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Review
. 2024 Jan-Dec;16(1):2395099.
doi: 10.1080/19490976.2024.2395099. Epub 2024 Sep 6.

The hidden base of the iceberg: gut peptidoglycome dynamics is foundational to its influence on the host

Richard Wheeler  1   2 , Ivo Gomperts Boneca  1
Affiliations
Review

The hidden base of the iceberg: gut peptidoglycome dynamics is foundational to its influence on the host

Richard Wheeler et al. Gut Microbes. 2024 Jan-Dec.

Abstract

The intestinal microbiota of humans includes a highly diverse range of bacterial species. All these bacteria possess a cell wall, composed primarily of the macromolecule peptidoglycan. As such, the gut also harbors an abundant and varied peptidoglycome. A remarkable range of host physiological pathways are regulated by peptidoglycan fragments that originate from the gut microbiota and enter the host system. Interactions between the host system and peptidoglycan can influence physiological development and homeostasis, promote health, or contribute to inflammatory disease. Underlying these effects is the interplay between microbiota composition and enzymatic processes that shape the intestinal peptidoglycome, dictating the types of peptidoglycan generated, that subsequently cross the gut barrier. In this review, we highlight and discuss the hidden and emerging functional aspects of the microbiome, i.e. the hidden base of the iceberg, that modulate the composition of gut peptidoglycan, and how these fundamental processes are drivers of physiological outcomes for the host.

Keywords: Gut; Microbiota; PG trafficking; chronic inflammation; host signaling; peptidoglycan; peptidoglycan processing; prophage.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
The “iceberg” of gut peptidoglycome dynamics in the host.
Figure 2.
Figure 2.
Interaction and feedback between major parameters of the gut ecosystem that shape the intestinal peptidoglycome.
Figure 3.
Figure 3.
Summary diagram of the peptidoglycan network and the peptidoglycan types and variants according to the scheme of Schleifer and Kandler. A; simple schematic of the peptidoglycan polymer and its soluble fractions, “muropeptides”, generated by glycosidase activity. Image shows a typical diderm peptidoglycan sacculus (atomic force microscopy height profile image of purified Helicobacter pylori peptidoglycan). B; schematic of type A peptidoglycan, represented based on a GM4 dimer. The most typical variants are indicated. C; schematic of type B peptidoglycan, represented based on a GM4 dimer. The most typical variants are indicated. Ala, alanine; dab, diaminobutyric acid; glu, isoglutamate; glx, isoglutamate or isoglutamine; gly, glycine; Hsr, homoserine; Hyg, threo-3-hydroxyglutamate; lys, lysine; mesoDAP, meso-diaminopimelic acid; mesoDAPNH2, amidated meso-diaminopimelic acid; orn, ornithine.
Figure 4.
Figure 4.
The specificity of microbiota and host enzymes and receptors for peptidoglycan. 1) the major peptidoglycan-degrading enzymatic activities of the microbiota or host discussed in this review. 2) lysozyme and PGLYRP-2 are the major host secreted enzymes capable of binding and cleaving polymeric peptidoglycan. PGLYRP-1, −3 and − 4 bind polymeric peptidoglycan but have no hydrolase activity. Green triangle, O-acetylation; red triangle, De-N-acetylation. 3) muropeptides released from bacteria must reach the eukaryotic cell cytosol to be detected. SCL15A-family and SLC46A-family membrane transporters are implicated in this function. Bulk transport of peptidoglycan or bacteria may occur via endocytosis pathways, but the muropeptides must be transported across the endosomal membrane to be sensed by PRRs. 4) the major host peptidoglycan receptors, NOD1 and NOD2, sense distinct muropeptide fractions. The minimal and classical ligands are indicated. NOD1 also senses 1,6-anhydro MurNAc-containing muropeptides whilst the presence of UDP expands the range of muropeptides recognized by NOD2. Phosphorylation of MurNAc by NAGK augments recognition by NOD2. 5) muropeptide binding triggers NOD1/2 oligomerization and recruitment of RIP2, initiating NF-κB or MAPK signaling pathways resulting in cellular response outputs. Alternatively, NOD1/2 can recruit ATG16L1 to initiate autophagy. 6) N-acetyl-D-glucosamine can be bound by hexokinase leading to its dissociation from the mitochondrial membrane, which triggers a pathway leading to NLRP3 inflammasome activation. Amidase, N-acetylmuramyl-L-alanine amidase; glucosaminidase, N-acetyl-β-D-glucosaminidase; Lys, lysine; mesoDAP, meso-diaminopimelic acid; mesoDAPNH2, amidated meso-diaminopimelic acid; mesoLan, meso-lanthionine; orn, ornithine.
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Grants and funding

The work was supported by the Agence Nationale de la Recherche [ANR-16-CE15-0021]; Agence Nationale de la Recherche [RHU Torino Lumière ANR-16-RHUS-0008]; Agence Nationale de la Recherche [Labex IBEID ANR-10-Labex-62-IBEID]; “Danone; Fondation Arthritis” [2022-068_GOMPERTS-BONECA_Peptidoglycome JIA]; Meiji.

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