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\begin{document}

\title{Gut microbiota and Lactobacillus species maintain the small intestine
stem cell niche and ameliorate the severity of necrotizing enterocolitis}



\author[1]{Svabova Tereza}%
\author[1]{Jelinkova Anna}%
\author[1]{Umesh Gautam}%
\affil[1]{Akademie ved Ceske republiky}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\textbf{Gut microbiota and\emph{Lactobacillus} species maintain the
small intestine stem cell niche and ameliorate the severity of
necrotizing enterocolitis}

Svabova Tereza\textsuperscript{1}*, Jelinkova Anna\textsuperscript{1},
Gautam Umesh Kumar\textsuperscript{1}

\textsuperscript{1}Laboratory of Gnotobiology, Institute of Microbiology
of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic.

*corresponding author: tereza.svabova@biomed.cas.cz

The microbiota plays an undisputed role in mammalian development and
physiology. It enhances energy extraction from ingested food, protects
against harmful pathogens, regulates immune function, and strengthens
biochemical signaling. In mammals, including humans, colonization of the
gut by microbes begins at birth\textsuperscript{1}, and several recent
studies have shown that the microbiome contributes to postnatal host
development in early childhood. In this sense, microbial dysbiosis in
infancy has been associated with certain diseases such as inflammatory
bowel disease, cardiometabolic disorders, cancer, and neuropsychiatric
disorders\textsuperscript{2}.

The intestinal epithelial cells are in direct contact with a large
number of bacteria and the external environment, forming a barrier
between inside and outside while fulfilling a critical role in the
absorption of nutrients. The small intestine crypt-villus architecture
is a unique structure that provides a microenvironment in which
intestinal stem cells (ISCs) differentiate into a variety of different
epithelial subtypes. These subtypes include enterocytes, also known as
intestinal epithelial cells (IECs), Paneth cells, goblet cells,
enteroendocrine cells, tuft cells, and microfold cells (M
cells)\textsuperscript{3}.

Kim et al. demonstrated that early life gut microbiota exposure promotes
the differentiation of intestinal stem cells into Paneth cells by
regulating numbers of CD206\textsuperscript{+}macrophages associated
with epithelial Wnt signaling, which maintains mesenchymal niche cell
proliferation (Figure 1). They suggested that the maintenance of this
stem cell niche is critical for small intestinal homeostasis and its
disruption (e.g., by antibiotic administration) can lead to inflammatory
conditions, which can manifest as necrotizing enterocolitis (NEC). NEC
is a severe inflammatory disease affecting the small intestine,
especially in preterm infants, and is the leading cause of death in this
group.

To investigate the role of the microbiota and intestinal stem cell
differentiation in the pathogenesis of NEC, Kim et al. induced NEC-like
phenotypes in neonatal mice by exposing them to hypoxia and gavage
feeding of hyperosmolar formula and LPS. ATB-induced dysbiosis resulted
in further impaired stem cell niche in the small intestine and led to
severe NEC manifestation. They also confirmed previous findings that
microbial dysbiosis in NEC is associated with an increased abundance
of\emph{Proteobacteria} and a concomitant underrepresentation
of\emph{Firmicutes} and \emph{Lactobacillus} \textsuperscript{4}. To
determine whether members of genus \emph{Lactobacillus} affect Paneth
cell formation during NEC onset, Kim et al. treated pregnant females and
their pups with selected \emph{Lacticaseibacillus rhamnosus} (Lr) strain
in the presence or absence of NEC experimental conditions. They found
that Lr transplantation corrected the impaired development of the
mesenchymal niche and Paneth cell differentiation and consequently
partially rescued the NEC-like phenotypes (Figure 1)\textsuperscript{4}.

Previous studies in germ-free mice and mice with Toll-like receptor
knockout have highlighted the key relationship between the microbiome
and NEC development\textsuperscript{5}. Probiotic administration has
been suggested as a potential strategy to prevent NEC. In general,
probiotic bacteria, including \emph{Lactobacillus} species, modulate
microbiota composition, intestinal epithelial barrier function, and
cytokine secretion. Kim et al. showed that transplantation of Lr
restored the amount of \emph{Lactobacilli} resulting in an improvement
of NEC-like phenotypes. We have recently shown that administration
of\emph{Lactiplantibacillus plantarum} WJL also increased the
proliferation of intestinal epithelial stem cells in chronically
undernourished juvenile mice, resulting in improved growth of the young.
This effect was strictly bacterial strain-dependent, and NOD2 signaling
in intestinal epithelial cells was essential for the bacteria-mediated
beneficial effect\textsuperscript{6}. A growing body of evidence
suggests that the strain specificity of probiotic microbes and their
efficacy in alleviating specific diseases are crucial aspects that are
often overlooked when selecting the best probiotic
microbes\textsuperscript{7}. Therefore, it would be important to
determine whether all probiotic bacterial species or even different Lr
strains promote the stem cell niche development by the same mechanism.
Further, as it has been shown that NOD2 signaling plays a crucial role
in epithelial stem cell proliferation, the role of this receptor in the
NEC prevention and development should be probed.

To sum up, the study by Kim et al. provides another important
contribution to the understanding of the mechanism of NEC pathogenesis.
However, more research is needed to fully understand the role
of\emph{Lactobacilli} and other probiotic bacteria in the prevention of
NEC and to strengthen their potential as therapeutic agents to combat
this serious disease.

\textbf{KEYWORDS}

necrotizing enterocolitis (NEC), \emph{Lacticaseibacillusrhamnosus} ,
microbiota, intestinal stem cells, Paneth cells

\textbf{ACKNOWLEDGMENTS}

The authors would like to thank Dr. Anna Globinska for figure design.

\textbf{CONFLICT OF INTEREST}

The authors have no conflict of interest to declare.

\textbf{FUNDING INFORMATION}

TS is supported by the grant from Czech Health Research Council
(NU20-05-00038). UKG and AJ are supported by the JUNIOR STAR grant from
the Czech Science Foundation (GACR 21-19640M).

References:

\begin{enumerate}
\tightlist
\item
  Kennedy, Katherine M., et al. ''Questioning the fetal microbiome
  illustrates pitfalls of low-biomass microbial studies.'' Nature
  613.7945 (2023): 639-649;
\item
  Cani, Patrice D. ''Human gut microbiome: hopes, threats and
  promises.'' Gut 67.9 (2018): 1716-1725.
\item
  Frazer, Lauren C., and Misty Good. ''Intestinal epithelium in early
  life.'' Mucosal Immunology 15.6 (2022): 1181-1187.
\item
  Kim, Ji-Eun, et al. ''Gut microbiota promotes stem cell
  differentiation through macrophage and mesenchymal niches in early
  postnatal development.'' Immunity 55.12 (2022): 2300-2317.
\item
  Murphy, Kiera, et al. ''Probiotics, prebiotics, and synbiotics for the
  prevention of necrotizing enterocolitis.'' Frontiers in Nutrition 8
  (2021): 667188.
\item
  Schwarzer, Martin, et al. ''Microbe-mediated intestinal NOD2
  stimulation improves linear growth of undernourished infant mice.''
  Science 379.6634 (2023): 826-833.
\item
  McFarland, Lynne V., Charlesnika T. Evans, and Ellie JC Goldstein.
  ''Strain-specificity and disease-specificity of probiotic efficacy: a
  systematic review and meta-analysis.'' Frontiers in medicine 5 (2018):
  124.
\end{enumerate}

\textbf{Figure 1} Summarized view of the article by Kim et al. (doi:
10.1016/j.immuni.2022.11.003). Treatment of Lacticaseibacillus rhamnosus
(Lr) partially rescues from necrotizing enterocolitis-like phenotypes in
a murine model. Lr transplantation corrected the impaired development of
the mesenchymal niche and Paneth cell differentiation. As a result of
exposure to the gut microbiota in early life, intestinal stem cells
differentiate into Paneth cells by regulating CD206+ macrophages
associated with epithelial Wnt signaling, which sustains the
proliferation of mesenchymal niche cells. NEC, necrotizing
enterocolitis; LPS, lipopolysaccharides; MNC, Mesenchymal niche cell;
WNT, Wingless-related integration site; M\selectlanguage{greek}Φ, \selectlanguage{english}macrophage; CD, the cluster
of differentiation.\selectlanguage{english}
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