How a Gut Bacterium Can Calm the Immune System
The ENDOTARGET consortium has released a new publication entitled “Odoribacter splanchnicus lipooligosaccharide: an uncommon structure with weak immunostimulatory activity.” The study investigates both the structure and function of a particular molecule from the gut bacterium Odoribacter splanchnicus and it is a joint effort by the ENDOTARGET consortium (University of Helsinki, Finland) and the University of Naples Federico II (Italy). Published in November 2025 in the journal Chemical Science, the research is authored by Marta Tiemblo-Martin, Marcello Mercogliano, Kaisa Hiippala, Luca De Simone Carone, María Asunción Campanero-Rhodes, Maria Masiello, Alessandro Cangiano, Antonio Molinaro, Luigi Paduano, Dolores Solís, Reetta Satokari, Flaviana Di Lorenzo, and Alba Silipo.
Why is the research topic important?
The human gut is home to trillions of microorganisms, collectively known as the gut microbiota. Over the past decades, research has shown that these microbes do far more than help digest food. They actively interact with the gut epithelium and immune system and can either promote or reduce inflammation.
Many chronic diseases, including inflammatory bowel disease, metabolic disorders, and rheumatic diseases, have been linked to changes in gut microbiota composition. In this context, certain gut bacteria are now being investigated as potential live biotherapeutic products (LBPs); microorganisms that may treat or prevent diseases rather than simply supplement digestion. O. splanchnicus is recognised as a prevalent and metabolically active member of the healthy gut microbial community, associated with health-promoting effects such as anti-inflammatory activity and reinforcement of the epithelial barrier. This contradicts the fact that O. splanchnicus is a Gram-negative bacterium, as this type of bacterium typically carries lipopolysaccharides (LPS) on its surface, which are known to strongly activate the immune system and trigger inflammation.
This raises the question: How can a Gram-negative bacterium, whose outer membrane normally contains highly inflammatory molecules, be linked to anti-inflammatory effects? This study addresses this apparent contradiction by closely examining the structure and function of a related molecule from O. splanchnicus, its lipooligosaccharide.
What is lipooligosaccharide (LOS), and why does it matter?
Lipooligosaccharides (LOS) are surface molecules found in some Gram-negative bacteria. They are closely related to LPS but lack one component, which is the long sugar chain known as the O-antigen. Despite this difference, LOS molecules still contain lipid A, the part usually responsible for triggering immune responses.
In many bacteria, lipid A strongly activates immune receptors, especially Toll-like receptor 4 (TLR4), leading to inflammation. This is helpful during infections but problematic when inflammation becomes chronic.
The central hypothesis of the study was that the LOS from O. splanchnicus must have unusual structural features that explain its weak immune activation and its apparent anti-inflammatory behavior.
How was the study conducted?
This study provides the first comprehensive structural and functional characterisation of the O. splanchnicus LOS.
Structural analysis was done by using advanced techniques such as:
- Nuclear Magnetic Resonance (NMR) spectroscopy
- Mass spectrometry
- Small-angle X-ray scattering
These methods allowed to determine the exact chemical structure of the LOS, including both its sugar components and its lipid portion.
Functional analysis was done by testing the isolated LOS in human cell models. It was examined:
- Whether the LOS activates immune receptors (TLR4 and TLR2)
- Whether it induces inflammatory signals in enterocytes ( intestinal epithelial cells)
- Whether it can interfere with or reduce inflammation caused by highly inflammatory bacterial LPS (such as those from Escherichia coli)
What does the analysis show us?
An unusual molecular structure
The study revealed an uncommon LOS structure of O. splanchnicus. Its lipid A component is mono-phosphorylated (only one phosphate group instead of two) and under-acylated (fewer fatty acid chains than strongly inflammatory LPS). Both features are known to reduce immune activation. In addition, the sugar core of the LOS contains rare sugar residues that are not commonly found in bacterial surface molecules.
A “shielded” inflammatory core
Due to the structural peculiarity of the O. splanchnicus LOS, its supramolecular organisation was analysed. It was revealed that in aqueous solution, the LOS self-assembles into spherical structures called micelles. Interestingly, in these micelles (i) the potentially inflammatory lipid A is hidden in the center, and (ii) the sugar components form a large outer shell. This physical arrangement acts like a protective shield, limiting the access of immune receptors to the inflammatory part of the molecule. As a result, immune cells have difficulty recognising and responding to it.
Weak immune activation
When tested in human immune cell models, the LOS:
- Activated TLR4 only very weakly
- Did not activate TLR2
- Did not induce the release of IL-8, a key inflammatory signal, in enterocytes
In contrast, classical E. coli LPS triggered strong inflammatory responses under the same conditions.
Even more interestingly, the O. splanchnicus LOS could reduce inflammation caused by inflammatory LPS, either by competing with it or by “pre-conditioning” cells to respond less strongly.
What can we learn from the study?
This study highlights the O. splanchnicus LOS as a structurally and functionally distinct bacterial molecule with important implications for host–microbe interaction. Its unique features converge to create a low-inflammatory phenotype that facilitates immune tolerance, epithelial integrity, and the commensal persistence of O. splanchnicus in the human gut. The work also supports the idea that beneficial gut bacteria could be developed into live biotherapeutic agents or inspire new strategies to control inflammation without suppressing the immune system entirely.
From an ENDOTARGET perspective, these findings are highly interesting, as chronic inflammatory diseases are increasingly understood as conditions involving disrupted communication between the gut and the immune system. Molecules like this LOS show how specific bacterial components can shape immune responses.
Read the full publication: Odoribacter splanchnicus lipooligosaccharide: an uncommon structure with weak immunostimulatory activity
Glossary
Core oligosaccharide (Core-OS): is the central sugar region of bacterial surface molecules such as LPS and LOS, linking the lipid A to the O-Antigen.
Enterocytes: are the main type of cells lining the small intestine, responsible for absorbing nutrients and forming a barrier between the gut contents and the bloodstream.
Gut microbiota: The community of microorganisms living in the human digestive tract, which plays a key role in digestion, immunity, and overall health.
Gram-negative bacteria: A type of bacteria with an outer membrane containing LPS or LOS, which can trigger immune responses.
Interleukin-8 (IL-8): is a signaling protein produced by cells during inflammation that attracts immune cells to the site of infection or tissue damage.
Lipopolysaccharides (LPS): Molecules found on the surface of Gram-negative bacteria that can cause inflammation when entering the bloodstream. It comprises three regions (i) lipid A, (ii) core OS, (iii) O-antigen.
Lipooligosaccharide (LOS): A shortened form of LPS that lacks the O-antigen but can still interact with the immune system.
Lipid A: is the part of LPS or LOS that anchors these molecules in the bacterial outer membrane. It is mainly responsible for triggering immune responses because it can activate immune receptors that detect bacterial components.
Live biotherapeutic products (LPB): microbial-based drugs with specific, scientifically demonstrated effect to treat or prevent diseases i.e. the they have effects beyond traditional probiotics
Mass spectrometry: is a technique used to identify and measure molecules by determining their mass and chemical composition. It allows scientists to analyse complex biological samples in great detail, such as proteins, lipids, or bacterial components.
Micelle: A spherical structure formed when certain molecules cluster together in water, often shielding hydrophobic components.
Nuclear Magnetic Resonance (NMR) spectroscopy: is a technique that allows to determine the structure of molecules by observing how their atoms behave in a strong magnetic field. It provides detailed information about the arrangement of atoms in a molecule, making it especially useful for studying complex biological substances.
O-antigen: is the outermost sugar chain of some bacterial surface molecules, such as lipopolysaccharides, and extends outward from the bacterial cell. It plays a role in how bacteria interact with the immune system and can influence how strongly the body recognises and responds to them.
Small-angle X-ray scattering: is a technique that uses X-rays to study the size, shape, and organization of molecules and particles in solution. It is especially useful for understanding how biological molecules assemble into larger structures, such as clusters or micelles, without altering their natural state.
Toll-like receptor 2 and 4 (TLR2, TRL4): are receptors on immune cells that detect bacterial molecules like LPS or LOS and trigger inflammation.
