Can Nature Overcome Invasive Gastrointestinal Infections?

Abstract

Invasive bacterial gastrointestinal infections represent a substantial clinical burden worldwide, contributing to significant morbidity and, in severe cases, mortality. The causative bacterial agents of these infections include Shigella spp., enteroinvasive Escherichia coli, Salmonella spp., Campylobacter jejuni, Yersinia enterocolitica, and Listeria monocytogenes. Given the growing challenges of therapy failures and rising antibiotic resistance, there is still an unmet need to identify novel, effective, and safe compounds exhibiting antimicrobial, anti-inflammatory, and immunomodulatory activities. In the present review, we aimed to compile current data regarding three alkaloids-berberine, sanguinarine, and cheleritrin-which hold significant promise in treating bacterial invasive gastrointestinal diseases. Our review extended beyond the direct antimicrobial properties of these compounds against pathogens capable of breaching the intestinal epithelial barrier. We also presented their modulatory effects on intestinal barrier integrity and their influence on the composition and function of the resident gut microbiota, thereby highlighting their potential indirect role in attenuating pathogen invasion and disease progression. Thus, our review presents alkaloids as potential preparations that potentiate the activity of classic anti-infective drugs, as well as substances that, by affecting the microbiome and intestinal mucosa, could be used for inflammatory bowel diseases.

Keywords: berberine; cheleritrin; intestinal barrier; invasion; permeability; sanguinarine.

Figure 1

Source and transmission of infections caused by invasive pathogens. (A) The Shigella spp., Salmonella spp., EIEC, and Yersinia enterocolitica internalization process. These bacteria penetrate M cells in Peyer’s tufts, leading to colon damage. (B) Campylobacter jejuni’s invasion into host cells. This takes place by endocytosis, leading to damage to the ileum and colon.

Figure 2

The source and transmission of Listeria monocytogenes infections. The specialized process of internalization of L. monocytogenes into the epithelium of the gastrointestinal tract is carried out by (1) the transcytosis of M cells in Peyer’s clusters and (2) the binding of internalin A (InlA) to E-cadherin on enterocyte microvilli, leading to damage to the ileum and colon.

Figure 3

Simplified scheme of Shigella spp. and EIEC enteroinvasion: (I) Bacterial internalization causing NOD activation and NF-κB signaling pathway upregulation resulting in IL-8 secretion. Neutrophil migration and activation cause the degradation of tight junctions (occludins and claudins), which potentiate bacterial infiltration of submucosal tissue. (II) Internalization of bacterial cells into M cells and their transcytosis to macrophages located downstream. Fusion of lysosome with endosome is inhibited, the bacterium escapes from the endosome to the cytosol, and virulence factor IpaB promotes apoptosis of macrophages. (III) Shigella/EIEC, after escaping from the macrophage, invades the enterocyte via T3SS and its effectors (e.g., IpaA-C). Then, the bacterium induces phagosome lysis and translocates into the cytosol, and the IcsA protein induces the formation of F-actin polymer (actin tail). The pathogen migrates to the surrounding enterocytes. Elements common to other pathogens can be found in the scheme: L. monocytogenes ((III) formation of actin tail), Salmonella and Yersinia ((I–III) the difference is that these pathogens do not polymerize F-actin and stay in primary formed vacuoles inside phagocytes or enterocytes—lack of phagosome escape). Abbreviations: CD4—cluster of differentiation 4; IcsA—Intracellular chromosome-mediated spreading Actin-based motility protein; IL—interleukin; INF-γ—interferon gamma; IpaA-D, IpgB1/2—invasiveness factors of Shigella/EIEC; Mφ—macrophage; MHC II—Major Histocompatibility Complex class II; NF-κB—nuclear factor κB; NK cell—natural killer type cell; NOD—nucleotide-binding oligomerization domain-like receptors; TCR—T-cell receptor; T3SS—type 3 secretory system; VirA—Virulence-associated protein A.

Figure 4

Molecular structure of BBR.

Figure 5

Molecular structure of SAN.

Figure 6

The impact of SAN on the intestines. (A) SAN suppresses the activation of the HMGB1/TLR4 pathway, reduces NF-κB expression, and lowers levels of pro-inflammatory cytokines [181,189]. (B) SAN decreases the level of pro-inflammatory cytokines (red square ) and increases the level of anti-inflammatory cytokines (green square ) [181,187,189]. (C) SAN strengthens the intestinal barrier function through improving the expression of tight junction proteins, especially ZO-1 [186].

Figure 7

Molecular structure of CHE.