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Received: 30 January 2025
Revised: 6 March 2025
Accepted: 18 March 2025
Published: 21 March 2025
Citation: Giambra, V.; Caldarelli, M.;
Franza, L.; Rio, P.; Bruno, G.; di Iasio,
S.; Mastrogiovanni, A.; Gasbarrini, A.;
Gambassi, G.; Cianci, R. The Role of
Notch Signaling and Gut Microbiota
in Autoinflammatory Diseases:
Mechanisms and Future Views.
Biomedicines 2025,13, 768.
https://doi.org/10.3390/
biomedicines13040768
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Review
The Role of Notch Signaling and Gut Microbiota in
Autoinflammatory Diseases: Mechanisms and Future Views
Vincenzo Giambra 1,† , Mario Caldarelli 2 ,3 ,† , Laura Franza 3 ,4 ,*, Pierluigi Rio 2,3 , Gaja Bruno 1,
Serena di Iasio 1, Andrea Mastrogiovanni 2,3, Antonio Gasbarrini 2,3, Giovanni Gambassi 2,3
and Rossella Cianci 2,3
1Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione
IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy;
v.giambra@operapadrepio.it (V.G.)
2Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, 00168 Rome, Italy;
mario.caldarelli01@icatt.it (M.C.); giovanni.gambassi@unicatt.it (G.G.); rossella.cianci@unicatt.it (R.C.)
3Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS),
00168 Rome, Italy
4Department of Emergency Medicine, AOU Modena, 41125 Modena, Italy
*Correspondence: cliodnaghfranza@yahoo.it
†These authors contributed equally to this work.
Abstract: Notch signaling is an evolutionarily conserved, multifunctional pathway in-
volved in cell fate determination and immune modulation and contributes to the pathogen-
esis of autoinflammatory diseases. Emerging evidence reveals a bidirectional interaction
between Notch and the gut microbiota (GM), whereby GM composition is capable of
modulating Notch signaling through the binding of microbial elements to Notch receptors,
leading to immune modulation. Furthermore, Notch regulates the GM by promoting
SCFA-producing bacteria while suppressing proinflammatory strains. Beneficial microbes,
such as Lactobacillus and Akkermansia muciniphila, modulate Notch and reduce proinflam-
matory cytokine production (such as IL-6 and TNF-
α
). The interaction between GM and
Notch can either amplify or attenuate inflammatory pathways in inflammatory bowel
diseases (IBDs), Behçet’s disease, and PAPA syndrome. Together, these findings provide
novel therapeutic perspectives for autoinflammatory diseases by targeting the GM via
probiotics or inhibiting Notch signaling. This review focuses on Notch–GM crosstalk and
how GM-based and/or Notch-targeted approaches may modulate immune responses and
promote better clinical outcomes.
Keywords: Notch signaling; autoinflammatory; gut microbiota; prebiotics; immunomodulation
1. Introduction
Discovered over a century ago, the Notch gene was named after the wings of Drosophila
melanogaster, which, in mutants, take on a notched appearance [1].
The Notch gene belongs to the transmembrane receptor family and participates in
one of the most conserved signaling pathways, the Notch signaling pathway, which is
important in intercellular communication and control of cell fate. This pathway regulates
many important biological processes including cell growth and stem cell differentiation
and maintenance during embryonic and adult development [2].
Consequently, abnormalities or dysregulation of Notch signaling are associated with a
wide variety of human diseases, such as developmental anomalies and adult cancers. In
Biomedicines 2025,13, 768 https://doi.org/10.3390/biomedicines13040768
Biomedicines 2025,13, 768 2 of 30
the past years, Notch has been found to regulate innate and adaptive immunity, providing
a basis for Notch-targeted therapeutic approaches in immune disorders [3].
The Notch pathway is at the crossways of innate and adaptive immune systems and
may be implicated in the pathogenesis of autoinflammatory diseases.
Autoinflammatory diseases (AIDs) are a heterogeneous group of diseases, which differ
from autoimmune diseases and are characterized by recurrent episodes of spontaneous,
dysfunctional, non-infectious sterile processes of inflammation [
4
]. Since the initial cloning
of the familial Mediterranean fever gene in 1997, there has been a notable acceleration in
identifying novel AIDs. As of 2022, the International Union of Immunological Societies
reported a total of 485 inborn errors of immunity, many of which exhibit characteristics
typical of autoinflammation [
5
]. The pathophysiology underlying AIDs is inherently
intricate: while certain conditions arise from rare mutations in genes that govern innate
immunity, others are polygenic in nature. In such cases, environmental triggers can
modify disease manifestation in individuals with a genetic predisposition [
6
]. Barriers
to diagnosing AIDs include limited access to advanced genetic testing and long waiting
times for genetic consultations [
7
]. Most physicians have access to panel testing, but this
may not include newly identified genes. One potential solution is research enrollment for
exome/genome sequencing and transcriptomic profiling. Wider availability, as technology
becomes more advanced and cheaper, may reduce diagnostic delays, increase accuracy,
and improve patient outcomes [8].
In 2015, Xu et al. studied the effect of altering Notch signaling on experimentally
induced inflammation using both genetic and pharmacological approaches. These methods
ranged from loss-of-function deletion of pathway components across lymphoid or myeloid
cell divisions to systemic inhibition of all classes of Notch signaling, as well as specific
blockading of certain Notch receptors and ligands [9].
Additionally, in macrophages, Notch signaling intersects with other signaling cascades,
such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-
κ
B) signaling,
in the context of inflammatory responses. Recently, in 2022, Li et al. reported that the
lipopolysaccharide (LPS), a ligand for Toll-like receptor (TLR)-4, could upregulate Notch1
expression in macrophages [
10
]. Notably, TLR4 signaling also promoted Notch target gene
transcription, including Notch1 and hairy and enhancer of split-1 (Hes1), suggesting that
Notch activation in macrophages is upregulated by TLR4 signaling.
Notch activation is known to induce a proinflammatory response, indicating that
pharmacological blockading of this pathway could be a potential therapeutic target for
the treatment of numerous inflammatory diseases [
11
]. These diseases are characterized
by aberrant activation of the immune system that leads to systemic inflammation. Al-
though similar to autoimmune diseases, autoinflammation primarily involves the innate
immune system [12].
The Notch pathway also interacts with the microbiota, which is composed of various
microorganisms living in the body, and it plays a key role in maintaining homeostasis
[13,14].
The microbial community living in the intestine, known as the gut microbiota (GM), has
been thoroughly studied and has been proven to be involved in many different diseases [
15
].
The GM consists of bacteria, viruses, and fungi living in the intestinal lumen [
14
]. Its
composition can vary between individuals and even within the same individual over time.
There are six main phyla (Firmicutes,Bacteroidetes,Actinobacteria,Proteobacteria,Fusobacteria,
and Verrucomicrobia) and their equilibrium has serious consequences on human health [
16
].
In particular, the GM has been shown to modulate the host’s immune system through
different pathways, impacting its development and interacting with both innate and adap-
tive immunity [
17
]. The GM initiates innate intestinal immune responses by activating
pattern recognition receptors (PRRs), releasing cytokines, and promoting the production
Biomedicines 2025,13, 768 3 of 30
of antimicrobial peptides, whereas it contributes to adaptive immunity by influencing the
differentiation of CD4+ T cells, B cells, and cells of the lamina propria [18].
Among its functions, the GM regulates the proliferation and differentiation of intestinal
stem cells (ISCs) through Notch and Wnt pathways via PRRs [19].
An imbalance in the interactions between the GM and immune system may result in
gut dysbiosis, disruption of the intestinal barrier, local and systemic inflammation, and
deregulated immune responses [20].
It has been demonstrated that the Notch pathway can mediate the impact of the GM
on autoinflammation.
For instance, Listeria monocytogenes infection blocks the Notch1/Hes1 pathway, which
stimulates the differentiation of intestinal stem cells into goblet cells and leads to diar-
rhea [
21
]. Similarly, Desulfovibrio vulgaris, which is pathologically upregulated in ulcerative
colitis (UC), induces Notch1 signaling in a TLR4-independent manner [
22
]. Flagellin has
been reported to upregulate Notch1 signaling and induce Intelukin-6 (IL-6) production
through both NF-
κ
B and the recombination signal binding protein for the immunoglobulin
kappa J region (RBP-Jκ) [23].
Conversely, certain beneficial microbes can modulate Notch signaling and promote
intestinal health. For instance, Lactobacillus acidophilus inhibits the Notch1 pathway,
which is beneficial for intestinal mucosal healing, and reduces the loss of goblet cells
in UC induced by Salmonella infection [
24
,
25
]. Similarly, Helicobacter pylori activation of
nucleotide-binding Leucine-rich repeat-containing 12 (NLRP12) suppresses Notch signal-
ing and leads to decreased intestinal epithelial cell production of inflammatory chemokines,
such as monocyte chemoattractant protein-1 (MCP-1) and Macrophage Inflammatory
Proteins-1α(MIP-1α) [26].
This interaction underscores the temporal and cumulative effects of microbial modula-
tion of the Notch pathway on gastrointestinal homeostasis and disease.
This narrative review describes the role of the Notch signaling pathway and GM
in the pathogenesis and modulation of autoinflammatory diseases. It also examines the
potential therapeutic benefits of GM modulation and Notch inhibition, identifies the pro-
biotic and anti-Notch strategies for immune modulation, and explores their impact on
clinical outcomes.
The review was performed based on an electronic literature search of PubMed, MED-
LINE, and Google Scholar, using keywords including “Notch pathway”, “autoinflammatory
diseases”, “inflammation”, and “gut microbiota”. We considered peer-reviewed articles,
including both original and review articles, written in English. We selected articles based
on their relevance to the subject, study design, approach, and sample size, with studies
both on small and large scales. A manual search of articles using references in relevant
articles was also conducted to increase the number of studies included in this review.
2. The Notch Signaling Pathway
Notch signaling is an evolutionarily conserved pathway that controls various develop-
mental and homeostatic processes in metazoans [27].
In mammals, the Notch pathway consists of Notch receptors, ligands, and signaling
effectors [
28
]. In Drosophila melanogaster [
29
], there is one Notch receptor ortholog, Notch1.
Most mammals, however, possess three other Notch receptors: Notch2, Notch3, and Notch4.
Notch receptors are type I transmembrane proteins with three major classes of domains:
the extracellular domain (NECD), the transmembrane domain (TMD), and the intracellular
domain (NICD) [30] (Figure 1).
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Biomedicines 2025, 13, x FOR PEER REVIEW 4 of 34
domains: the extracellular domain (NECD), the transmembrane domain (TMD), and the
intracellular domain (NICD) [30] (Figure 1).
Figure 1. Notch1 receptor includes the extracellular (NECD) and intracellular (NICD) domains. The
NECD consists of 36 epidermal growth factor (EGF)-like repeat and LIN-12/Notch repeat (LNRS)
regions. NECD and NICD are linked by the transmembrane domain (TMD). NICD contains ankyrin
repeats (ANKs), a nuclear localization domain (NLS), transcription activation domain (TAD), and
proline-glutamic acid-serine-threonine (PEST) domain (created with BioRender.com, accessed on 11
October 2024).
NICD include the recombination signal binding protein for the immunoglobulin
kappa J region (RBPJ) association module (RAM) that mediates NICD binding to RBPJ to
activate transcriptional activity; nuclear localization sequences (NLSs) that allow NICD
transport into the nucleus to function as a transcription factor; ankyrin repeats (ANKs)
involved in protein–protein interactions during Notch signaling complex assembly; a
transactivation domain (TAD) that recruits co-activators required to activate the
transcription of target genes; and a conserved proline/glutamic acid/serine/threonine-rich
motif (PEST) that regulates NICD degradation [31].
In humans and mice, five delta-like ligands bind to the extracellular regions of Notch
receptors [32]. The ligands can be divided into serrate-like (Jagged1, JAG1, and Jagged2,
JAG2) and delta-like (DLL1, DLL3, and DLL4) families, depending on the presence of a
cysteine-rich domain [32]. Notch ligands are also transmembrane proteins with structural
resemblance to Notch receptors. JAG1 and JAG2 contain DSL, EGF-like repeats, and
cysteine-rich regions in their extracellular domains. In contrast, DLL1, DLL3, and DLL4
have EGF-like repeats homologous to JAG1 and JAG2 in their extracellular domains but
lack the cysteine-rich region [33].
The Notch signaling pathways are divided into canonical and non-canonical
pathways.
The canonical pathway plays a significant role in cell fate determination and
intercellular communication, regulating embryonic development, tissue differentiation,
Figure 1. Notch1 receptor includes the extracellular (NECD) and intracellular (NICD) domains. The
NECD consists of 36 epidermal growth factor (EGF)-like repeat and LIN-12/Notch repeat (LNRS)
regions. NECD and NICD are linked by the transmembrane domain (TMD). NICD contains ankyrin
repeats (ANKs), a nuclear localization domain (NLS), transcription activation domain (TAD), and
proline-glutamic acid-serine-threonine (PEST) domain (created with BioRender.com, accessed on
11 October 2024).
NICD include the recombination signal binding protein for the immunoglobulin kappa
J region (RBPJ) association module (RAM) that mediates NICD binding to RBPJ to activate
transcriptional activity; nuclear localization sequences (NLSs) that allow NICD transport
into the nucleus to function as a transcription factor; ankyrin repeats (ANKs) involved in
protein–protein interactions during Notch signaling complex assembly; a transactivation
domain (TAD) that recruits co-activators required to activate the transcription of target
genes; and a conserved proline/glutamic acid/serine/threonine-rich motif (PEST) that
regulates NICD degradation [31].
In humans and mice, five delta-like ligands bind to the extracellular regions of Notch
receptors [
32
]. The ligands can be divided into serrate-like (Jagged1, JAG1, and Jagged2,
JAG2) and delta-like (DLL1, DLL3, and DLL4) families, depending on the presence of a
cysteine-rich domain [
32
]. Notch ligands are also transmembrane proteins with structural
resemblance to Notch receptors. JAG1 and JAG2 contain DSL, EGF-like repeats, and
cysteine-rich regions in their extracellular domains. In contrast, DLL1, DLL3, and DLL4
have EGF-like repeats homologous to JAG1 and JAG2 in their extracellular domains but
lack the cysteine-rich region [33].
The Notch signaling pathways are divided into canonical and non-canonical pathways.
The canonical pathway plays a significant role in cell fate determination and intercel-
lular communication, regulating embryonic development, tissue differentiation, and gene
regulation, as well as contributing to both benign and malignant diseases [34]. The Notch
signaling pathway involves multiple steps for the maturation and activation of Notch
proteins [35] (Figure 2).
Biomedicines 2025,13, 768 5 of 30
Biomedicines 2025, 13, x FOR PEER REVIEW 5 of 34
and gene regulation, as well as contributing to both benign and malignant diseases [34].
The Notch signaling pathway involves multiple steps for the maturation and activation
of Notch proteins [35] (Figure 2).
Figure 2. Notch1 pathway. Notch1 ligand (DLL, JAG) on the sending cell (Signal Sending Cell). The
Notch1 receptor is activated on the receiving cell (Signal Receiving Cell), undergoes endocytosis,
and is processed by ADAM metalloprotease and γ-Secretase. The release of NICD into the
cytoplasm allows it to translocate into the nucleus where it binds to CSL, MAML, and co-factors to
modulate the expression of Notch1 target genes (i.e., HES4, DTX1, MYC) in cooperation with other
transcriptional regulators. FBXW7 and PEST mediate NICD degradation .
Activation progresses from the Golgi apparatus to the cell membrane, where Notch
proteins change from single-chain precursors to functional proteins. In response to
stimulation by ligands, Notch receptors are activated and associate with the DNA-bound
centromere binding factor-1 (CBF1) and the Suppressor of Hairless, Lag-1 (CSL) co-
repressor complex to initiate the transcription of downstream target genes [36]. In the
Figure 3, we report the steps of the Notch activation process.
Figure 2. Notch1 pathway. Notch1 ligand (DLL, JAG) on the sending cell (Signal Sending Cell). The
Notch1 receptor is activated on the receiving cell (Signal Receiving Cell), undergoes endocytosis, and
is processed by ADAM metalloprotease and
γ
-Secretase. The release of NICD into the cytoplasm
allows it to translocate into the nucleus where it binds to CSL, MAML, and co-factors to modulate the
expression of Notch1 target genes (i.e., HES4, DTX1, MYC) in cooperation with other transcriptional
regulators. FBXW7 and PEST mediate NICD degradation.
Activation progresses from the Golgi apparatus to the cell membrane, where Notch pro-
teins change from single-chain precursors to functional proteins. In response to stimulation
by ligands, Notch receptors are activated and associate with the DNA-bound centromere
binding factor-1 (CBF1) and the Suppressor of Hairless, Lag-1 (CSL) co-repressor complex
to initiate the transcription of downstream target genes [
36
]. In the Figure 3, we report the
steps of the Notch activation process.
Biomedicines 2025,13, 768 6 of 30
Biomedicines 2025,13, x FOR PEER REVIEW 6of 34
Figure 3. In the flowchart, the various steps of the Notch activation process are reported.
In particular, S1 cleavage occurs at the Golgi apparatus, producing a heterodimeric
receptor [37] and, when ligands bind to the cell surface, they induce cleavage at the S2 site
by disintegrins and metalloproteinases, thus freeing a component (TMD + NICD) known
as NeXT [38]. At the S3 site, γ-secretase cleaves NeXT, releasing the NICD. The NICD
moves into the nucleus, where it forms a complex with CSL and co-activator proteins,
with a subsequent change into a co-activator complex [27]. This shift promotes the
expression of Notch target genes, whereas, in the absence of NICD, CSL represses gene
expression [39].
Non-canonical Notch signaling modulates other pathways, such as Wingless
(WNT)/β-catenin, Janus Kinase/Signal Transducer and Activator of Transcription
(JAK/STAT), Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT), and NF-κB
through post-translational mechanisms [40]. In malignancy, non-canonical Notch
activation has been associated with cell proliferation, apoptosis regulation, and tumor
vascularization [41].
Research has associated the Notch signaling pathway with some inflammatory
mediators. For instance, Jundt et al., in 2004, demonstrated that increased Jagged1,
Notch1, and Notch2 levels correlate with myeloma progression [42]. Furthermore, there
is evidence that Notch has an activating role in proliferative signals mediated by IL-6 in
the bone marrow niche, leading to enhanced tumor growth [43].
Using a murine model for pancreatic cancer, Maniati et al. observed that the
combination of tumor necrosis factor (TNF)-α, basal Notch signaling, and IκB kinase 2—
a component of the NF-κB pathway—suppresses the nuclear receptor peroxisome
proliferator-activated receptor gamma (Pparg) [44]. Pparg is repressed by Hes1, which
upregulates the inflammatory activity of pancreatic tumor cells in an autocrine manner,
releasing inflammatory mediators, such as TNF-α, IL-6, and IL-1β. This process induces a
positive feedback loop, which further drives the advancement of pancreatic cancer via
Notch pathway activation [44].
Figure 3. In the flowchart, the various steps of the Notch activation process are reported.
In particular, S1 cleavage occurs at the Golgi apparatus, producing a heterodimeric
receptor [
37
] and, when ligands bind to the cell surface, they induce cleavage at the S2 site
by disintegrins and metalloproteinases, thus freeing a component (TMD + NICD) known
as NeXT [
38
]. At the S3 site,
γ
-secretase cleaves NeXT, releasing the NICD. The NICD
moves into the nucleus, where it forms a complex with CSL and co-activator proteins, with
a subsequent change into a co-activator complex [
27
]. This shift promotes the expression of
Notch target genes, whereas, in the absence of NICD, CSL represses gene expression [39].
Non-canonical Notch signaling modulates other pathways, such as Wingless (WNT)/
β
-
catenin, Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), Phos-
phoinositide 3-Kinase/Protein Kinase B (PI3K/AKT), and NF-
κ
B through post-translational
mechanisms [
40
]. In malignancy, non-canonical Notch activation has been associated with
cell proliferation, apoptosis regulation, and tumor vascularization [41].
Research has associated the Notch signaling pathway with some inflammatory media-
tors. For instance, Jundt et al., in 2004, demonstrated that increased Jagged1, Notch1, and
Notch2 levels correlate with myeloma progression [
42
]. Furthermore, there is evidence that
Notch has an activating role in proliferative signals mediated by IL-6 in the bone marrow
niche, leading to enhanced tumor growth [43].
Using a murine model for pancreatic cancer, Maniati et al. observed that the combi-
nation of tumor necrosis factor (TNF)-
α
, basal Notch signaling, and I
κ
B kinase 2—a com-
ponent of the NF-
κ
B pathway—suppresses the nuclear receptor peroxisome proliferator-
activated receptor gamma (Pparg) [
44
]. Pparg is repressed by Hes1, which upregulates
the inflammatory activity of pancreatic tumor cells in an autocrine manner, releasing
inflammatory mediators, such as TNF-
α
, IL-6, and IL-1
β
. This process induces a posi-
tive feedback loop, which further drives the advancement of pancreatic cancer via Notch
pathway activation [44].
Notch signaling is essential for sustaining stem cell features and directing cell fate in
the intestinal mucosa, while homeostasis is maintained by the balance of epithelial-derived
cells. Endogenous Notch activation promotes epithelial repair after inflammatory stress [
45
].
A study by Kim et al. showed that, in a murine model, Notch activation suppressed intesti-
nal adenoma progression, indicating that Notch may have a tumor suppressor role. These
results underline the potential role of Notch signaling in the intestinal microenvironment
as a mechanism for tissue repair and cancer prevention [
46
]. Several studies have also
Biomedicines 2025,13, 768 7 of 30
reported the cooperation between the WNT and Notch pathways in chronic inflammatory
contexts, such as colitis-associated tumorigenesis [
47
]. Taniguchi et al. discovered that the
co-receptor gp130 activates Yes-Associated Protein and Notch to promote epithelial cell
proliferation, providing a new connection between Notch and inflammation [48].
Notch signaling is also modulated in the immune cells, including macrophages, which
contribute to carcinogenesis [
49
]. Macrophage polarization (classically activated, M1, versus
alternatively activated, M2) is dependent on environmental signals and is important for
the relationship between Notch and inflammatory pathways in cancer development [50].
M1 macrophages respond to microbial stimuli from the TLR pathway by upregulating
inflammatory mediators, whereas M2 macrophages express fewer inflammatory factors
and play a role in host defense and the resolution of inflammation. Inflammatory mediators
vary with disease progression: during the shift from acute to chronic colitis, there is a
transition from Th1-Th17 cytokines to a Th2-mediated inflammatory response [51].
Different macrophage functional phenotypes are associated with Notch activation. A
study by Outz et al. showed that Notch1 deficiency in macrophages alters the expression
of vascular endothelial growth factor receptor-1 (VEGFR-1) and inflammatory cytokines
including TNF-
α
, ultimately resulting in decreased inflammation during the process of
wound healing [
52
]. Furthermore, Notch1 contributes to M1 polarization via the RBP-J-
TLR4-IRF8 axis [53].
In 2015, Kueanjinda et al. identified a new function for the protein Numb, a negative
regulator of Notch1 signaling, in amplifying the production of proinflammatory cytokines,
including TNF-
α
, IL-6, and IL-12 by macrophages [
54
]. Notably, in the bone marrow, per-
sistent Notch activation due to Numb loss did not interfere with monocyte differentiation
into macrophages [54].
Notch signaling also contributes markedly to inflammation in several pathological
conditions where specific receptors and ligands interact with effector inflammatory cells
and/or endothelial cells [
55
,
56
]. Emerging evidence indicates that Notch signaling is closely
associated with inflammatory responses. This interaction is mainly mediated in immune
cells by the direct functional role of Notch in several critical cellular processes [55].
Notch-related signaling has been shown to play a role in inflammatory responses
and, given the multitude of AIDs, understanding how Notch signaling interacts with these
diverse immune disorders is critical.
Altered immune responses with multi-organ involvement and resulting tissue dam-
age are hallmarks of AIDs. This injury is linked to hazard cues, including non-microbial
damage-associated molecular patterns (DAMPs) and microbial pathogen-associated molec-
ular patterns (PAMPs), perceived by PRRs. The receptors that belong to this category are
TLRs and nucleotide-binding oligomerization domain-containing (NOD)-like receptors
(NLRs). These receptors initiate an inflammatory response by inducing the release of proin-
flammatory cytokines, mainly from innate immune cells, including neutrophils, monocytes,
macrophages, and mast cells, upon ligation [57].
Furthermore, some AIDs are recognized as IL-1-mediated diseases and can be effec-
tively treated by anti-IL-1 agents, suggesting that targeted therapeutics could be successful
in managing these diseases [
58
]. Hyperactivation of the innate immune system and uncon-
trolled production of proinflammatory cytokines (IL-1
β
, IL-18, TNF, type-1 interferons) are
characteristic features of autoinflammation [
59
]. The NLR family pyrin domain-containing
3 (NLRP3) inflammasome, an intracellular molecular sensor that stimulates inflammation
and causes programmed cell death, can release IL-1
β
and IL-18. Nuclear factor-kB (NF-kB)
signaling is another major pathway involved in autoinflammation [
60
]. This pathway
is governed by multiple post-translational mechanisms and is essential for triggering in-
Biomedicines 2025,13, 768 8 of 30
flammation by enhancing the expression of proinflammatory chemokines and cytokines,
including IL-1, IL-6, and TNF, as well as by modulating inflammasome signaling [61].
As previously discussed, Notch signaling interacts bidirectionally with the GM: on
the one hand its composition can influence the Notch pathway, while on the other, Notch
signaling can drive shifts in GM composition [
62
]. In the following sections, we will
discuss GM composition and its complex crosstalk with Notch signaling in the context of
autoinflammatory diseases.
3. Gut Microbiota and Autoinflammatory Diseases
The GM has both a direct and indirect effect on immune function: a healthy GM, for
instance, helps maintain a healthy gut barrier, preserving the normal mucus layer, as in the
case of Akkermansia muciniphila, or avoiding colonization from harmful pathogens, which
has also been associated with Akkermansia muciniphila, but also with Escherichia coli H22. The
mechanism through which Akkermansia muciniphila is able to prevent dysbiosis is linked
to its ability to produce short chain fatty acids (SCFAs), which in turn are also linked to
metabolic health and direct immune modulation [
63
]. Other bacteria producing SCFAs have
indeed also been associated with health benefits: Bifidobacterium, for instance, promotes
both immune system maturation and the integrity of the intestinal barrier, similarly to
Lactobacillus,Bacteroides, and other strands [64].
The role of the GM on the innate immune system is highly relevant in the context of
autoinflammatory diseases [
65
,
66
]. Research has focused on the relationship between GM
and autoinflammatory conditions, uncovering various underlying mechanisms [67].
Notably, the interaction between the innate immune system and the GM is particularly
complex [
68
]: the GM is capable of influencing TLR signaling, the myeloid differentiation
primary response protein (MyD88), tumor necrosis factor (TNF), receptor-associated factor
6 (TRAF6) and NF-
κ
B essential regulator (NEMO), receptor-interacting serine/threonine-
protein kinase 1 (RIPK1), FAS-associated death domain protein (FADD) and caspase-8,
and NOD-containing protein 2 (NOD2) through interaction with the epithelial cells of
the intestine [
69
]. The GM is also responsible for the maturation of myeloid cells and of
macrophages. For instance, in a study by Erny et al., it was observed that microglia in
germ-free mice present numerous defects and do not develop correctly [
70
]. The GM also
has an effect on innate lymphoid cells. While it does not appear to affect their development,
innate lymphoid cells fail to function correctly in the absence of commensal microorgan-
isms [
71
]. Additionally, a healthy GM has been linked to the proper monocyte functions.
For instance, it was observed that GM modulation, promoting the presence of Akkerman-
sia muciniphila, can increase monocyte IFN-I production in the context of cancer [
71
,
72
].
Neutrophils are another component of the innate immune system which has a complex
crosstalk with the GM: they are influenced in their development and function and, on
the other hand, they contain the GM population [
73
]. In particular, components of the
GM can promote the proinflammatory activity of neutrophils, through the activation of
the TLR-Myd88 pathway; on the other hand, SCFAs exhibit the capacity to inhibit their
overactivation [
73
]. Neutrophils produce IL-1
β
, a crucial player in AIDs, and the GM can
also modulate this aspect of neutrophil activity: in murine models, the development of
IL-1
β
is impacted by the GM and can be modulated through the diet [
74
]. GM modulation
has proven to offer some potential in AIDs also through other methods, such as fecal
microbiota transplantation [75].
The importance of the GM in the pathophysiology of autoinflammatory disorders
has been extensively studied. In a study by Manukian et al., individuals with familial
Mediterranean fever exhibited high levels of circulating antibodies against different GM
components, particularly Bacteroides,Parabacteroides,Escherichia,Enteroccocus, and Lacto-
Biomedicines 2025,13, 768 9 of 30
baccilus [
76
]. It is worth noting that Enterobacter,Klebsiella, and Ruminococcus gnavus were
found to be elevated in this group of patients and these bacteria taxa have all been linked
to increased inflammation. However, when patients were treated with colchicine, their
GM composition changed in favor of taxa with anti-inflammatory properties, such as
Faecalibacterium and Roseburia [77].
The inflammasome has become one of the key players in the pathogenesis of AIDs [
78
].
Dysregulation of inflammasome function has been recognized as a crucial element
in AID pathogenesis. Inflammasomes are specialized intracellular sensors that respond
to a variety of stress signals and pathogens. Studies have demonstrated that GM changes
can modulate inflammasomes, specifically the NLRP3 inflammasome. In murine models,
dietary modifications reduce the activity of the NLRP3 inflammasome. These data imply
that dietary interventions could modulate inflammasomes and inflammatory processes
related to AIDs [74].
CD103
+
dendric cells, as well as IL-17-producing
γδ
T cells, are promoted by the GM
and are influenced by GM composition during differentiation. These
γδ
T cells play a role
in the pathophysiology of autoinflammatory diseases (AIDs). Research in murine models
has demonstrated that dysbiosis can impair CD103
+
dendritic cells and subsequently alter
the activation of IL-17-producing γδT cells [79].
As discussed above, AIDs are characterized by the activation of the innate immune
system and the Notch pathway acts at the intersection of the adaptive and innate immune
system [
80
]. The GM has been shown to modulate Notch signaling through the MyD88
pathway in zebrafish [
74
]. Conversely, Notch signaling has been shown to influence GM
composition, particularly by reducing proinflammatory bacteria, such as Enterococcus and
Escherichia-Shigella, while promoting the presence of SCFA-producing bacteria [
81
]. In the
following section, we will explore the role of the Notch pathway in autoinflammatory
diseases and the potential mediating role of the GM.
4. Notch Pathway, Gut Microbiota, and Autoinflammation
Recent evidence has linked Notch signaling to both innate immunity and inflammation.
Active Notch signaling has been detected in various inflammatory diseases, such as rheuma-
toid arthritis, systemic lupus erythematosus, and some autoinflammatory diseases [82].
Notch signaling in T cell development and regulation is an active area of investigation.
In research by Hoyne et al., Notch signaling promotes a regulatory phenotype in murine
peripheral CD4
+
T cells interacting with antigen-presenting cells (APCs) that overexpress
the human Jagged1 [
83
]. Notch signaling was also shown recently to be required for
polarization of several T helper cells, including Th1, Th17, and Th2 cells, and the regulatory
T cell (Treg) population [
11
]. This has prompted speculation that Notch acts as an unbiased
amplifier of polarizing signals, e.g., cytokines, instead of playing an instructive role in the
T helper polarization process [84].
Conversely, Notch signaling plays a pivotal role in the differentiation of cytotoxic
(CD8
+
) T cell effectors and in T cell activation processes, including the enhanced production
of IL-2, a critical factor in T cell proliferation [85].
Loss-of-function experiments have emphasized the key role of Notch signaling in the
context of innate immunity. Recent data have revealed it mediates the proinflammatory
activation of
in vitro
-obtained primary human blood monocyte-derived macrophages. For
example, proinflammatory stimuli can activate DLL4 expression through a TLR4-NF
κ
B-
dependent pathway [86].
Due to the profound impact of the Notch pathway on inflammatory responses, the
scientific community is evaluating the association between Notch signaling and AIDs.
Although this is a rapidly expanding field, at present only a handful of AIDs connected
Biomedicines 2025,13, 768 10 of 30
to changes in the Notch signaling pathway are known. Despite not falling under the
category of genetic disorders, studies have associated AIDs with inherited polymorphisms
in proteins including
γ
-secretase and other Notch-signaling-related proteins [
87
]. These
polymorphisms could alter the response of the inflammasome to various stimuli (such
as hormones, tobacco, and adipokines associated with insulin resistance and obesity).
As mentioned earlier, GM seems to participate in the pathogenesis of these diseases,
indeed adding to the complexity of environmental, genetic, and microbial interaction in
AIDs (Figure 4).
Biomedicines 2025, 13, x FOR PEER REVIEW 10 of 34
Conversely, Notch signaling plays a pivotal role in the differentiation of cytotoxic
(CD8+) T cell effectors and in T cell activation processes, including the enhanced
production of IL-2, a critical factor in T cell proliferation [85].
Loss-of-function experiments have emphasized the key role of Notch signaling in the
context of innate immunity. Recent data have revealed it mediates the proinflammatory
activation of in vitro-obtained primary human blood monocyte-derived macrophages. For
example, proinflammatory stimuli can activate DLL4 expression through a TLR4-NFκB-
dependent pathway [86].
Due to the profound impact of the Notch pathway on inflammatory responses, the
scientific community is evaluating the association between Notch signaling and AIDs.
Although this is a rapidly expanding field, at present only a handful of AIDs connected
to changes in the Notch signaling pathway are known. Despite not falling under the
category of genetic disorders, studies have associated AIDs with inherited
polymorphisms in proteins including γ-secretase and other Notch-signaling-related
proteins [87]. These polymorphisms could alter the response of the inflammasome to
various stimuli (such as hormones, tobacco, and adipokines associated with insulin
resistance and obesity). As mentioned earlier, GM seems to participate in the pathogenesis
of these diseases, indeed adding to the complexity of environmental, genetic, and
microbial interaction in AIDs (Figure 4).
Figure 4. GM is a key player in inflammation and can contribute to the onset of autoinflammatory
diseases. Proinflammatory GM release substances that are able to activate several mediators of
inflammation, such as interleukins. On the other side, some beneficial bacteria can secrete
compounds that help to create an anti-inflammatory environment. Notch is a main player in this
game. When Notch is activated, inflammation increases, and autoinflammatory diseases may
develop. Some drugs can downregulate the Notch activity, reducing inflammation. In this way,
Notch represents a potential target to treat autoinflammatory diseases.
Notch signaling can influence AIDs in different ways, which may vary slightly
between diseases, but are generally similar. For instance, alterations in the function of γ-
secretase have been linked to different AIDs [88]. The γ-secretase complex is a diverse
Figure 4. GM is a key player in inflammation and can contribute to the onset of autoinflammatory
diseases. Proinflammatory GM release substances that are able to activate several mediators of
inflammation, such as interleukins. On the other side, some beneficial bacteria can secrete compounds
that help to create an anti-inflammatory environment. Notch is a main player in this game. When
Notch is activated, inflammation increases, and autoinflammatory diseases may develop. Some
drugs can downregulate the Notch activity, reducing inflammation. In this way, Notch represents a
potential target to treat autoinflammatory diseases.
Notch signaling can influence AIDs in different ways, which may vary slightly between
diseases, but are generally similar. For instance, alterations in the function of
γ
-secretase
have been linked to different AIDs [
88
]. The
γ
-secretase complex is a diverse transmem-
brane protease composed of presenilin catalytic and cofactor subunits, including presenilin
enhancer-2 (PSENEN), nicastrin, and anterior pharynx defective 1 (APH1). These subunits
are encoded by the genes PSEN1/PSEN2, PSENEN, NCSTN, and APH1A/APH1B, respec-
tively [
89
]. While it is not directly and only involved with Notch signaling, it is responsible
for cleaving more than 140 type I membrane proteins, including cadherins and Notch [
89
].
This suggests that
γ
-secretase and its downstream signaling pathways, including Notch,
contribute to epithelial remodeling and the chronic inflammation observed in autoinflam-
matory skin diseases. Also,
γ
-secretase complex inhibition, a key player of Notch signaling,
decreases IL-17, IFN-
γ
, and CD4+ T cell differentiation into Th17 cells, inflammatory medi-
ators of CD4+ T cells, suggesting a role as a therapeutic strategy particularly in the context
of AIDs affecting the intestine. In a paper by Kar et al., it was observed that
γ
-secretase
activation was influenced by GM composition: modulation through the administration of
Biomedicines 2025,13, 768 11 of 30
Bifidobacterium bifidum and Lactobacillus salivarius reduced its activation, which could have
interesting consequences in many pathological conditions [90].
Cytokines also play a key role in Notch activation. For example, IL-1
β
and TNF-
α
,
two major inflammatory cytokines, are well-established Notch activators [
91
]. High levels
of inflammatory cytokines, such as TNF and IL-1
β
, are released during innate immune
responses and inflammation—key defense mechanisms against numerous pathogens. In
cases of hyperinflammation and autoimmunity, aberrant regulation of these cytokines can
have deleterious and pathogenic effects [
82
]. One example is that TNF is important in
the pathogenesis of rheumatoid arthritis (RA) and a confirmed drug target for RA. Notch
pathway activation is characterized by TNF-induced nuclear translocation of NICD and its
expression of Notch1, Notch4, and Jagged2, and these are the hallmarks of RA synovial
fibroblasts [
92
]. Crawford et al. (2009) also showed that deleting Notch3 or inhibiting
its signaling in a mouse model prevented joint damage in inflammatory arthritis [
93
]. It
is worth noting that TNF, in the context of RA, also influences the composition of the
GM: patients who are undergoing therapy with anti-TNF drugs can experience a partial
restoration of their GM, particularly experiencing a reduction of Euryarchaeota, which
was directly linked to disease activity [
94
]. A similar mechanism may occur in CAPS.
Ottaviani et al. (2010) reported that IL-1
β
induces expression of the Notch target gene Hes1
in chondrocytes via activation of the receptor Notch1, implying that, like TNF, IL-1
β
is
also a Notch activator [
95
]. Interestingly, production of IL-1
β
can also be influenced by
the GM: in murine models, for instance, it was observed that its secretion is promoted
during infections by the commensal GM, further highlighting the interaction between
inflammation, Notch, and the GM [96].
TGF
β
also has Notch-activating potential, as shown by studies demonstrating that
TGF
β
directly induces Hes1 expression in diverse cell types [
97
], and it also has the ability
to regulate the GM: interestingly, the activity it exerts on the GM is part of a crosstalk that
influences TGF
β
activity in a loop communication, which also impacts Notch signaling [
98
].
Overall, the role of the GM in inducing and interacting with Notch-activating cy-
tokines is very interesting, as it further highlights the interaction between Notch and GM
composition: in a paper by Singh et al., it has been discussed that sulfate reducing bacteria
are able to promote the expression of IL-1
β
and other cytokines, which in turn induce the
activation of Notch signaling [
22
]. This observation offers interesting prospectives on the
possibility of modulating Notch signaling in the context of a number of diseases.
In addition, Notch signaling and Hypoxia-inducible factor (HIF)-1
α
are crucial for
both physiological and pathological homeostasis. Hypoxia potentiates Notch signaling and
promotes the recruitment of HIF-1
α
to the NICD complex [
99
]. Hypoxia also determines
changes in the GM, which can in turn impact Notch signaling: HIF-1
α
is a key regulator
of GM homeostasis and helps maintain a healthy microbiota, particularly promoting the
expression of SCFA-producing bacteria, showing that its role in modulating Notch signaling
may be more nuanced than what could appear at first glance [
100
]. SCFAs are, indeed,
able to modulate the expression of Notch, blocking or promoting its activation in different
settings [
101
]. Moreover, it has been shown that the miR-497-195 cluster can also induce
angiogenesis by maintaining endothelial Notch and HIF-1αactivity [102].
Non-coding RNAs (ncRNAs) have also been studied in the context of AIDs, and Gu
et al. (2023), for instance, observed that small ncRNAs, such as miRNAs, and large lncRNAs
are important regulators in AIDs [
103
] and can have a direct impact on Notch signaling,
as in the case of miR-23b, which also induces Th1/Th17 cell response. IL-17- and IFN-
γ
-
expressing T cells increased after transfection of CD4+ T cells with a miR-23b inhibitor [
22
].
This immune activation, along with the loss of miR-23b’s immunomodulatory properties,
may lead to excessive Notch pathway activation and inflammatory cell proliferation,
Biomedicines 2025,13, 768 12 of 30
reinforcing its potential role in the pathogenesis of specific AIDs [
22
]. GM is influenced by
the activity of ncRNAs, too, once again highlighting that the mechanisms through which
Notch is regulated are often more complex than what could appear at first glance [104].
Hildebrand et al. (2018) demonstrated that TLR signaling promotes the expression
of the Notch receptor ligand delta-like 1 (DLL1) and activates Notch signaling in human
blood-derived monocytes. The induction of DLL1 by TLR activation occurs indirectly,
mediated by cytokine stimulation and autocrine signaling via cytokine receptors, which
activate the STAT3. Furthermore, their findings reveal a positive feedback loop between
Notch signaling and the Janus kinase (JAK)/STAT3 pathway
in vitro
, facilitated by Notch-
enhanced IL-6 production [
105
]. Once again, this Notch regulatory mechanism can also be
modulated by the GM, with complex implications: TLRs, for instance, are able to recognize
harmful GM components, thus tying dysbiosis to Notch activation, but on the other hand,
SCFAs are also implicated in modulating TLRs, in a positive sense in this case, overall
highlighting that the GM plays a critical role in Notch modulating [106].
4.1. Pyoderma Gangrenosum and Acne Spectrum Disorders
Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, Proline-
Serine-Threonine Phosphatase-Interacting Protein 1.-associated myeloid-related proteine-
mia inflammatory (PAMI) syndrome, pyoderma gangrenosum, acne and purulent acne
hidradenitis (PASH) syndrome, and pyogenic arthritis, pyoderma gangrenosum, acne
and purulent hidradenitis syndrome (PAPASH) are all autoinflammatory diseases that
result in persistent inflammation and tissue damage [
107
]. Besides the mechanisms
previously discussed, mutations in the Protein O-Fucosyltransferase 1 and Protein O-
Glucosyltransferase 1. genes, which encode GDP-fucose protein O-Fucosyltransferase 1
and protein O-glucosyltransferase 1—two proteins involved in Notch signaling—have been
identified in patients with Hidradenitis Suppurativa (HS) and Dowling-Degos disease [
1
].
Dowling-Degos disease is an autosomal dominant skin disorder characterized by flexural
hyperpigmentation that may occur independently or in association with HS [11].
The GM, in this group of disease, appears to be involved in particular in the
γ
-secretase
pathway and specific microorganisms have been associated with the disease: Ruminococcus
gnavus and Clostridium ramosum have been associated with the onset of HS, while the skin
microbiota also appears to be affected [108].
4.2. Behçet’s Disease
Behçet’s disease (BD) is a multisystem polygenic autoinflammatory disorder of un-
known cause, mainly characterized by recurrent episodes of genital ulcers, oral aphthous
ulcers, and uveitis [
109
]. The pathogenesis of BD is characterized by a highly complex
genetic background. In addition to the well-established role of the HLA-B*51 allele as
a dominant genetic susceptibility factor, genome-wide association studies (GWASs) and
targeted deep resequencing of specific immune response-related genes have identified
associations between BD and rare variants in several genes, including TLR4, NOD2, MEFV
(innate immunity regulator), IL-10, ERAP1 (endoplasmic reticulum aminopeptidase 1),
STAT4 (signal transducer and activator of transcription 4), IL-23Receptor, and IL-12RB2
(interleukin-12 receptor subunit beta 2) [
110
]. BD exhibits both autoimmune and autoin-
flammatory characteristics. It is strongly associated with the HLA-B51 gene and is marked
by hyperactivation of Th1 and Th17 cells [
111
]. These cells produce increased levels of
several inflammatory substances, such as cytokines, like IL-18, INF-
γ
, IL-2, and IL-12,
which contribute to the symptoms of BD [112].
Ciccarelli et al. suggest that BD has autoinflammatory features, most notably patho-
genetic intrinsic neutrophilic hyperactivation. This heightened activity is probably re-
Biomedicines 2025,13, 768 13 of 30
lated to greater production of reactive oxygen species and heightened phagocytosis and
chemotaxis [
113
]. These inflammatory responses are characterized by increased levels of
proinflammatory cytokines such as IL-1, IL-6, IL-8, and TNF. This is an important insight
into BD as an autoinflammatory disease and highlights the fundamental role played by
innate immunity and inflammatory processes in many diseases [114].
Qi et al. examined the involvement of Notch signaling factors in BD patients with and
without signs of active uveitis, a typical manifestation of the disease [
115
]. They found that
Notch pathway activity in patients with active uveitis is associated with enhanced Th17
responses. Notably, the GM has been implicated in the Th17/Treg imbalance. A decrease
in Clostridium populations directly reduces SCFAs, which are essential for maintaining
Th17/Treg balance [
116
]. In this patient group, Succinivibrionaceae are a common component
of the GM, a trait also observed in other autoinflammatory diseases [117].
As demonstrated by Ma et al. (2021), there is a notable elevation in the signal trans-
ducer and activator of transcription 3 (STAT3) phosphorylation levels in patients diagnosed
with BD [
116
]. STAT3 regulates the Notch pathway via a positive feedback loop, suggesting
that modulating Notch signaling could be a therapeutic strategy for BD [105].
4.3. Inflammatory Bowel Diseases
Inflammatory bowel diseases (IBDs) are non-infectious chronic inflammatory diseases
that typically affect the epithelium of the gastrointestinal system [
118
]. IBD is a chronic, pro-
gressive, and relapsing condition. Immune dysregulation and inflammation significantly
impact patients’ quality of life [
119
]. These disorders include Crohn’s disease (CD), ulcera-
tive colitis (UC), indeterminate colitis (IC), and unclassified colitis (IBD-U), in addition to
other non-infectious inflammatory conditions [120].
Notch signaling is important for intestinal homeostasis and ISC survival [
121
]. Within
the context of IBD, dysregulated activation of Notch has been associated with upregulation
of the HES1 transcription factor in human colonic cell lines [
122
]. This is associated with
elevated differentiation of secretory cell lineages, resulting in an impaired mucus barrier
and progression to chronic colitis.
Kuno et al. (2021) discovered that the expression of mRNA for Olfactomedin 4, a
marker of ISC, is upregulated by TNF-
α
and the Notch pathway in patients with IBD [
123
].
In addition, the Notch signaling pathway has been documented as a pivotal factor in
preserving the integrity of tight junctions and adherent junction proteins in murine models.
Ahmed et al. demonstrated that during infection with Citrobacter rodentium, the absence of
Notch signaling impairs the function of tight and adherent junctions. This impairment can
lead to increased epithelial permeability, resulting in greater exposure of luminal contents
to the immune system and promoting inflammation [124].
Fibrosis is one of the most crucial complications of CD, and the Notch signaling path-
way is a critical mechanism for the fibrogenic process, including epithelium mesenchymal
transition (EMT) and fibroblast senescence [125].
Recent studies have shown that DLL4 interacts with Notch4 to activate MET transcrip-
tion factors in colonic epithelial cells. This highlights the complexity of Notch signaling
in CD, as it can promote both fibrogenesis via EMT and tissue regeneration via MET.
These mechanisms can represent potential therapeutic targets for the control of fibrosis
in CD [125].
Ortiz-Masiá et al. (2016) found that M1 but not M2 macrophages promote Notch signal-
ing in epithelial cells by inducing Jag1- and delta-like canonical Notch ligand 4 (Dll4) [
126
].
This leads to increased HES1 protein levels and Inhibitor of Apoptosis Protein (IAP) activity.
In chronic CD patients, the abundance of M1 macrophages correlates with Notch signaling
and enterocyte differentiation markers, suggesting that macrophages contribute to the
Biomedicines 2025,13, 768 14 of 30
impaired Notch signaling and enterocyte differentiation seen in this disease. In the mucosa
of chronic CD patients, an abundance of M2 macrophages is associated with reduced Notch
signaling and impaired enterocyte differentiation [
126
]. The role of the GM in IBDs has long
been discussed. While some researchers previously suggested that GM changes result from
IBD, it is now widely accepted that the GM actively contributes to IBD pathogenesis [
127
].
Bifidobacterium longum,Eubacterium rectale,Faecalibacterium prausnitzii, and Roseburia intesti-
nalis are reduced in IBD, whereas Bacteroides fragilis is increased. Akkermansia muciniphila
has also been associated with the development of IBDs, even though there is contrasting
evidence on its role [
128
]. A particularly interesting aspect for the purpose of this review
is the role of the GM in the interaction between Notch signaling and IBD development
and progression: in a study conducted on mice, Liu et al. observed that administrating
Lactobacillus rhamnosus dm905 and Lactococcus lactis had a positive effect on inflammation
in IBD, which was at least in part due to the reduction in the inflammatory activity of the
Notch pathway [129].
Furthermore, the role of immune activation in the mechanisms and pathophysiology
of irritable bowel syndrome (IBS) is currently believed to be the most relevant [
130
]. This
linkage provides a potential mechanism for Notch signaling pathway abnormalities in the
pathogenesis of IBS. In agreement, other studies have noted that aberrant Notch signaling
initiates an inflammatory response that drives disease more rapidly in IBS [
131
]. This
suggests that Notch signaling pathway inhibition may be a novel therapeutic approach for
IBS therapy [132].
4.4. Autosomal Dominant Autoinflammatory Disease
Among the autoinflammatory diseases, it is imperative to mention recurrent fevers,
and particularly cryopyrinopathies.
Mutations in the NLRP3 gene are responsible for autosomal dominant autoinflam-
matory disease (NLRP3-AID), and hearing loss (HL) may be the primary or even the
only significant symptom of NLRP3-AID. NLRP3 was identified because of its associa-
tion with autosomal dominant autoinflammatory diseases (NLRP3-AIDs), also known as
CAPSs (cryopyrin-associated periodic syndromes) [
133
]. These disorders include a range
of inflammatory symptoms, including urticaria, conjunctivitis, myalgia, arthralgia, fever,
headache, and fatigue, with varying degrees of severity. In a study by Yao et al., it has
been observed that GM modulation appears to be able to reduce NLRP3 hyperactivation
through the induction of Tregs [
134
]. The mechanisms through which Notch influences
this group of diseases have been discussed previously, but it is worth noting that studies
on how the interaction between Notch and the GM are showing some promise in further
understanding the complex underlying crosstalk [
135
]. One particularly promising area of
research is the composition of the oral microbiota in the context of AIDs: the presence of
specific strands, such as Streptococcus salivarius, have been linked to reduced cytokine load,
particularly those defined as Notch-activating proinflammatory cytokines, but research is
still progressing [136].
5. Notch-Targeted Drugs and Future Perspectives
Notch signaling differs from other pathways by operating through stoichiometric interac-
tions between its components [
137
]. Although phenotypic responses to NICD overexpression
vary, the downstream effects of Notch activation are typically dose-dependent [
138
]. This
suggests that complete pathway inhibition may not be necessary for therapeutic efficacy [
139
].
Notch signaling triggers cell-specific responses at different times, and systemic inhi-
bition could affect multiple tissues. To maximize therapeutic effectiveness, it is crucial to
calibrate the level and timing of pathway inhibition to manage disease progression while
Biomedicines 2025,13, 768 15 of 30
minimizing adverse effects [
11
]. The roles of different Notch receptors and ligands in driv-
ing specific outcomes remain largely unexplored. Due to their accessibility to circulating
therapeutic agents and their role in inflammatory diseases, these transmembrane proteins
represent promising therapeutic targets.
However, as observed in cancer research, the potential disadvantages of Notch inhi-
bition need to be carefully taken into account. For instance, the loss of Notch-dependent
differentiation of gastrointestinal precursor cells into epithelial cells leads to an imbalance
with an excess of secretory goblet cells and gastrointestinal toxicity [140,141].
According to the mechanism employed, Notch-targeted drugs can be classified as
illustrated in Table 1.
One potential approach involves the inhibition of
γ
-secretase. Gamma-secretase in-
hibitors (GSIs), including DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine
t-butyl ester) and DBZ (dibenzazepine), have emerged as promising therapeutic agents for
diseases where Notch signaling plays a key role in pathogenesis or progression [142].
The initial clinical trial involving MK-0752 was conducted over a decade ago, with
participants diagnosed with T cell acute lymphoblastic leukemia/lymphoma (T-ALL).
Subsequent studies have examined the efficacy of MK-0752 in treating refractory central
nervous system, pancreatic, and both metastatic and early-stage breast cancer [11].
A phase 3 trial of the GSI semagacestat was terminated before completion due to a
lack of clinical efficacy and safety concerns [
143
]. The adverse events observed in this trial
included infections, skin reactions, and cancers, which suggested that these issues were
related to on-target inhibition of Notch signaling.
Similarly, gastrointestinal and dermatologic adverse effects emerged as the main
reasons for treatment discontinuation in a phase 2 study aimed at evaluating the safety of
the GSI avagacestat in Alzheimer’s disease [144].
The adverse events determined by GSIs generally depend on their non-selective
blockage of the overall Notch pathway [
140
]. The scientific community has proposed
the employment of “Notch-sparing” substrate-selective GSIs in order to minimize the
toxicity of Notch-inhibiting treatments, particularly related to gut epithelium proliferation
and maturation [145].
Novel approaches are currently of particular interest in the field of oncology.
An example is the small-molecule ADAM inhibitor INCB7839, which underwent
early-phase clinical trials for solid tumors and breast cancer [
146
]. Although trials did
report mild adverse events (e.g., asthenia and nausea) when the compound was applied as
a monotherapy, they also showed significant toxic effects, such as deep vein thrombosis.
Another approach involves CB-103, which disrupts the assembly of the transcriptional
complex [
147
]. This predicted binding site occupies the same pocket as the RAM domain
of NICD. CB-103 has demonstrated effectiveness in preclinical trials and, notably, does not
appear to cause the gastrointestinal side effects commonly linked to GSIs.
A more elegant and specific approach compared to Notch inhibition is the modu-
lation of its effectors with monoclonal antibodies (mAbs), like Brontictuzumab or Tarex-
tumab [
27
,
148
]. Compared to conventional pharmacotherapy, monoclonal antibodies offer
several advantages, including increased potency, less frequent dosing regimens, and en-
hanced specificity towards the target. MAbs are also generally well tolerated with off-target
effects such as hypersensitivity reactions tending to occur less commonly than target-
related adverse events [
149
]. However, in a phase 1 study by Ferrarotto et al., a potential
gastrointestinal toxicity of Brontictuzumab has been described as an on-target effect of
Notch1 inhibition [
150
]. Similarly, Tarextumab, a cross-reactive antibody inhibiting both
Notch2 and Notch3, is well tolerated at lower doses, whereas it may cause nausea, vom-
iting, diarrhea, and fatigue at higher doses [
151
]. The implication is that mAbs require
Biomedicines 2025,13, 768 16 of 30
accurate dosing and monitoring, as well as conventional treatments. MAbs targeting Notch
are based on the IgG scaffold, with distinct domains for antigen binding and effector
functions [
11
]. These modifiable structures have been employed to engineer advanced
therapies, which offer prolonged circulation and targeted cell destruction through immune
mechanisms, such as antibody-dependent cellular cytotoxicity, antibody-dependent cellular
phagocytosis, or complement-dependent cytotoxicity [152].
Due to Notch signaling function in inflammation and increasing interest in combina-
tions to treat inflammatory diseases, studies have been performed.
Real et al. demonstrated that the combination of the GSI dibenzazepine with the gluco-
corticoid dexamethasone leads to significant improvement in survival in a mouse xenograft
model of glucocorticoid-responsive T cell acute lymphoblastic leukemia (T-ALL) [
153
]. Ad-
ministration of the glucocorticoid dexamethasone in combination with GSI reduced lethal
gut toxicity of the GSI, and induced apoptosis in T-ALL xenografts more effectively than
either agent alone. GSI has been demonstrated to potentiate glucocorticoid receptor (GR) ac-
tivity, resulting in increased GR-mediated toxicity via a synergistic effect [
154
]. Importantly,
dexamethasone mitigates GSI-induced gastrointestinal toxicity; however, mechanistic de-
tails are unclear. Moreover, it has been shown that the Notch1 inhibition-mediated efficacy
of brontictuzumab is potentiated by dexamethasone due to its synergistic effect [154].
Huang et al. (2016) emphasized that the most promising clinical success of mAbs in
a Notch context has been observed with the combination of the Notch ligand delta-like
4 (DLL4) and vascular endothelial growth factor (VEGF) blockade [
155
]. This assertion
is substantiated by their preclinical studies demonstrating the efficacy of enoticumab
in combination with the anti-VEGF IgG1 Fc-fusion (aflibercept) across various cancer
models [
156
]. ABL001, a bispecific antibody targeting DLL4 and VEGF, has demonstrated a
stronger biological activity than DLL4 or VEGF-targeting mAbs alone. Among the related
adverse events, systemic and pulmonary hypertension, asthenia, headache, and anemia
have been reported, although ABL001 is generally more tolerated than other mAbs and has
no dose-limiting toxicity [157,158].
Table 1. Key regulators of the Notch signaling pathway and their mechanisms of action. The
table compares the classes of compounds targeting Notch signaling, such as
γ
-secretase inhibitors,
inhibitors of transcriptional complex formation, ADAM metalloprotease inhibitors, and monoclonal
antibodies. Currently, there is an extensive investigation of these molecules in the therapeutic setting
to exploit their potential in different diseases, mainly in the context of autoinflammatory diseases
and cancer.
Molecules Mechanism of Action References
DAPT Inhibition of γ-secretase [142]
Dibenzazepine Inhibition of γ-secretase [142]
MK-0752 Inhibition of γ-secretase [11]
Semagacestat Inhibition of γ-secretase [143]
INCB7839 ADAM inhibitor [146]
CB-103 Inhibitors of formation [147]
Brontictuzumab, Tarextumab Monoclonal antibodies [27,148]
An intriguing study by Qi et al. (2014) investigated the potential association between
Notch signaling and BD, with a particular focus on patients with and without active uveitis,
a prevalent manifestation of BD [
115
]. The study’s findings indicated that Notch pathway
activation led to an enhanced Th17 response in patients with active uveitis. Furthermore,
the administration of
γ
-secretase inhibitors led to a substantial reduction in the expression
Biomedicines 2025,13, 768 17 of 30
of key inflammatory mediators (IL-17 and IFN-
γ
), as well as an impact on the differentiation
of naïve CD4+ T cells into Th17 or regulatory T cells. This was indicated by a decrease in
STAT3 phosphorylation, a hallmark of the BD phenotype [115].
Furthermore, several miRNAs have been shown to regulate the Notch signaling
pathway. In BD, the activation of the Notch pathway has been associated with a decrease in
the expression of miRNA-23b [
115
]. In patients with BD, lower levels of miR-23b have been
implicated in the activation and amplification of Th17 and Th1 cell functions, as well as
the Notch signaling pathway. Inhibition of the Notch signaling pathway has been shown
to selectively suppress the Th17 response [
159
]. Research indicates that members of the
NF-
κ
B family regulate miR-23b transcription through the Act-1/IL-17 signaling pathway,
establishing a positive feedback loop among miR-23b, Notch signaling, and IL-17 [103].
As for PAPA syndrome and other autoinflammatory disorders with skin involvement,
in a study by O’Sullivan et al., where the
γ
-secretase inhibitor niragacestat was admin-
istered, 71% of individuals experienced adverse skin toxicities [
160
]. Additionally, 53%
developed follicular and cystic lesions with surrounding inflammation in areas like the
axilla and inguinal regions, resembling hidradenitis suppurativa. The resolution of these
lesions upon the discontinuation of niragacestat suggests a pivotal role for
γ
-secretase in
the pathogenesis of follicular inflammation [161].
In the context of IBD research, the role of Notch in the gastrointestinal tract has
been examined using GSIs or RBP-J genetic modulation [
162
]. GSIs induce a shift in
enterocyte progenitors to secretory cells, activating Atoh1/Math1 and downregulating
Hes1. A comparable effect is observed in RBP-J knockout [
163
]. The observed changes are
primarily attributable to Notch1 inhibition, as blocking Notch2 did not affect intestinal
morphology. In spite of data supporting the proinflammatory role of Notch in IBD, a
non-selective blockage of this pathway may impair the intestinal epithelium integrity, and
adverse events may overwhelm the positive effects at this level. In fact, Notch-1 expression
regulates innate and adaptive immune responses in the gut [
164
], and its complete absence
has been associated with a higher disease severity in experimental models of colitis [
11
].
For this reason, further research assessing the benefits and risks of Notch manipulation in
IBD is needed.
The investigation of Notch inhibition in CAPS has received attention, as contempo-
rary guidelines advocate for the utilization of IL-1 inhibitors, which have proven to be
efficacious and well tolerated by patients [
165
]. In addition, the Notch signaling pathway
has been implicated in the regulation of chronic inflammation mediated by the NLRP3
inflammasome, a protein complex involved in autoinflammatory diseases [166].
It would be beneficial to conduct studies aimed at developing new drugs that target
the Notch pathway, as this may provide a novel therapeutic target for conditions such as
CAPS. Targeting Notch could act upstream of IL-1 and NLRP3, potentially offering a way
to modulate the inflammatory response more effectively and potentially addressing some
of the limitations of current treatments.
Concerning GCA, Piggott et al. (2011) demonstrated that the inhibition of Notch
signaling with a GSI or soluble Jagged1 led to a reduction in vascular inflammation in
a humanized mouse model [
167
]. This blockade suppressed Th1 and Th17 cell activity
by disrupting communication between CD4
+
T cells and endothelial or smooth muscle
cells expressing Jagged1 [
168
]. Furthermore, the study identified a correlation between
impaired Notch4 signaling and compromised Treg function, thereby promoting vascular
inflammation [169].
The importance of Notch signaling in inflammatory diseases is a relatively recent
discovery, and most of the available data still come from preclinical studies.
Biomedicines 2025,13, 768 18 of 30
Despite some encouraging results, in certain cases Notch-targeted therapies have failed
to meet the expectations of the scientific community, due to concerns about their toxicity, the
low affinity of antibody-drug conjugates, and the activation of alternative pathways [63].
Among the strategies to increase the efficacy of Notch-based treatments, pulsed Notch
inhibition, high selectivity, and combination therapies have been proposed [170].
Furthermore, the design of tailored treatments for patients with inflammatory disor-
ders requires multi-OMICS studies and the integration of molecular and clinical data for a
better comprehension of the pathogenic mechanisms involved [135].
6. A New Way Forward: Modulating the GM with Precision Probiotics
As previously mentioned, the Notch pathway is deeply involved in immune and
inflammatory processes, modulating the secretion of multiple inflammatory cytokines,
such as IL-1
β
, IL-6, TNF-
α
, IL-18, and IFN-
γ
[
82
]. It plays a complex role in inflammation
and can induce the activation of immune cells, such as T lymphocytes and macrophages,
leading these cells to secrete these factors. The ratio of these molecules can dictate the
intensity and duration of the inflammatory response.
One promising strategy is GM modulation with specific probiotic strains. For exam-
ple, Bifidobacterium longum ES1 has demonstrated anti-inflammatory effects on intestinal
diseases in various models, e.g.,
in vitro
and animal models, attenuating both spontaneous
and chemically induced colitis via the regulation of cytokines or a targeted induction of
immune regulation mechanisms [171].
Sichetti et al. simulated the intestinal epithelial barrier function
in vitro
with B. longum
and macrophages, proving that probiotics significantly influenced the production of IL-
10. At the same time, the secretory IL-1
β
and IL-6 levels were inhibited by 70% and
80%, respectively [172].
Similarly, Singh et al. reported that B. longum can modulate cellular signaling path-
ways, leading to decreased levels of proinflammatory cytokines, such as IL-1
β
, IL-6, and
IL-8. Furthermore, it alleviates the DSS-induced alteration of the
in vitro
epithelial barrier
and regulates the inflammatory response [173].
Another emerging player is Clostridium butyricum. Its anti-inflammatory effects and
ability to stimulate Treg responses are closely linked to its capacity to increase IL-10
levels [
174
]. In a murine colitis model, Hayashi et al. documented the essential role of
macrophage-derived IL-10 in mediating the protective effect of CBM 588, as its depletion
abrogated the protective effect of the strain. C. butyricum induces colonic macrophage IL-10
production through TLR2 activation [
175
]. CBM 588 is known to change TLR2 signaling
and inhibit pathogen-induced inflammation and apoptosis
in vitro
[
176
]. C. butyricum
induces an anti-inflammatory Treg response, mediating IL-10 and TGF-
β
, possibly via the
activation of a TLR2-dependent pathway [177].
Streptococcus salivarius is particularly noteworthy in the context of recurrent pharyn-
gitis or GM oralization. This bacterium colonizes the human oral cavity within days of
birth and remains one of the most abundant oral commensals. It has also been found in the
stomach and jejunum, which suggests that it may play an important role in the ecology
of both the oral cavity and gastrointestinal tracts [
178
]. In different studies focusing on
gingival, bronchial, pharyngeal, and intestinal epithelial mucosa, suppression of NF-
κ
B
activation and IL-8 production was observed following stimulation with flagellin from
other microorganisms [
179
]. Macdonald et al. demonstrated that Streptococcus salivarius
can prevent the immune activation by periodontal disease pathogens [
180
]. In gingival
fibroblasts stimulated with the pathogens Porphyromonas gingivalis and Fusobacterium nu-
cleatum, administration of S. salivarius K12 and M18 has an effect on the production of IL-6:
Biomedicines 2025,13, 768 19 of 30
when both probiotics were administered either with pathogens or after pre-treatment of
fibroblasts, a decrease in cytokine production was recorded.
Finally, research by Kim et al. showed that threonyl-tRNA synthetase (AmTARS)
secreted by purified Akkermansia muciniphila ARSs stimulates M2 macrophage polarization
and regulates IL-10 [
181
]. The relevant pathways include MAPK and PI3K/AKT, and these
pathways ultimately converge upon the cAMP response element-binding protein (CREB).
This pathway enhances IL-10 synthesis and suppresses the key inflammatory mediator,
NF-kB. Furthermore, a pasteurized strain of A. muciniphila Muc
T
and its outer membrane
protein Amuc-1100 have been shown to downregulate collagen and proinflammatory
cytokines in murine CRC, and decrease mRNA expression of proinflammatory cytokines
in DSS-induced colitis [
182
]. Live A. muciniphila had no effects on TNF or IL-1b expression
in inflamed colon tissue but enhanced IL-10 release, in line with an anti-inflammatory
profile. Proinflammatory markers were elevated by heat-killed A. muciniphila and E. coli.
Akkermansia showed a positive correlation with IL-10 and a negative correlation with
IL-6 and TNF [
183
]. Higher Tlr2 and Smad3 expression induced particularly with live
A. muciniphila points towards an immune modulatory function, potentially through the
TGF-βpathway [184].
Moreover, Molaaghaee-Rouzbahani et al. explored the anti-inflammatory properties of
Akkermansia muciniphila in gliadin-stimulated macrophages (MQs) [
185
]. Gliadin triggered
a proinflammatory M1 phenotype with TNF-
α
and IL-6. A. muciniphila pre- and post-
treatment induced the shift of MQs to an anti-inflammatory M2 phenotype and reduced
the proinflammatory markers (IL-6, TNF-
α
) while boosting the level of anti-inflammatory
markers (IL-10, TGF-
β
). However, Akkermansia muciniphila is currently only available as
a postbiotic [186].
Other well-studied probiotics include Lactobacillus rhamnosus GG, which acts through
the upregulation of anti-inflammatory cytokines, including IL-4 and IL-10, along with the
downregulation of inflammatory cytokines, including IL-1, IL-6, and TNF-
α
[
187
]. Multiple
members of the Lactobacillus and Bifidobacterium families have shown potential organ-
targeting ability in terms of therapy, supporting the need for further studies. Moreover, if
the right combination of Lactobacillus and Bifidobacterium species is exhibited to reduce
symptoms in multiple areas of the body, it could reduce the need for multiple doses
and/or medications [187].
A meta-analysis conducted by McLoughlin et al. evaluated 29 prebiotic studies [
188
].
Fourteen of these studies, accounting for 48%, reported a decline in inflammatory mark-
ers. More specifically, among the 13 studies that focused on oligosaccharide prebiotics,
nine (approximately 69%) observed a substantial reduction in at least one inflammatory
biomarker (namely TNF-
α
, IL-6, CRP, or interferon-
γ
) when compared to control groups.
Conversely, two crossover studies involving healthy participants indicated an increase
in inflammatory markers (CRP, TNF-
α
, and IL-6), while two additional studies targeting
populations with gastrointestinal disorders, such as Crohn’s disease and acute diarrhea,
did not find significant effects on inflammation.
In the context of polysaccharide prebiotics, only two of the ten studies (20%) revealed
a noteworthy reduction in inflammation when compared to their control or baseline mea-
surements, with the remaining eight studies indicating no evidence of an anti-inflammatory
impact [
188
]. Of the two studies investigating resistant starch supplementation, the one
of Aliasgharzadeh et al. reported a meaningful decrease in TNF-
α
and IL-6 levels [
189
].
Furthermore, a high soluble fiber diet (10.7 g daily) was associated with a significant
reduction in CRP compared to a low soluble fiber diet (2.5 g daily). A cross-sectional
study conducted by Ma et al. established an inverse relationship between soluble fiber
consumption and systemic inflammation (IL-6 and TNF-
α
-R2) [
190
]. However, numerous
Biomedicines 2025,13, 768 20 of 30
papers are contradictory. The existing data on efficacy are not yet robust enough to satisfy
the demanding criteria the United States Preventive Services Task Force uses for a preven-
tive recommendation [
191
]. But this does not mean probiotics are not effective in healthy
people—it means there are not enough data to support a population-wide recommenda-
tion by the United States Preventive Services Task Force. The research around probiotics
is still relatively young, and a lack of definitive evidence of effectiveness should not be
interpreted as evidence that they do not work. Indeed, probiotics are the only reasonable
option in certain circumstances based on available efficacy and safety data [
192
]. However,
the evidence is not strong enough to justify broad preventive recommendations for the
general population.
Yet, probiotics can also have side effects. Recent evidence has associated specific pro-
biotic strains with serious infections, potentially resulting in sepsis, bacteremia, fungemia,
endocarditis, and other opportunistic infections [
193
]. Besides that, the production of
cytokines, such as IL-1
β
, IL-6, IFN, and TNF-
α
, associated with probiotics may elicit an
excessive immune response, resulting in an inflammatory response or autoimmune dis-
eases [
194
]. These risks warrant a reconsideration of the use of probiotics in patients with
autoimmune diseases, particularly in people who are at higher risk.
In addition, probiotic interventions could lead to sensitization in susceptible children
and adults. Reduced microbial diversity-associated allergic disorders have been documented
in early childhood, corresponding with lower levels of lactobacilli and bifidobacteria [195].
The diversity in strain types, dosages, and study populations needs further evalua-
tion for effective and consistent probiotic therapy. Various uncertainties and challenges
still exist; however, probiotics have proven to be a potentially safe and effective adjunct
treatment option for a wide range of disorders, improving the quality of life of patients and
helping them regulate their gut health [
196
], Further research is needed to better elucidate
mechanisms of action, formulations, and strain responses before utilizing probiotics for
therapeutic gains in gastrointestinal health.
Table 2summarizes the immunomodulatory effects of the mentioned probiotics.
Table 2. Probiotics and their respective strain-specific immunomodulatory properties.
Probiotic Immunomodulatory Effect References
Bifidobacterium Longum ES1 - Inducing IL-10 production
- Reduction in IL-1βand IL-6 IL-8 levels [171–173]
Clostridium butyricum
CBM 588
- Stimulating Treg response
- Modifying TLR2 signaling to inhibit pathogen-induced inflammation
- Inducing IL-10 and TGF-β
[174,176,177]
Streptococcus salivarius - Inhibition of NF-κB activation and IL-8 production [179]
Akkermansia muciniphila
(currently available on the
market only as a postbiotic)
- Inhibition of NF-κB activation
- Enhanced IL-10
- Modulation of TGF-β
- Reduction IL-6 and TNF-αlevels
[181,183–185]
Lactobacillus rhamnosus GG - Upregulation of anti-inflammatory cytokines IL-4 and IL-10
- Downregulation of inflammatory cytokines IL-1, IL-6, and TNF-α[187]
Modulating the GM may have beneficial effects in autoinflammatory diseases through
their influence on the immune system and the Notch signaling pathway, but the risks,
uncertainties, and paradoxical data must also be considered, too.
Findings from animal models do not always translate directly to humans. Further-
more, human responses to probiotics are extremely heterogeneous based on age, gender,
genetics, diet, gut microbiota composition, and health status [
197
]. Additionally, probiotic
interventions should not be viewed in isolation, but as part of a comprehensive system
Biomedicines 2025,13, 768 21 of 30
that includes general dietary and lifestyle factors. Diet quality, exercise, stress, and sleep
patterns are among the factors that play a very important role in maintaining gut health
and microbial balance, thereby influencing the efficacy of probiotics [198].
7. Conclusions
Notch signaling is a key regulator of inflammation in several autoinflammatory dis-
eases. Its wide-ranging implications suggest that mutations affecting Notch regulatory
mechanisms are highly context-dependent across different diseases, preventing a one-size-
fits-all therapeutic approach. Insights into the pathways involved in Notch activation
and their interplay with other signaling networks will provide important information to
delineate the unique clinical findings of each disease.
Such effects indicate that Notch signaling inhibition could provide an effective thera-
peutic target. However, the variability in therapeutic responses highlight the need to study
differences in Notch regulation at the tissue- or cell-type level to guide the development of
improved targeted inhibitors.
A key component is the interaction between Notch signaling and the GM: evidence
supports the idea that GM could regulate Notch activity, and that Notch could in turn
influence GM composition and contribute to gut health and inflammation. Strain-specific
probiotics may not only restore the GM balance, but also enhance Notch signaling regula-
tion, resulting in a synergistic therapeutic strategy.
Nevertheless, large-scale studies are essential to establish standardized microbiota as-
sessment protocols and determine the effective probiotics for each patient. GM composition
and immune response vary considerably from person to person, arguing for a personalized
approach in therapy.
Notably, the knowledge gained about Notch signaling and the GM may offer bases
for new therapeutic strategies against autoinflammatory diseases. The additive interplay
of Notch inhibitors and probiotics can propose a transient semi-meditated therapeutic
strategy intending to ameliorate clinical outcomes, as well as enhance the quality of life in
patients. Nevertheless, discrepancies remain in the literature regarding the link between the
Notch signaling pathway and the GM in autoinflammatory diseases. However, the overall
effects of all GM variations on Notch signaling in different disease contexts, as well as the
specific underlying mechanisms responsible for this interaction, are not entirely known.
Moreover, although some studies imply that targeted probiotics might modulate the inflam-
matory response via Notch, clinical evidence is scarce and fragmented. Subsequent studies
must concentrate on pinpointing exact molecular targets and clinical trials of therapeutic
approaches based on the modulation of Notch and the GM to pave the way for increasingly
personalized and effective strategies in the handling of autoinflammatory diseases.
Author Contributions: Conceptualization, R.C.; methodology, R.C.; validation, V.G., A.G. and G.G.;
writing—original draft preparation, M.C., L.F., P.R., G.B., S.d.I. and A.M.; writing—review and
editing, V.G., M.C., L.F., A.G., G.G. and R.C. All authors have read and agreed to the published
version of the manuscript.
Funding: This work was supported by the Italian Ministry of Health within the PNRR Mission 6
initiative on Health (Project no. PNRR-MAD-2022-12376383, CIMA).
Institutional Review Board Statement: Not applicable.
Acknowledgments: The authors are grateful to the platform—BioRender.com (accessed on 11 October
2024) for creating Figure 1.
Conflicts of Interest: The authors declare no conflicts of interest.
Biomedicines 2025,13, 768 22 of 30
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