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Microbes & Immunity Sepsis and gut microbiome

Megasphaera, and Prevotella (especially Prevotella copri) senescent red blood cells during lipopolysaccharide-
could potentially confer a protective effect against sepsis. induced inflammation. Furthermore, these mice exhibited
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Similarly, research on a septic animal model treated reduced immune apoptosis and an elevated presence
with cecal ligation and puncture (CLP) indicated that of fecal IgA+ bacteria, which potentially contribute to
a high-fiber diet could mitigate systemic inflammation intestinal inflammation. This finding illustrated how
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and mortality. Conversely, a high-fat diet was found to impaired intestinal permeability can promote bacterial
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increase mortality and organ damage in the CLP mouse growth and increase the susceptibility to sepsis.
model of sepsis, corroborating findings from a U.S. Within the intricate third layer are intestinal epithelial
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cohort study involving 21,404 participants which indicated cells, comprising enterocytes, goblet cells, stem cells,
that a Southern dietary pattern was linked to a higher risk neuroendocrine cells, and Paneth cells. Enterocytes, the
of sepsis. However, the specific impact of a high-fat diet predominant cell type among intestinal epithelial cells, are
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on the gut microbiota remains elusive. Further study to responsible for nutrient absorption and immunoglobulin
deepen understanding of the relationship between diet and secretion. They facilitate cell–cell communication through
microbiota could unveil novel approaches in formulating structures such as tight junctions, adherent junctions,
dietary interventions for septic patients. The Surviving and gap junctions. Paneth cells, primarily found in the
Sepsis Campaign recommends early enteral nutrition for small intestine, can activate toll-like receptors through
adult patients with sepsis or septic shock due to its potential direct contact with bacteria. Generating microbial cell
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impact on reducing gastrointestinal complications and wall components such as pathogen-associated molecular
influencing gut permeability, inflammation, and immune patterns such as lipopolysaccharide and peptidoglycan
responses. 32,33 can trigger excessive immune activation. In addition,
3. Host defense mechanisms against sepsis damage-associated molecular patterns originating from
apoptotic intestinal epithelial cells, such as HMGB1 and
3.1. Intestine as a barrier in sepsis mtDNA, can elevate adhesion molecules on the intestinal
The intestinal barrier is a complex structure comprising endothelium, leading to the recruitment of neutrophils
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three essential layers: the luminal layer, mucus layer, and macrophages. The migration of these immune
and epithelial layer. In the luminal layer, commensal cells to the gut can induce systemic inflammation
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gut microbiomes are crucial in inhibiting opportunistic characterized by the release of proinflammatory cytokines
and pathogenic microbial species from colonizing the through MAPK/NF-κB pathways. This cascade can
intestines, especially in ICU patients. The mucus layer increase intestinal permeability, exacerbating gut barrier
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acts as a physical barrier that lubricates the contents passing dysfunction by modulating tight junction proteins.
through the intestine and aids in digesting enzymes. The redistribution of the tight junction proteins may
This layer thrives in the presence of the microbiome. In facilitate the translocation of local bacteria from the
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addition, it interacts with secretions from Paneth cells gut lumen. One such protein, claudin-2, which forms
and enterocytes, such as lysozyme and immunoglobulin paracellular cation and water channels, is selectively
A (IgA), which collectively exert an antibacterial effect. upregulated in septic patients. Deletion of claudin-2 in
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Wilmore et al. revealed the critical role of beneficial mice was found to protect against sepsis-induced pore
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microbes in stimulating the production of serum IgA pathway permeability, reducing IL-17 production, T-cell
antibodies. These IgA antibodies can help mitigate the activation, and intestinal damage. This leads to decreased
severity of polymicrobial sepsis by neutralizing pathogens numbers of neutrophils, macrophages, dendritic cells
and impeding their dissemination from the gut into (DCs), and bacteria in the peritoneal fluid of mice.
the systemic circulation. Furthermore, the mucus layer Consequently, claudin-2 deletion significantly improves
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is rich in mucins (MUCs) produced by goblet cells. The survival in sepsis. By targeting claudin-2, interventions
small intestine has a monolayer of mucus, whereas the could modulate the microbiome composition and
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large intestine features two substantial layers. Among function, offering new avenues for sepsis management
these mucins, MUC2 stands out as the predominant and treatment strategies.
protein responsible for maintaining mucosal homeostasis 3.2. Intestinal immune responses in sepsis
by restricting the interaction between pathogens and the
underlying epithelial layer. In a study with Muc2-deficient While bacteria and endotoxins may not directly enter
(Muc2 ) mice, characterized by the absence of an intestinal circulation, they have the potential to trigger immune
-/-
mucus layer and increased intestinal permeability, it responses within the local gut-associated lymphoid
was noted that the efficacy of splenic macrophages tissue (GALT), leading to systemic inflammation. GALT,
in erythrophagocytosis decreased when recognizing functioning as a secondary lymphatic organ, protects

Volume 2 Issue 1 (2025) 6 doi: 10.36922/mi.4742