Different Dietary Components Alter Gut Microbiota. What Does That Mean for Immunity?

B. theta and the Study Aim

Nutrition, health status, stress, and circadian rhythm all shape the environment in which gut bacteria live—and these microbes influence our immune defense. Strains of the same bacterial species can regulate the immune system in different, sometimes even opposing ways—pro -⁠ or anti-inflammatory, for example. The microbial “neighbors” also play a key role.

The study focused on a key member of the gut microbiota: Bacteroides thetaiotaomicron (B. theta), a gram-negative anaerobe known for its anti-inflammatory properties, enhancement of gut barrier function, and protective role against pathogens. B. theta carries over 80 genes for polysaccharide digestion—polysaccharide utilization loci (PULs)—enabling it to metabolize a wide variety of dietary carbohydrates that reach the colon undigested. The availability of these polysaccharides depends on the host's diet, and using PULs allows the bacteria to adapt to environmental changes.

The researchers aimed to investigate how B. theta responds to different human diets and how these responses influence the host's immune system. The topic was further explored using experimental in vivo and in vitro models.

Findings in Humans

The human cohort included individuals with inflammatory bowel disease (IBD) and healthy participants from the IBDMDB (The Inflammatory Bowel Disease Multi'omics Database), totaling 132 individuals. This database offers a robust resource for analyzing microbiome behavior in the context of IBD.

One key adaptation mechanism for gut bacteria is **reversible DNA inversions**, allowing transcriptional plasticity. Some inversions affect promoter regions—turning gene expression on or off—while others relocate dormant genes to transcriptionally active areas. Researchers examined how various foods influenced the frequency of these inversions, using the PhaseFinder software to identify inversion events and dietary questionnaires filled out by participants.

Consumption of diverse foods (plant proteins, processed meats, fruit juices, alcohol, soda, whole grains, starch) was indeed reflected in the frequency of DNA inversions in B. theta. The most significant changes were linked to the intake of sugars—especially sweetened beverages and fruit juices.

Findings in Mice

To test how sugary drinks impact B. theta and its potential immunomodulatory effects, researchers used germ-free (GF) mice, which are raised in sterile conditions and lack microbes. Some mice were monocolonized with B. theta. Ten days later, they were split into two groups: one drank plain water, and the other 9% sugar water.

After several days, researchers examined immune cell populations in the colon, spleen, and mesenteric lymph nodes (mLN), and measured levels of TNF-α, IL-6, and zonula occludens proteins in colon tissue. B. theta exhibited genomic and metabolic changes in response to sugar, and its immunomodulatory functions were linked to DNA inversion patterns.

The plasticity of B. theta’s immune-modulating ability was confirmed. In a follow-up, three groups of monocolonized mice were compared—those drinking plain water, sugar water, or sugar water followed by plain water after 7 days. After switching to plain water, both B. theta DNA and immune markers were comparable to the control group, showing reversibility of effects.

In Vitro Findings

To analyze how specific carbohydrates influenced DNA inversions in B. theta, researchers cultured it for 24 hours in minimal media supplemented with one of 190 carbon sources. B. theta utilized 22 of these—ranging from mono-, di-, and oligosaccharides to polysaccharides.

Since previous research showed that gut bacteria can modulate host immunity via secreted molecules, researchers tested the immunomodulatory function of B. theta using conditioned media (CM)—media in which the bacteria had grown. CM was introduced to splenocytes from specific-pathogen-free mice. After 5 days of culture, T cell populations and cytokine levels were assessed.

The immune effects of B. theta varied with the carbon source. Researchers further explored the role of short-chain fatty acids (SCFAs), known to stimulate anti-inflammatory cytokine production. Although carbon source influenced SCFA concentrations in the CM, SCFA levels generally did not correlate with immunomodulatory effects. Instead, carbon sources led to different protein expression profiles—particularly membrane proteins from the PUL family. Follow-up experiments suggest that secreted proteins may help the bacteria adapt to different environments.

What’s Next?

"Our results highlight the importance of studying bacterial functionality under different conditions and the potential impact of dietary carbohydrates on bacterial immunomodulatory capacity," the authors concluded.

According to the study, understanding how specific dietary components affect key gut microbes and their immune-modulating potential could have real-world benefits: enabling personalized nutrition guidance based on an individual’s microbiome composition.

Editorial Team, Medscope.pro

Source: Gal-Mandelbaum N., Carasso S., Kedem A. et al. Dietary carbohydrates alter immune-modulatory functionalities and DNA inversions in Bacteroides thetaiotaomicron. Nat Commun 2025; 16 (1): 4938, doi: 10.1038/s41467-025-60202-9.