit activation by chenodeoxycholic acid [339]. In line with these observation FXR showed a
dose-dependent activation by BA, with the following rank order of potency: chenodeoxycholic acid > deoxycholic acid = lithocholic
acid > cholic acid = chenodeoxycholic acid. However, the FXR binding site is not perfectly conserved between species. This makes, for
instance, the mouse FXR much more responsive to cholic acid than its human counterpart [340]. To note that mice do not have cheno-
deoxycholic acid, the most potent natural activator of human FXR, which in mice is converted to β-muricholic acid.

receptor TGR5 (also called GPBAR1 or M-BAR/BG37) [116] (Box 2).
Besides FXR and TGR5, BAs are able to activate other nuclear receptors
including pregnane X receptor and vitamin D receptor. Ligand-activated
nuclear receptors such as FXR control a broad range of metabolic
processes including hepatic BA transport and metabolism, lipid and
glucose metabolism, drug disposition, hepatic regeneration, fibrosis,
cell differentiation, tumour formation and also inflammation [116].
The diversity of BA pool in terms of molecular structures largely
depends on gut microbiota composition and activity. Dietary influences
which regulate the composition of the gut microbiota will also influence
microbial bioconversion of host BA, BA pool size and its chemical
composition/structure (Box 2) [117]. The ongoing ERA-HDHL action
project CABALA_DIETH&HEALTH (CirculAting Bile Acids as bio-
markers of metabolic Health_Linking microbiotA, diet and Health,
http://www.cabalaproject.eu/) will provide new insight into how diet
shapes the gut microbiota, its ability to modulate circulating BAs and
impact on human physiological processes through altered BA signaling.
This will fill a current gap in knowledge since most studies thus far have
been conducted in animals and few studies have measured how specific
interactions between foods rich in fibers, polyphenols and probiotics
can alter BA signaling in humans. Importantly, this project will achieve
this through a combination of existing large scale studies, the RoCAV
cohort [118] and the Med diet and exercise dietary intervention DI-
RECT-PLUS in Israel (ClinicalTrials.gov Identifier: NCT03020186), and

6
L. Rizzetto et al.
also bespoke mechanistic studies combining chronic dietary interven-
tion to modulate gut microbiota composition and post-prandial food
challenge tests to provide new knowledge on how oats, apples and the
probiotic Lactobacillus reuteri NCIMB 30242 can influence circulating
BA profiles and their cell signaling potential (ClinicalTrials.gov Iden-
tifier: NCT03369548). Providing the mechanistic basis by which fibers,
polyphenols and BSH active probiotics can modulate circulating BA
profiles will provide much needed support for designing efficacious
dietary interventions to prove cause and effect relationships between
functional food ingestion and beneficial physiological effects observed
in animal models, both in terms of immune related diseases and me-
tabolic diseases, but for which current literature in humans is contra-
dictory. Importantly CABALA_diet&health partners in University Col-
lege Cork (Ireland) will investigate how different profiles of circulating
BA influence activation of BA cell signaling receptors. This is particu-
larly important since different BA have very different ligand potentials
and activation potentials, as described in Box 2.
BA signaling through FXR and TGR5 binding attenuates pro-in-
flammatory innate immune response as demonstrated in several dis-
eases, including MS [119,120], and LPS-induced hepatic damage [121],
atherosclerosis [122] and IBD [123]. Activation of FXR in lamina pro-
pria monocytes and macrophages results in repression of NF-kB binding
to its responsive elements [124]. Its activation reduces inflammation,
downregulating IL-1β, IL-2, IL-6, TNF-α, and IFN-γ gene expression and
attenuates experimentally induced colitis [124]. BA-dependent FXR
activation also controls bacterial overgrowth and maintains mucosal
integrity in the small intestine under physiological conditions by in-
ducing the transcription of multiple genes involved in intestinal mu-
cosal defence against microbes [125].
In addition to FXR, BA exert anti-inflammatory effects via TGR5
engagement. TGR5 signaling also suppresses NF-kB mediated pro-in-
flammatory gene regulation impacting on macrophage [122] and B
cells activation in vivo [121]. Using in vitro human monocyte-derived
DCs, it has been demonstrated that TGR5 activation by BAs can induce
differentiation of IL-12 hypo-producing DCs through TGR5-cAMP
pathway [126,127]. TGR5 has also been found to inhibit the in-
flammatory response associated with liver ischemia through suppres-
sion of the TLR4-NF-kB pathway [128]. Activation of this receptor also
suppressed gastric inflammation [129,130] and TGR5 deficiency ex-
acerbated injury-induced colitis in mice [131], while its activation in-
hibits inflammation and prevents colitis development [123]. Consistent
with these observations, treatment of wild-type mice with oleanolic
acid, a triterpene molecule extracted from olive leaves acting as a TGR5
agonist and with a shape resembling the secondary BA litocholic acid
[132], attenuated colitis development and monocyte infiltration into
the colon [131]. This indicates that the TGR5 pathway may have po-
tential as a therapeutic target for Th1 dominant chronic inflammatory
disorders, such as Crohn's disease and psoriasis [133] but also Th1-
driven autoimmune diseases.
Indeed, BA activity is not merely limited to the liver but influences
host immune function systemically. Indication on the potential use of
BA as immunosuppressant is discussed below.
4. Gut microbiota dysbiosis in extra-intestinal AID
Several evidence are suggesting that alterations of the gut microbial
composition may be correlated to AID manifestation [14,134–139],
influencing both immune homeostasis and gut permeability.
4.1. Type 1 diabetes
T1D is an organ-specific AID characterized by an autoimmune re-
sponse against the host pancreatic β cells, leading to insufficient insulin
production from the pancreas [140]. Even though it is still unclear
whether intestinal permeability is an initiator or accelerator of T1D or
merely an outcome of disease progression [141,142], studies in T1D
7
Journal of Autoimmunity xxx (xxxx) xxx–xxx
patients and animal models have indicated that impaired intestinal
barrier function occurs before disease onset [105,143]. Studies using
the permeability markers lactulose and mannitol verified that Bio-
Breeding diabetes (BB-D) prone rats, which spontaneously develop T1D
due to genetic susceptibility, exhibit a highly permeable gut associated
with low levels of intestinal claudin, a major intercellular TJ protein,
before the onset of T1D [144]. Intestinal myeloperoxidase activities and
goblet cell density are also higher in the diabetes-prone rats than in
controls, supporting the notion of an early intestinal inflammatory re-
sponse linked to increased early intestinal permeability. This is not a
phenomenon occurring only in animal models of diabetes. In humans
with a propensity to develop T1D also appear to possess an abnormal
intestinal barrier. Intestinal samples from individuals at risk of [145] or
already diagnosed with T1D [146,147] demonstrated abnormalities
identified with sugar permeability tests, the clinical standard for mea-
suring intestinal permeability. A loss of the intestinal barrier function
has been observed in non-celiac T1D patients with a frequent associa-
tion with mucosa ultra-structural alteration [148]. Moreover, the po-
tential pathogenic role that increased intestinal permeability plays in
T1D appears to be dependent on high plasma levels of Zonulin-1, a
secretory protein identical to prehaptoglobin 2 regulating epithelial TJ
function [149]. Its production relies on bacterial colonization [150] and
increased TJ paracellular transport [151]. Reversion of intestinal bar-
rier dysbiosis by adding a Zonulin-1 inhibitor ameliorated T1D mani-
festations in disease-prone rats [152]. Recent mechanistic studies in
animal models show that microbial translocation, a consequence of
increased intestinal permeability due to decreased intestinal epithelial
integrity, contributes to T1D development [163]. Gut bacterial trans-
location into mesenteric and pancreatic lymph nodes has been shown to
increase destruction of insulin-producing pancreatic β cells in strepto-
zotocin-induced T1D mice [163]. Translocated bacteria in pancreatic
lymph nodes triggered the nucleotide-binding oligomerization domain
containing 2 (NOD2) receptor activation, highly expressed by DCs and
macrophages, but not NOD1, leading to NOD2-mediated induction T
helper 1 (Th1) and Th17 responses in pancreatic lymph nodes and
pancreas. This unchecked inflammatory response exacerbated T1D
symptoms [163]. These findings suggest that a leaky intestine in the
setting of T1D could allow a greater exposure of the intestinal immune
system to antigens and a continuous source of inflammatory triggers
systemically. The recent evidence showing epigenetic modification as
important trigger for T1D development [71], further suggests intestinal
microbiota and its dietary derived-metabolites involvement in immune
function through HDAC inhibition could exert an important role in
contributing to disease onset.
Altered microbiota composition has also been reported in T1D
compared to healthy controls. In Non-obese diabetic mice, Bacteroides,
Oscillospira, Sutterella, and Bifidobacterium genera were more abundant
compared to controls [113]. Oscillospira is an important gut microbe
previously shown to mediate the disruption of the intestinal epithelial
barrier, thus causing the translocation of bacteria from the gut in
obesity [153]. A culture-independent analysis of the bacteria in fecal
samples collected from Biobreeding diabetes (BB-D) prone rats and BB-
D resistant rats revealed that Lactobacillus and Bifidobacterium are
dominant genera in BB-D resistant rats, showing that these species are
negatively correlated with the onset of T1D [154]. Antibiotic treatment
accelerated disease onset in Non-obese diabetic mice in concomitance
with an expansion of Th1 cells and a reduction of Th17 cells in the gut
lymphoid tissues [155]. Fecal transplantation of Non-obese diabetic
microbiota in non-obese resistant mice resulted in insulitis induction,
revealing that Non-obese diabetic animals bear a diabetogenic gut mi-
crobial community. This gut microbiota is characterized by increased
ileal level of Anaeroplasma and Desulfovibrio species with respect to non-
obese resistant mice. Lactobacillus abundance was reduced. Non-obese
diabetic mice colon appeared devoid of Bacteroides acidifaciiens and
showed decreased abundance of Ruminococcus gnavus and increased
abundance of Prevotella [155,156].
L. Rizzetto et al. Journal of Autoimmunity xxx (xxxx) xxx–xxx

Table 1 Table 1 (continued)

Key findings supporting a role for gut dysbiosis in AID. Studies investigating the
gut microbiota of AID in animal models and in patients compared with healthy Disease Human cohort/animal Major finding (AID vs HS) Reference
studies
subjects. AID, autoimmune disease; T1D type 1 diabetes; SLE, systemic lupus
erythematosus; MS, multiple sclerosis; HS, healthy subjects.
Relapsing HS (n = 31), MS Prior vitamin D [343]
Disease Human cohort/animal Major finding (AID vs HS) Reference remitting (n = 30); 4 MS supplementation,
studies patients with pre- and ↓ Bacteroidaceae
post vitamin D ↓ Faecalibacterium,
T1D supplementation ↑ Ruminococcus
Animal study non-obese diabetic ↑ Bacteroides [341] Relapsing HS (n = 50), MS ↓ frequencies of specific [213]
mice ↑ Oscillospira remitting (n = 20) Clostridium cluster and
↑ Sutterella Bacteorides
↑ Bifidobacterium Relapsing HS (n = 36), MS ↑ Pedobacter, [216]
Animal study Biobreeding diabetes ↓ Bifidobacterium [154] remitting (n = 59) ↑ Flavobacterium,
(BB-D) prone, BB-D ↓ Lactobacillus ↑ Blautia,
resistant rats ↑ Dorea,
Human study, T1D (n = 16) vs HS ↑ Clostridium [157] ↑ Pseudomonas
pediatric (n = 16) ↑ Bacteroides ↑ Mycoplana
↑ Veillonella ↓ Adlercreutzia,
↓ Lactobacillus ↓ Collinsella,
↓ Bifidobacterium ↓ Parabacteroides,
↓ Blautia coccides- ↓ Erysipelotrichaceae,
Eubacterium rectale ↓ Lachnospiraceae,
↓ Prevotella ↓ Veillonellaceae,
Human study, Mexican T1D children ↑ Bacteroides [158] ↓ Lactobacillus,
pediatric (n = 21), 8 newly ↓ Prevotella ↓ Coprobacillus,
diagnosed, 13 ↓ Haemophilus
established T1D Relapsing HS (n = 43), MS ↑ Methanobrevibacter, [217]
Human study, European T1D newly ↑ Bacteroidetes [159] remitting (n = 60) ↑ Akkermansia
pediatric diagnosed children ↑ Streptococcus ↓ Butyricimonas
(n = 28), vs HS ↓ Clostridium cluster IV Relapsing HS (n = 71), MS ↑ Akkermansia [218]
(n = 27) and XIVa remitting (n = 71) ↑ Acinetobacter
Human study, Russian vs Finnish and ↑ Bacteroides LPS in [161] ↓ Parabacteroides
pediatric Estonia children Finnish and Estonia Relapsing Monozygotic twin, ↑ Akkermansia [219]
(n = 222) children, with high remitting discordant for MS
incidence of T1D (n = 34)
Human study, Scandinavia infants, Reduced bacterial alpha- [160] Relapsing HS (n = 43), MS No differences in alpha [214]
pediatric predisposed to T1D diversity remitting, (n = 60) diversity and beta
(n = 33) ↑ Blautia pediatric diversity
↑ Rikennellaceae subjects Early microbiota
↑ Ruminococcus alterations in MS found at
↑ Streptococcus specific taxonomic levels:
↓ Lachnopiraceae ↑ Faecalibacterium
↓ Veillonellaceae ↑ Enterobacteriaceae
Human study, Finnish children ↑ Bacteroides [163] ↑ Clostridiales
pediatric (n = 8), predisposed ↑Bifidobacterium ↑ Bacteroides
to T1D fragilis
Human study, Scandinavia children ↑ Bacteroides [162] ↓ Methanobrevibacter
pediatric with HLA-conferred ↑Bifidobacterium Relapsing HS (n = 9), MS Found microbiota [215]
susceptibility to T1D remitting, (n = 15) dysfunction
(n = 18), HS (n = 18) pediatric ↑ Desulfovibrionaceae
SLE subjects ↓ Lachnospiraceae
Animal study MRL/lpr mice Female lupus prone mice [202] ↓ Ruminococcaceae
showed
↓ Lactobacillaceae
↓ Lachnospiraceae Initial findings indicate that the gut microbiota of subjects with
Animal study SNF1 mice Decreased beta-diversity [203]
prediabetes or T1D is different to that of healthy people (Table 1). The
↓ Lactobacillacus
↓ Firmicutes/Bacteroides analysis of 16 T1D pediatric patients revealed a marked increase in the
ratio relative abundance of Clostridium, Bacteroides and Veillonella and a
Human study HS (n = 20), SLE ↓ Firmicutes/Bacteroides [198] concomitant decrease in Lactobacillus, Bifidobacterium, the Blautia coc-
(n = 20) ratio cides-Eubacterium rectale group and Prevotella compared to healthy
↓ bacterial metabolites
(homoserine lactone, N-
children [157]. Higher abundance of Bacteroides and lower abundance
acetylmuramic acid, of Prevotella characterize also newly-diagnosed Mexican pediatric T1D
ribose-1,5-bisphosphate) patients compared to healthy children [158]. A European study showed
Human study HS (n = 17), SLE ↓ metabolites associated [199] that < 3 years old patients had increased level of Bacteroidetes and
(n = 18) to pyrimidine, purine and
streptococci and reduced abundance of Clostridium cluster IV and XIVa
aminoacid metabolism
MS species. Increased microbial diversity and decreased level of butyrate
Relapsing HS (n = 31), MS Type A Clostridium [342] producing clostridia have been found in pediatric T1D who were < 3
remitting (n = 30) perfringes reduced in MS years old with respect to healthy age-matched control [159]. Com-
Type B C. perfringes found paring the gut microbiota of subjects who develop T1D with those who
in one MS patient
do not, has revealed that a reduced bacterial diversity is more evident
before the time of diabetes onset [160]. A recent study reported that
Russian children, who have a low incidence of T1D have a low relative
abundance of Bacteroides in contrast with the high relative abundance

8
L. Rizzetto et al.
of Bacteroides shown in children from Finland and Estonia, where the
incidence of T1D is much higher [161]. Three human studies including
T1D patients were carried out in Scandinavia where the incidence of
T1D is high [160,162,163]. Similar to observations in animal experi-
ments, T1D patients showed an increased abundance of Bacteroidaceae
and decrease of bifidobacteria [157,163]. Specifically, Brown et al.
[162] and De Goffau et al. [163] identified a decrease in lactate- and
butyrate-producing bacteria being associated with development of au-
toimmunity, with a dearth of Bifidobacterium adolescentis and B. pseu-
docatenalatum species, whereas Kostic et al. [160] did not see similar
changes in patients that developed autoimmunity during the study
period. However, the authors showed that T1D children bear higher
abundance of Blautia, Rikennellaceae, Ruminococcus and Streptococcus
and a lower abundance of Lachnospiraceae and Veillonellaceae [118].
Differences in methods and study groups (patients with established T1D
vs. patients with anti-pancreatic antibodies who later develop overt
diabetes) may account for the differences or contradictions in the re-
sults. Importantly, all studies found that the alpha-diversity of T1D
patient microbiota was reduced, indicating that T1D is characterized by
a reduced bacterial diversity, possibly reduced functional diversity and
possibly low community stability.
Activation of TLRs has been linked to the pathogenesis of T1D
[164]. TLR4 has been identified as the main receptor on pancreatic β
cells contributing to islet cell inflammation during the course of T1D
development [165]. LPS is the major ligand triggering TLR4 signaling
activation. Controversial results have suggested a role of LPS as an
etiological agent increasing the risk of developing T1D [166] or as a
suppressive agent on the incidence and severity of the disease by in-
creasing Tregs [167,168]. LPS administration to Non-obese diabetic
mice during the prediabetic state did not reverse insulitis but delayed
the onset of diabetes [169]. Multiple-injection, rather than single in-
jection, of LPS was found to suppress T cell proliferation, to promote
Tregs expansion and to induce the differentiation of tolerogenic DC
with low TLR4 expression. Explanting those cells into Non-obese dia-
betic/SCID diabetic mice protects those animals from T1D progression
[169].
Interestingly, Non-obese diabetic mice deficient in the innate sig-
naling molecule MyD88 are protected from the development of T1D
[170]. However, such protection is lost when Myd88−/− mice of the
Non-obese diabetic strain are housed under germ-free conditions. The
absence of MyD88 in Non-obese diabetic mice leads to over-re-
presentation of the bacterial phylum Bacteroidetes [170] and suppres-
sion of diabetes, presumably through the production of an, as yet uni-
dentified, immunomodulatory microbial product. MyD88 deficiency
changes the composition of the distal gut microbiota, and that exposure
to the microbiota of specific pathogen-free MyD88−/−Non-obese dia-
betic donors attenuates T1D in germ-free Non-obese diabetic recipients.
Transfer of gut microbiota of Myd88−/− Non-obese diabetic to wild-
type Non-obese diabetic mice reduced the intensity of insulitis and
delayed the onset of T1D. This result has been shown to correlate with a
decreased abundance of Lactobacillaceae, an increased abundance of
Lachnospiraceae and Clostridiaceae, increased level of TGF-β in the
lamina propria and increased number of CD8+, CD103+ and CD8 α/β T
cells [171]. Together, these findings indicate that the interaction be-
tween the gut microbiota and the innate immune system could be an
important factor modifying T1D predisposition.
So far, few studies have investigated the association between altered
gut microbial communities and autoimmunity prior to islet autoanti-
body development [172,173]. A shift in the ratio of Bacteroidetes and
Firmicutes [159] and a higher abundance of Bacteroides dorei and
Bacteroides vulgatus [174] have been associate with increased risk of
islet autoantibody. Autoantibody positive children also show lower
relative abundance of butyrate-producing and mucin-degrading bac-
teria [162]. Recently, co-occurrence analysis on the BABYDIET cohort
[172,175] revealed a functional association between diet, gut micro-
biota structure and metabolism and islet auto-antibody development
9
Journal of Autoimmunity xxx (xxxx) xxx–xxx
[173]. The authors showed that alterations in the composition of mucin
degrading bacteria, with increasing Bacteroides and decreased abun-
dance of Akkermansia, associate with the risk of early development of
islet auto-antibodies [173]. Thus, changes in microbial diversity and
differences in relative abundance, in particular of mucin-degrading and
butyrate-producing bacterial taxa, between diabetic subjects and
healthy/control, highlight that gut microbiota and associated increased
gut permeability may contribute to disease onset or progression. In-
triguingly, the above study also suggests that diet-microbe interactions
and their influence in immune function early in life hold significant
potential in developing dietary, population based strategies to reduce
the risk of T1D.
4.2. Systemic Lupus Erythematosus (SLE)
SLE is an autoimmune disorder characterized by severe and per-
sistent inflammation that leads to tissue damage in multiple organs
[176,177]. Although SLE affects both men and women, women of
childbearing age are diagnosed about 9 times more often than men
[178]. It has been shown that LPS can promote SLE development and
disease progression upon penetration of the intestinal epithelium and
translocation into systemic tissues [179]. In SLE patients, either in ac-
tive phase or remission, the higher level of soluble CD14 compared to
healthy subjects correlates with disease activity parameters, suggesting
the involvement of free circulating LPS in SLE development [180]. In
addition, repeated injections of LPS into lupus-prone mice result in
increased autoantibody production and development of glomerulone-
phritis [181,182]. Activation of TLR4 also promotes lupus disease ac-
tivity in lupus prone mice, as the apolipoprotein E-deficient (ApoE−/−)
mice [181,183,184]. Mice spontaneously develop lupus when TLR4
responsiveness is increased, whereas the exacerbated disease phenotype
can be significantly ameliorated when the commensal gut microbiota,
as a source of LPS, is removed by antibiotics [181]. Ni et al. found
increased levels of serum autoantibodies and more severe lung injury
when challenging ApoE−/− mice with LPS [185]. Moreover, im-
munization of non-autoimmune mice with phospholipid-binding pro-
teins induced lupus-like disease and can be facilitated by the adminis-
tration of LPS [186]. Conversely, inhibition of TLR4 results in reduced
autoantibody production and lowered renal glomerular IgG deposits in
lupus-prone mice [187,188]. Taken together, these data suggest LPS
stimulation and TLR4 activation or hyper-responsiveness, as factors
contributing to SLE initiation in genetically susceptible hosts.
Circulating lipoteichoic acid (LTA), an inflammatory component of
the Gram-positive bacterial cell walls, has also been linked lupus dis-
ease. The expression of TLR2, the receptor of LTA, has been reported to
be increased in SLE patients [189]. In lupus-prone mice, TLR2 activa-
tion triggers lupus nephritis whereas TLR2 knockout attenuates lupus-
like symptoms [187,190,191]. Recently, another bacterial antigen that
may mimic self-antigens has been recognized to induce autoantibody
production [192].
Since the hallmark of SLE is the presence of high levels of anti-
double-stranded DNA autoantibody (anti-dsDNA) in sera, the con-
tribution the nucleic acid receptor, recognizing bacterial hypomethy-
lated CpG DNA sequences, TLR9, in the pathogenesis of SLE has been
investigated in a transgenic mice carrying anti-dsDNA antibody trans-
gene and challenged the mice with TLR4-and TLR9-agonists [183].
Splenocytes from these mice were found to secrete higher levels of in-
terleukin-10 (IL-10) and anti-dsDNA. Concomitant activation of extra-
cellular TLR4 and intracellular TLR9 affect SLE progression in vivo by
accelerating the accumulation of anti-ds-DNA autoantibody [183].
Several downstream proteins in the TLR7 and 9 signaling cascade
are highly relevant to the pathogenesis of SLE [193]. Deficiency of
MyD88 in B cells, in particular, has been shown to ameliorate lupus
disease in MRL/lpr mice, the classical animal model of lupus nephritis
[30,194] by ameliorating nephritis, reducing IgG anti-nuclear anti-
bodies production and activation of nephrotoxic T cells [194].
L. Rizzetto et al.
Conversely, there is a paucity of data pertaining to NLRs such as
NOD1 and NOD2 which are associated with inflammasome formation
[195,196]. Interestingly, NLRP3/ASC inflammasome were found com-
promised in New Zealand Blackmice, a lupus-prone model. Consistent
with this finding, loss of ASC in B6-Faslpr mice led to exacerbation of
lupus-like disease by increasing lung T cell infiltrates and nephritis as
well as increasing DCs and macrophages activation and expansion of T
and B cells [197]. These results suggest opposite role for TLRs and NLRs
in contributing to SLE. The evidence that TLR-mediator deficiencies
ameliorate lupus symptoms while NLR-mediator deficiencies exacer-
bate it, suggest distinct contributions for those receptors in SLE pa-
thogenesis. Both receptor's family are involved in sensing bacterial
components, leading to hypothesize that they could differently re-
cognize translocated bacteria through a leaky gut, eliciting pro-in-
flammatory response or tolerance, respectively.
Intestinal dysbiosis has been reported in SLE patients (Table 1).
Preliminary 16S rRNA profiling showed that the fecal Firmicutes/Bac-
teroidetes ratio was significantly lower in SLE patients compared to
healthy controls, even during remission [198]. Fecal metabolite con-
centrations measured by liquid chromatography coupled with a time of
fly mass spectrometry (LC-ESI-QTOF-MS) and capillary electrophoresis
mass spectrometry technique showed that SLE patients exhibited re-
duced levels of homoserine lactone, N-acetylmuramic acid and ribose-
1,5-bisphosphate compared to healthy subjects [199]. The same re-
search group also described a deficiency in metabolites associated with
pyrimidine, purine, and amino acid metabolism [199]. The authors
suggested that SLE patients bear deficiencies in chemical species par-
ticipating in, for example, quorum sensing, cell-to-cell communication
and cell wall biosynthesis, which are known to be important for gut
microbiota homeostasis.
In mouse models, a role for the intestinal gut microbiota in the
development of SLE is not completely clear since the onset and severity
of lupus-like disease is not profoundly altered in the germ-free state
[200,201]. However, there is emerging evidence that there is dysbiosis
and gut-pathology in different animal models of lupus. Consistent with
findings of microbiota composition in human SLE patients [198], lupus-
prone MRL/lpr mice have increased microbial diversity in the feces
compared to non-disease controls [202], and the relative abundance of
Lactobacillus and the ratio of Firmicutes/Bacteroidetes were higher in
mice with lower lupus severity [203]. Moreover, female lupus-prone
MRL/lpr mice displayed a significant reduction of Lactobacillaceae fa-
mily and increase of Lachnospiraceae both prior to disease onset and in
the late stage of disease with severe lupus symptoms [202].
Zhang et al. observed that there were sex-related changes in the gut
microbiota of lupus-prone mice compared to healthy mice. Females
were more likely to have higher Lachnospiraceae abundance, which
correlated with the development of more severe disease [202]. Another
study also showed that gender-related differences in the gut of lupus-
prone mice. Female SWR x NZBF1 (SNF1), which develop more severe
nephritis than male mice, have more plasma cells and α4β7-expressing
T cells in the Peyer's patches than male SNF1 mice [204]. Analysis of
RNA expression in the distal ileum showed that female SNF1 mice ex-
press much higher levels of pro-inflammatory mediators including IL-6,
IL-9, IL-17, IL-22, IFN-α and IFN-β than male mice [204]. Although the
gut microbiota was not analyzed in this study, it does further support a
role for the gut microbiota in lupus development and in the gender bias
of this disease, given the regulation of these inflammatory cytokines by
the gut microbiota and their metabolites.
4.3. Multiple Sclerosis (MS)
MS is a chronic inflammatory demyelinating disease of the central
nervous system with a pathogenesis characterized by a breakdown of
the blood-brain barrier and demyelination of the central nervous
system by infiltrating autoreactive T cells [205,206]. Epidemiological
and genetic studies suggests that MS is provoked by exposure to
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Journal of Autoimmunity xxx (xxxx) xxx–xxx
environmental factors inducing loss of tolerance and activation of self-
reactive T cells recognizing myelin antigens [205]. Studies on EAE
animal models suggest a strong influence of the gut and its microbiota
in disease development and associated inflammation [67,207–209]. An
altered gut mucosa and a disrupted mucosal immune homeostasis have
been suggested to contribute to the emergence of the disease (REF). An
increased intestinal permeability preceding EAE onset which worsens
during disease progression has been described [207]. Intestinal per-
meability was shown to be associated with an alteration of mucosal
structure, as indicated by the increased crypt depth and thickness of
jejunum and ileum mucosa, and an overexpression of Zonulin-1 [207]
as previously observed in T1D [152,210]. These changes lead to a
higher immune cells infiltration during MS progression. Elevated Th1
and Th17 pro-inflammatory responses was observed in lamina propria,
Payer's patches and mesenteric lymphnodes as well as in spleen. This
increase was concomitant with lower Treg cell numbers [207].
The complete absence of microbes in gnotobiotic mice C57BL/6
mice subjected to the induction of active EAE [67] and in gnotobiotic
transgenic mice [209] that develop the disease spontaneously sig-
nificantly affects the development of disease. Germ-free EAE animals
produce lower levels of the pro-inflammatory cytokines IFN-γ and IL-
17A in both intestine and spinal cord but display a reciprocal increase
in Treg cells. This was associated with a reduced ability of germ-free
animal DCs to stimulate pro-inflammatory T cell responses. In germ-free
mice demyelination was shown to initiate following colonization with
feces isolated from SPF mice and is caused following entry of auto-
antigen specific B cells into the germinal center of cervical lymph nodes
[209]. Furthermore, oral treatment with a mixture of non-absorbing
antibiotics beginning one week prior to sensitization also reduce sig-
nificantly the severity of EAE [211]. Microbiota depletion ameliorates
the development of EAE by reducing the production of pro-in-
flammatory cytokines from the draining lymph node cells, as well as by
reducing mesenteric Th17 cells in an invariant NK cells dependent
manner [211]. Moreover, antibiotic treatment, by reducing gut bac-
terial populations protects against EAE development by inducing
FoxP3+ Treg cells accumulation in the mesenteric and cervical
lymphnodes [208,212].
Although the cause of MS is unknown, the gut microbiota seems to
be important in the onset and/or progression of the associated systemic
autoimmunity. Studies conducted so far suggest the presence of a dis-
rupted or altered microbiota in relapsing remitting MS patients com-
pared to healthy people [213–217] (Table 1). Detailed faecal micro-
biome analyses of 31 MS patients revealed that MS patients had distinct
microbial community profile compared to healthy subjects (n = 36)
[216]. Chen et al. observed a higher abundance of Psuedomonas, My-
coplasma, Haemophilus, Blautia and Dorea genera in MS patients,
whereas control group showed higher abundance of Parabacteroides,
Adlercreutzia and Prevotella genera. Other studies reported that MS pa-
tients, compared to healthy subjects, bear significantly lower Clostridia
XIVa and IV clusters, e.g. Butyricimonas [217] and Bacteroides
[213,214], and higher relative abundances of Methanobrevibacter and
Akkermansia [217]. The differences observed correlated with variation
in the gene expression of molecules involved in DC maturation, inter-
feron and NF-kB signaling pathways in circulating T cells and mono-
cytes [217]. In contrast, another study comparing 16S rRNA profiles
from 60 faecal MS samples with 43 healthy donors showed no sig-
nificant differences in the diversity of microbial populations in MS
[214]. Moreover, the gut microbiota analysis of 15 pediatric MS pa-
tients revealed an inverse association of Bacteroides with Th17 immune
markers, while Fusobacteria correlated with Treg expression in healthy
children [215]. Very recently, Cekanaviciute et al. reported higher le-
vels of Akkermansia muciniphila and Acinetobacter calcoaceticus in MS
patients compared to healthy subjects [218]. These two bacterial spe-
cies induced a pro-inflammatory response ex vivo, while, Para-
bacteroides distasonis, found reduced in MS, induced an anti-in-
flammatory response in mice, driven by the expansion of IL-10+ Treg
L. Rizzetto et al.
cells [218]. It is noteworthy to observed that monocolonization of mice
with Acinetobacter calcoaceticus but not with Akkermansia, exacerbated
EAE symptoms [218]. Similarly, the gut microbial profiles of MS twins
and healthy twins were compared, evidencing an increased Akker-
mansia relative abundance in untreated MS twins [219]. When human
MS microbiota was transplanted in mice, the modest dysbiosis observed
in MS subjects determined spontaneous autoimmune encephalomyelitis
in recipient healthy germ free mice [219], which spleen T cells pro-
duced less IL-10 after transplantation.
Recently, Benedek et al. [34] showed that treatment with pregnancy
levels of 17-β-estradiol significantly increasing the relative abundance
of lactobacilli and Lachnospiraceae and induces regulatory B cells and
anti-inflammatory macrophage proliferation in MLN. These studies in-
deed associate changes in the relative abundance of gut species with
phenotypic modification and balance of immune regulatory cell popu-
lations. The changes in the abundance of these microbial species could
have different effects on the immune systems. For example, different
profiles of gut bacteria are likely to impact on SCFA profiles, including
acetate, butyrate and propionate (Box 1) and also modulate BA profile
and pool size (Box 2), which can directly regulated Treg expansion
[95–97,100,220], oxidative stress, reinforce the intestinal barrier and
blood-brain barrier function [221,222] as also described above.
5. Can microbiota modulation improve AID associated symptoms
and chronic inflammation?
The prospect of restoring a normal microbiota is an appealing hy-
pothesis to manage conditions associated with a gut microbiota dys-
biosis. Restoration of the composition of gut microbiota and its com-
munity structure conceivably leads to restoration of its function.
Several ways for manipulating gut microbiota composition and function
include the use of dietary intervention, prebiotics, probiotics and fecal
microbiota transplantation, as discussed in the following sections.
5.1. Dietary microbiota modulation and its immune-regulatory potential in
AID
Findings from population studies and intervention trials provide
some evidence that adherence to a healthy diet over time reduces the
risk of long-term inflammation and associated diseases. The
Mediterranean diet, with beneficial fats, high polyphenols and fibers,
and low refined sugars and low energy, has been shown to lower in-
flammatory markers in patients with metabolic disease and in the el-
derly [223–225].
Indeed, treating chronic inflammation has become one of the most
promising targets for reducing the disease burden, especially since it
appears responsive to diet, with beneficial fats, polyphenols and fibers
all shown to impact on inflammatory markers [223–226]. In addition,
such interventions also boost gut bacteria that potentially suppress in-
flammation. Human fecal butyrate-producing Clostridia clusters XIVa
and IV, as well as Bacteroides fragilis have been correlated with sup-
pression of inflammatory conditions through the induction of Foxp3+
Tregs [227,228]. Indeed, the ultimate goal of therapies targeting the
gut microbiota is to the growth of anti-inflammatory commensal bac-
teria or their metabolites while eliminating potential pathobionts and to
reverse gut permeability (Fig. 2). Prebiotics and probiotics and dietary
intervention with certain whole foods have shown some promise for
this respect [229].
5.1.1. Probiotic administration to reverse chronic systemic inflammation
associated to AID
Probiotics are “live microorganisms which when administered in ade-
quate amounts confer a health benefit on the host” [230]. Probiotic spe-
cies, mainly lactobacilli and bifidobacteria, have been shown to possess
properties which protect the intestinal barrier by targeting different
components of the mucosa [231,232] and by inhibiting pro-
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Journal of Autoimmunity xxx (xxxx) xxx–xxx
inflammatory signaling pathways [233–237].
Evidence mainly from animal studies suggests effects of probiotics
in regulation of EAE via IL-10 expansion [67,238–242]. Oral adminis-
tration of a mixture of L. paracasei DSM 13434, L. plantarum DSM 15312
and DSM 15313 suppressed established EAE disease [239]. The treat-
ment resulted in IL-10-dependent activation of Tregs in gut-related
lymphoid organs as well as the central nervous system, followed by a
concomitant reduction of immune cells promoting and inducing the
production of TNF-α, IFN-γ and IL-17 [239]. Treatment with Pedio-
coccus acidolactici R037 [241], Bifidobacterium animalis (a strain by
Numico Research, NL) [240], and Bifidobacterium animalis PTCC 1631 –
alone or in combination with L. plantarum A7 - [243] improved central
nervous system inflammation through the induction of Treg cells in the
gut mucosa by promoting the secretion of transforming growth factor-β,
and inducing decreased Th1/Th17 inflammatory subsets
[240,241,244]. Similarly, a probiotic mixture consisting of Lactobacillus
casei, Lactobacillus acidophilus, Lactobacillus reuteni, Bifidobacterium bi-
fidum, and Streptococcus thermophilus (Korea Yakult Co) has been shown
to prevent EAE, delay disease onset and reduce the infiltration of in-
flammatory cells into the CNS [244]. Furthermore, oral treatment with
capsular polysaccharide A, derived from commensal Bacteroides species,
protects mice against EAE through the induction of regulatory CD39+ T
cells and Tregs [238,245]. B. fragilis and Lactobacillus rhamnosus have
also been shown to interact directly with neurons in the enteric nervous
system affecting their function [246]. A randomized double‐blind pla-
cebo‐controlled clinical trial analyzed the effect of the intake of a
probiotic supplementation containing L. acidophilus, L. casei, L. fer-
mentum and Bifidobacterium bifidum for 12 weeks in 60 MS patients. The
study indicated that probiotic administration improved Expanded Dis-
ability Status Score, insulin resistance and decrease the levels of in-
flammatory markers in MS patients [247]. T1D pathogenesis appears to
be responsive to dietary intervention early in life in some animal
models. Formula feeding during the neonatal period accelerates the
development of T1D in BBD prone rats through regulation of Treg cells
and anti-inflammatory cytokines [248]. The administration of a hy-
drolyzed casein diet [249] or antibiotics [250,251] accelerates disease
development. Furthermore, a reduced abundance of lactobacilli and
bifidobacteria has been associated with onset and progression of T1D
[154]. Lai et al. (2009) showed that Lactobacillus strains with cinnamoyl
esterase activity, namely L. johnsonii N6.2 and L. reuteri TD1, were
negatively correlated with T1D development [252]. This led to the in-
vestigation of the potential use of L. johnsonii N6.2 in the treatment of
T1D [253]. The administration of L. johnsonii isolated from BB-D re-
sistant rats delayed or inhibited the onset of T1D in T1D-prone rats. In
particular, L. johnsonii N6.2 induced changes in ileal microbiota, de-
creased oxidative response of the intestinal mucosal and reduced in-
flammation by inhibiting IFN-γ production. L. johnsonii N6.2 adminis-
tration also resulted in higher levels of interephitelial junction proteins
boosting intestinal integrity [253]. In a recent study in NOD mice, oral
administration of a the probiotic VSL#3- which consists of a mixture of
L. casei, L. plantarum, L. acidophilus, L. delbrueckii subsp. bulgaricus), B.
longum, B. breve and B. infantis and Streptococcus salivarius subsp. ther-
mophilus - protects mice from T1D by suppressing IL-1β expression and
the release of immunomodulatory indoleamine 2,3-dioxygenase (IDO)
and by promoting the differentiation of gut tolerogenic DCs reducing
differentiation/expansion of Th1 and Th17 cells in the intestinal mu-
cosa and at the sites of autoimmunity [254]. Moreover, the effect of
early exposure of probiotics on T1D onset and progression has also been
studied in humans [255]. Use of probiotics supplemented though diet
or taken in infant formula has been recorded in the large “The en-
vironmental Determinants of Diabetes in the Young” (TEDDY) cohort,
encompassing 8676 children at increased risk of T1D. Early probiotic
supplementation, within the first 27 days of life, was associated with a
decreased risk of islet autoimmunity when compared with probiotic
supplementation after 27 days or no supplementation [255].
In a lupus-like animal model, restoring Lactobacillus spp. by
L. Rizzetto et al.
Fig. 2. Proposed intervention for gut dysbiosis recovery and schematic model on how diet could contribute to chronic inflammation. Diet induces changes
to gut microbiota, and reduces the production of BAs and SCFAs, leading to impaired signaling activation, epigenetic transcriptional changes and resulting in
alteration of gut homeostasis, Treg activity and immune homeostasis. Therapeutic targeting gut dysbiosis can be approached by a direct manipulation of the
microbiota through antibiotic administration or faecal transplantation or by promoting growth of beneficial bacteria by dietary administration of prebiotic or
probiotic or by consuming high fiber diet.
administration of retinoic acid improved lupus symptoms, and sug-
gesting the use of lactobacilli as a probiotic to diminish inflammation in
patients with SLE [202]. In this context, a 3-weeks oral administration
of a mixture of 5 lactobacilli, namely L. oris F043, L. rhamnosus LMS201,
L. reuteri CF48-3A, L. johnsonii 135-1-CHN and L. gasseri JV-V03, has
been shown to promote Treg proliferation in the kidney of lupus-prone
MRL/lpr mice [256]. To note, the probiotic administration also im-
proved gut epithelium integrity, and decreased inflammation by de-
creasing gut IL-6 levels and concomitantly increase both gut and cir-
culating IL-10 levels. Modulating the gut microbiota revealed that lupus
nephritis is influenced by gut microbiota in a sex-dependent fashion as
probiotics has been shown to be effective in female and castrated male
mice but not in intact males [256].
Further investigations are warranted focusing on understanding the
molecular and metabolic mechanisms underlying the health effect of
probiotics in ameliorating the chronic systemic inflammation asso-
ciated to AID. Particular focus should be paid on the ability of pro-
biotics to reduce intestinal permeability and whether this reduces the
risk of AID by reducing chronic systemic inflammation in humans.
5.1.2. Prebiotic administration to reverse chronic systemic inflammation
associated to AID
Prebiotics are “non-digestible food ingredient that beneficially affects
the host by selectively stimulating the growth and/or activity of one or a
limited number of bacteria in the colon” [257]. Most common prebiotics
are dietary fibers which specifically target the gut microbiota. They
show promise, at least in animal studies, to modulate inflammatory
processes in AID. Several in vitro and in vivo approaches have shown
that prebiotics can modulate the gut microbial composition towards a
potentially healthier community structure, especially increasing bifi-
dobacteria levels. Prebiotics, especially the inulin-type fructans, have
also been shown to improve the barrier integrity by stimulating the
growth of protective bacteria and the intestinal production of SCFA,
that upregulate epithelial defense mechanisms that protect against in-
testinal inflammation. These bacteria or SCFA restore intestinal barrier
function by enhancing TJ between intestinal epithelial cells and by
increasing mucus production [258]. Prebiotics have also been shown to
decrease the levels of circulating LPS [259,260], whilst increasing GLP-
1 secretion and TJ expression, and reducing chronic low grade in-
flammatory state associated with metabolic endotoxemia. Other dietary
fibers, such as inulin, arabinoxylan, guar gum and citrus fibers, have
been shown to directly increase mucin production, resulting in reduced
intestinal permeability [261]. An increase in sulphomucin production
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Journal of Autoimmunity xxx (xxxx) xxx–xxx
in inulin-fed rats has also been reported [262,263]. Similarly, increased
SCFA production from fermentation of various fibers has been shown to
increase mucin production in the colon of laboratory animals [264].
Mucin is important in the intestine because it fortifies the intestinal
barrier and also provides carbohydrate to members of the gut micro-
biota, and also supports community stability and resilience trough
inter-species metabolic cross-feeding. Some of these microorganisms
especially Akkermansia muciniphila have been shown to impact on im-
mune function by promoting intestinal barrier and by increasing bu-
tyrate levels thus increasing its immuno-modulatory activity
[265–267].
Prebiotics B galactooligosaccharide [268] and short chain fructoo-
ligosaccharides [269] have been shown to inhibit production of pro-
inflammatory cytokines and enhance production of anti-inflammatory
cytokines in animal models. These effects appear, at least in part, to be
mediated by SCFA produced upon prebiotic fermentation.
A study on the TEDDY cohort showed that increasing dietary soluble
fiber intake in early childhood did not decrease the risk of developing
T1D [270]. However, Mariňo et al. (2017) recently showed that spe-
cialized diets containing acetylated or butyrilated starch provided
protection from T1D in the non-obese diabetic mouse model [271].
Compared to controls, both diets promoted a significant reduction of
insulitis and diabetes development, as well as an increase in gut in-
tegrity. The protective effect was augmented when SCFA were provided
combined in the diet. Acetate was particularly effective at decreasing
the proliferation of autoreactive T cells by modulating splenic B cells
expansion, while butyrate was superior in promoting the number and
function of Treg cells [271]. Downregulation of the expression of co-
stimulatory molecules and MHC class I on B cells of non-obese diabetic
mice fed the acetate rich diet correlated with a low frequency of
IGRP+CD8+ T cells and diminished the proliferation of autoreactive
NOD8.3 T cells in vivo. The authors also found that diabetes protection
of MyD88-deficient non-obese diabetic mice housed in SPF condition is
associated with high level concentration of circulating SCFA [271].
Very recently Needell et al. (2017) investigated the ability of maternal
therapy with SCFA to modulate the intestinal microbiota and reverse
virus-induced T1D in LEW. WR1 rat offspring [272]. Administration of
SCFA through drinking water prior to pregnancy and further treatment
of the offspring with SCFA not only decreased the pro-inflammatory
milieu induced by Kilham Rat Virus but also prevented islet auto-
immunity. SCFA administration determined also a modulation of the
gut microbiota, with an increase in the relative abundance of Bacter-
oidetes and a decrease in Firmicutes level. SCFA treatment resulted also
L. Rizzetto et al.
in a reduced abundance of Clostridium and Bifidobacterium compared
with rats infected by the virus only [272]. The effect of SCFAs admin-
istration in MS has been recently investigated in the EAE mice model
[220,273]. Oral administration of SCFA suppressed EAE progression by
inhibiting lymphocyte-mediated systemic inflammation [273]. In par-
ticular butyrate treatment promoted Treg expansion and decreased Th1
cells, even though a slight increase of Th17 was observed as previously
reported [220,274]. Similarly, oral administration of propionate re-
sulted in an increase of Treg and IL-10 production [220].
Overall, by changing microbiota profiles and impacting on immune
function through increased/changed levels of SCFA [275], prebiotics
hold the promise as a not invasive strategy for treating AID. Further
investigations should follow for translating the evidence collected in
animal studies in controlled randomized human trial.
5.1.3. BA as potential immunosuppressant in AID therapy
Circulating BA pool is also strongly dependant on the profile of BA-
converting bacteria. Therefore, microbiota modulation through the diet
might be exploited to modulate microbially-driven changes in BA pool
both in terms of BA chemical structures and in circulating concentra-
tions of BA (Box 2).
BA-based therapies are efficacious to treat chronic diseases with a
strong inflammatory component and have so far focused on hydro-
philic, less toxic BA or synthetic potent agonists, some of which acting
as dual FXR and TGR5 ligands. Among the natural ligands, urso-
deoxycholic acid is regarded as a minor secondary BA as it is formed by
7β-epimerization of chenodeoxycholic acid by the intestinal micro-
biota. The portion of ursodeoxycholic acid in the human total BA pool is
less than 3% [276]. Chenodeoxycholic acid also has im-
munosuppressive properties, inhibiting lymphocyte proliferation to
mitogens, suppressing IL-1β, IL-6, TNF-α and IFN-γ production from
mononuclear cells [277,278].
In the context of AID, the immunosuppressive effects of urso-
deoxycholic acid and chenodeoxycholic acid were investigated in F1
mouse model of SLE [279]. Chenodeoxycholic acid, but not urso-
deoxycholic acid, delayed development of autoimmune glomerulone-
phritis and prolonged the life span of lupus-prone mice. chenodeoxy-
cholic acid treated mice showed also a significantly lower serum IFN-γ
concentration, revealing an immuno-suppressive activity of this bile
acid [279]. Ho and Steinman treated orally EAE mice with obeticholic
acid (OCA, also referred as 6-ethyl-chenodeoxycholic acid, 6-ECDCA) -
asynthetic FXR agonist having more affinity to FXR than its natural
ligand chenodeoxycholic acid [280] - known to improve lamina propria
permeability and chronic inflammation associated with IBD [123] and
attenuate intestinal ischemia reperfusion injury in rats [281], and with
the natural FXR ligand, the BA CDCA. OCA inhibited both active and
passive EAE more effectively than chenodeoxycholic acid, by reducing
IFN-γ production and modulating both T and B cell trafficking and
checkpoint inhibitors. Nevertheless, human patients receiving experi-
mental OCA therapy have been observed to exhibit side effects, devel-
oping severe skin itching and showing an increase in total cholesterol,
LDL cholesterol and insulin, conferring an increased risk of develop-
ment of atherosclerosis. Thus, treatment of MS through the BA-FXR
interaction needs further investigation before transfer to clinical prac-
tice [282]. Interfering with the BA-TGR5 interaction has also been
shown to be effective in amelioration of MS-associated inflammation
[119]. Furthermore, Lewis at al. showed that the TGR5 synthetic ago-
nist BIX02694 was able to alter cytokine production in response to LPS
activation in vivo and reduced EAE severity by decreasing monocytes
and microglia activity and reducing the numbers of central nervous
system infiltrating monocytes and T cells. This results in the EAE model
are consistent with a report that oleanolic acid, a TGR5/FXR agonist,
can reduce disease severity in EAE by impacting myeloid cell activation
and pro-inflammatory cytokine and chemokine production [120]. Si-
milarly, McMahan et al. [127] demonstrated that a dual TGR5/FXR
agonist increased the proportion of Ly6C-low monocytes and increased
13
Journal of Autoimmunity xxx (xxxx) xxx–xxx
the proportion of genes associated with activation of macrophage to-
wards an anti-inflammatory phenotype.
In summary, the broad immuno-metabolic actions of BA-activated
receptors hold considerable promise in the development of pharma-
ceuticals or nutraceuticals capable of tackling inflammation in an au-
toimmune setting (Fig. 2). While BA are synthesized within the liver,
the significant diversity of the bile acid pool is ultimately generated by
the gut microbiota (Box 2). Thus, alteration of the gut microbiota will
influence the signaling properties of the BA pool in the host, de-
termining health or disease.
5.1.4. Diet and sex-dependent effects
Recent data show sex-specific impact of diet on the gut microbiota,
and the apparent sex-specific nature of gut microbiota modulation of
host health [46]. In particular, the impact of diet on the gut microbiota
has been shown to be different in males versus females. For example,
Lactobacillus, Alistipes, Lachnospiraceae and Clostridium were more
abundant in males fed a high-fat rather than chow diet, whereas in
females these genera were less abundant in high-fat diets [46]. Kar-
unasena et al. [283] monitored the response to the probiotic Lactoba-
cillus animalis NP-51 in male and female mice infected with the pa-
thogen Mycobacterium avium sub. paratuberculosis, a model of IBD. The
authors discovered that probiotic was able to repress Mycobacterium-
driven inflammation in female mice, but not in male mice [283]. They
showed that, regardless of treatment, differences in the pro-in-
flammatory cytokines level existed between male and female animals
and also at a metabolite level [284]. M. avium sub. paratubercolosis lead
to an increase in SCFA, especially butyrate and acetate, and xylose in
males and greater increases in o-phosphocholine or histidine in female
colon tissues. This was accompanied by an increased abundance of
Staphylococcus and Roseburia in female mice, even though these two
genera were found over-represented in females regardless of treatment.
Interestingly, animals maintained on a diet with the probiotics de-
monstrated no difference in Lactobacillus species, while after probiotic
and synbiotic treatments, Lactobacillus species were found in greater
numbers in female colonic tissues [284]. Indeed, it appears that sex and
diet interactively control microbiota composition, highlighting the need
to identify and explain how this interplay occurs, how they relate to the
immune response and the underlying molecular basis of this response.
5.2. Fecal microbiota transplantation for restoring gut microbiota
functionality
Restoring microbial health by transplanting a foreign gut microbiota
has received much medical attention drawn by the success in treating
recurrent Clostridium difficile associated diarrhea [285,286]. Whole
fecal microbiota transplantation (FMT, Fig. 2) is being investigated for
the management of both intestinal and extra-intestinal disorders asso-
ciated with a microbiota dysbiosis. Theoretically, FMT increases gut
microbiota diversity, altered microbial metabolism, i.e. SCFA produc-
tion and bile acid biotransformation, thus limiting gut permeability and
reducing local and systemic inflammation [287]. FMT has also been
demonstrated to be durable, mostly safe and carry relative few side
effects [288,289]. FMT has shown some effects in IBD patients
[290–292] and other gastro-intestinal disorders, such as irritable bowel
syndrome and pouchitis as recently reviewed [293,294]. Currently the
studies investigating the potential of FMT therapy include case reports,
case series, but few controlled randomized trial and cohort studies. One
Crohn's disease patient, previously failing immunosuppressant therapy,
showed remission of colitis after a single FMT infusion [295]. A ran-
domized controlled clinical trial showed that 6-weeks FMT treatment
(once a week) induces remission in a significantly greater percentage of
patients with active UC than placebo (9 patients vs 2 patients, out of 70
completing the study) [296].
Some evidence exists on the efficacy of FMT in the treatment of
extra-intestinal disorders [212,293,297]. A case report study on a
L. Rizzetto et al.
hepatic encephalopathy patient showed that after a 4 weeks FMT
treatment his mental status returned to baseline, suggesting the efficacy
of FMT in ameliorating hepatic encephalopathy [298]. A recent clinical
trial [299] evaluated a modified FMT protocol, termed Microbiota
Transfer Therapy (MTT), to resolve symptoms associated with autism in
children. A 7–8 weeks MTT treatment resulted in 82% reduction in
gastrointestinal symptoms, e.g. constipation, diarrhea, indigestion, ab-
dominal pain. This effect was maintained after eight weeks of cessation
of therapy.
Only few studies have so far demonstrated the impact of FMT in
ameliorating AID associated symptoms. A case series study showed an
improvement in the neurological symptoms and quality of life of three
MS patients after FMT for chronic constipation [300]. Disease pro-
gression was also halted in one of those patients [300]. A phase I/II
clinical trial evaluating the efficacy and safety of FMT in treating
cholestatic liver disease in ongoing [301]. FMT has been shown success
in two men affected by alopecia areata, an AID causing hair loss [302].
The effect of FMT on T1D development was investigated in Non obese
diabetic mice showing that short-term oral transfer of fecal bacteria,
from different diabetes resistant mouse strains into diabetes-prone mice
delayed the onset of T1D [156].
Thus, despite preliminary indications of the potential efficacy of
FMT in improving AID associated with gut dysbiosis, randomized
controlled trials on large population should be performed to determine
the effectiveness of the therapy. Furthermore, FMT approaches are
probably unsuitable at present for AID prevention trials because of the
problems of standardizing stool composition that could include com-
municable pathogens as well as current clinical investigation highlight
the importance of choosing the right donor to have the expected results.
6. Conclusions
AID is a constellation of chronic, debilitating, often severe and fatal
immune related diseases affecting about 10% of the population and is
rapidly increasing in incidence wherever Western diet and modern life-
style prevail. For many patients, treatments are ineffective and they
often present with serious co-morbidities. Genetic and environmental
triggers have long been considered as the main drivers of auto-
immunity. Increasing evidence in recent years suggests that microbial
translocation, and the consequent immunological homeostasis disrup-
tion are important environmental factors involved in AID manifestation
and development.
The clinical impact of microbiota dysbiosis is not completely un-
derstood and whether dysbiosis precedes AID manifestation or whether
the disease itself alters microbiota composition and function, remains to
be fully elucidated. The discovery of specific activating and inhibitory
receptors triggered by the microbiota and its metabolites and engaged
in autoimmunity also suggests a strong microbiota-autoimmunity con-
nection. This microbiota connection has been strengthened by the re-
cent suggestions of a tight reciprocal regulation between immune
functions, sexual hormones and microbiota composition. Future ad-
vances could be achieved by specific efforts to go beyond mere corre-
lation and description of changes in microbiota composition at phylum,
genus or even species levels, towards metabolic functionality. Gut mi-
crobiota members in fact, do not function as single isolated individuals
and gut microbiota activities are exerted in concert and synergistically
with a high degree of cooperation between different bacterial compo-
nents therein, as a whole (Box 1 and 2). Given the observed connections
between gut microbiota composition and metabolic output and AID, the
potential use of dietary interventions designed to correct the im-
munological defects contributing to AID progression may hold promise.
Dietary manipulation of microbial composition on relative abundance
within the gut has the potential to radically resolve chronic unchecked
inflammation by changing the metabolic activity of the gut microbiota.
SCFA and BA have been shown to influence host metabolic function,
integrity of the intestinal epithelium and also the immune system both
14
Journal of Autoimmunity xxx (xxxx) xxx–xxx
within the gut and at other body sites. Boosting beneficial bacterial
metabolites, including SCFAs and BA, using prebiotics and/or probio-
tics or by incorporating them into the diet seems to be a very attractive
strategy. At least in animal studies such approaches have been shown to
downregulate pro-inflammatory mediators and increase the number of
Treg cells, which is particularly important for T-cell mediated AID.
However, although most studies suggest that SCFAs and BA receptor
agonisms ameliorate chronic inflammation associated to AID, caution is
needed, as such metabolites could also exacerbate some autoimmune
disorders, as observed in mice antibody induced-arthritis, where SCFA
administration increased cellular infiltration and cartilage and bone
destruction [273]. Dietary microbiota modulation might also account
for why diet apparently affects male and female differently, potentially
requiring dietary intervention studies to be powered to be able to
measure sex effects. In conclusion, several lines of evidence, the ma-
jority of which have been retrieved from animal studies, indicate an
important contribution of the gut microbiota and its metabolites to
immune homeostasis and regulation of intestinal permeability, two
physiological processes thought to be involved in the onset of extra-
intestinal AID. The potential of their manipulation through tailored
dietary interventions as a strategy in reducing the risk of AID at a po-
pulation level may therefore prove a promising preventative strategy.
Use of dietary interventions to treat AID is still in its infancy however,
with few studies showing positive effects.
Conflicts of interest
The authors declare that no conflicts of interest exist.
Funding
This study was funded in part by Accordo di Programma between
Fondazione Edmund Mach (San Michele all’Adige, Italy) and
Autonomous Province of Trento (Trento, Italy); in part by the ERA-
HDHL action project “CABALA_DIETH&HEALTH. CirculAting Bile Acids
as biomarkers of metabolic Health_Linking microbiotA, diet and
Health” (http://www.healthydietforhealthylife.eu/index.php/64-open-
calls/309-cabala-diet-health).
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List of abbreviations
6-ECDCA: 6-ethyl chenodeoxycholic acid
AID: autoimmune disease
BA: bile acid
BB-D: Biobreeding diabetes
BSH: bile salt hydrolase
DC: dendritic cell
L. Rizzetto et al. Journal of Autoimmunity xxx (xxxx) xxx–xxx

EAE: experimental autoimmune encephalomyelitis NK: natural killer

ERα: estrogen receptor α NOD: nucleotide-binding oligomerization domain containing
IBD: inflammatory bowel disease OCA: obeticholic acid
HDAC: histone deacetylase regB: regulatory B cells
Ig: immunoglobulin SCFA: short chain fatty acids
IL: interleukin SFB: segmented filamentous bacteria
FMT: fecal microbiota transplantation SLE: systemic lupus erythematosus
FXR: farnesoid X receptor SPF: specific pathogen free
GPCR: G protein coupled receptor T1D: type 1 diabetes
LPS: lipopolysaccharide Th: T helper cells
MAMPs: microbe-associated molecular patterns TJ: tight junction
MDP: muramyl dipeptide TLR: Toll like receptors
MS: multiple sclerosis Treg: regulatory T cells
NLR: NOD like receptor

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