University of Illinois Chicago-led researchers have found that a common gut yeast, Candida albicans, can help Salmonella Typhimurium take hold in the intestine and spread through the body. When interacting, a Salmonella protein called SopB prompts the yeast to release arginine, which turns on Salmonella’s invasion machinery and quiets the body’s inflammation signals.

Gut microbes shape human health across colonization resistance, immune training, digestion, and signaling that reaches distant organs. Bacteria dominate both abundance and research attention, while roles for viruses and fungi remain less defined.

Altered mycobiome composition appears in multiple gastrointestinal diseases, and integration of fungi into gut ecology and into interactions with commensal and pathogenic bacteria remains largely unknown.

Non-typhoidal Salmonella ranks among the best-studied enteric pathogens, infecting an estimated 100 million people each year. Healthy individuals typically experience localized inflammatory diarrhea, while immunocompromised patients face risks of spread to peripheral organs.

Establishing gut colonization requires competition with resident microorganisms, and commensal fungi occur across tested mammalian species, yet mycobiome contributions during enteric infection remain largely unexplored.

Candida albicans is a frequent colonizer of human mucosal surfaces, present in the gut of more than 60% of healthy humans. Usual behavior is commensal, with pathogenic potential particularly in immunocompromised hosts. A key virulence trait is morphology switching from yeast to epithelium-penetrating hyphae.

Associations with inflammatory bowel disease, specifically Crohn’s disease, have been reported. C. albicans cannot induce gut inflammation and has been shown to exacerbate it. Both Salmonella and C. albicans thrive under inflammatory gut conditions, and C. albicans likely resides in the gut of many patients at the time Salmonella infection occurs.

In the study, “Commensal yeast promotes Salmonella Typhimurium virulence,” published in Nature, researchers investigated cross-kingdom interactions to determine how Candida albicans influences Salmonella colonization, systemic dissemination, and host inflammatory responses.

Mouse cohorts included C57BL/6 and CBA/J strains under streptomycin pre-treatment and antibiotic-free conditions. Additional models featured germ-free and altered Schaedler flora mice. In vitro assays used human colonic epithelial cell lines T84 and Caco2.

Researchers ran two kinds of mouse tests. One with an antibiotic primer and one where mice were first colonized with Candida albicans without antibiotics. Infections used a 10:1 Salmonella to Candida ratio, with checks at 24, 48, and 72 hours for gut levels, spread to spleen and liver, and weight loss. Some mice were germ-free or carried an eight-member altered Schaedler flora. Drinking water sometimes included 2% L-arginine at pH 7 or 20 mM L-lysine.

In lab dishes, human colon cell lines T84 and Caco2 were exposed to Salmonella at MOI=1 for two hours, alone or together with live Candida at the same 10:1 ratio, with heat-killed Candida and curdlan as controls. Binding between microbes was measured by sedimentation and microscopy, and mannose reduced binding.

Genetic tests removed Salmonella parts for binding and secretion and an arginine transporter. Candida lines lacked arginine production or had it restored.

Readouts included RNA sequencing with pathway analysis, rt-qPCR for invasion and arginine genes, single-cell SPI-1 reporters, metabolomics of amino acids in cultures and mouse gut contents, tests of co-culture supernatants on invasion, ITS and 16S sequencing of the microbiota, and host measures such as gene expression, serum cytokines, neutrophil infiltration, and pathology scores.

Candida in the gut led to higher Salmonella loads in the large intestine and more bacteria reaching the spleen and liver, with co-infected mice losing more weight. Candida also boosted Salmonella entry into human colon cell lines. Gene readouts showed Salmonella’s invasion machinery switched on near Candida.

Co-cultures contained millimolar arginine, and adding L-arginine alone increased invasion in a dose-dependent way, while an arginine-transporter mutant did not respond to Candida. Candida lacking arginine production also failed to boost Salmonella invasion or gut colonization, and an ARG4 revertant restored the effect.

SopB triggered Candida arginine biosynthesis genes and arginine release and deleting sopB eliminated the effect.

Co-infected mice showed lower inflammatory signals such as Il17, Cxcl1, serum IFNγ, and neutrophil influx. 2% L-arginine in drinking water mimicked this drop and increased spread to organs, and L-lysine partly reversed Candida-driven changes.

Authors conclude that C. albicans colonization represents a susceptibility factor for Salmonella infection, with arginine acting as a pivotal metabolite connecting fungus, bacterium, and host. Findings point to SopB-driven arginine production in Candida that boosts Salmonella’s invasion program while softening host inflammatory signals.

Prevalence of C. albicans during Salmonella Typhimurium illness in patients remains unclear. A referenced study in Cameroon reported a fourfold rise in recurrent typhoid or paratyphoid when patients were colonized with Candida. The authors propose antifungal treatment as a potential option for vulnerable groups.

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