Gut bacteria found to influence cerebral malaria severity

University of the Ryukyus reports world-first findings in infected mice

A research team including Assistant Professor Tomoyo Taniguchi and Professor Hidehiro Kishimoto of the Graduate School of Medicine at the University of the Ryukyus, Professor Emeritus Hiroshi Suzuki of Obihiro University of Agriculture and Veterinary Medicine, and Group Director Hiroshi Ohno of the RIKEN Center for Integrative Medical Sciences has revealed for the first time in the world that specific gut bacterial species and compositions are involved in the pathogenesis of cerebral malaria, the most severe complication of Plasmodium falciparum malaria. This study demonstrated a new potential for prevention strategies against cerebral malaria through the regulation of gut microbiota. The findings were published in Tropical Medicine and Health.

Malaria is the most significant tropical parasitic infection transmitted through mosquito bites, with an estimated 282 million cases and 610,000 deaths worldwide in 2024, according to the WHO's World malaria report 2025. In Japan, all reported malaria cases are imported infections, with individuals contracting the disease while visiting malaria-endemic areas and developing symptoms after returning home country. Because the infection initially presents with cold-like symptoms, such as fever, headache, and chills, delayed diagnosis and treatment may lead to severe disease progression, which is a significant clinical concern. Cerebral malaria is a severe complication of P. falciparum infection characterized by impaired consciousness, convulsions, and coma.

To investigate whether the host's gut microbiota affects cerebral malaria, the joint research group altered the gut microbiota via antibiotic administration and examined its effects on experimental cerebral malaria (ECM).

ECM is an experimental model in which C57BL/6 mice infected with the rodent malaria parasite P. berghei ANKA develop small-intestinal lesions and neurological symptoms similar to those observed in human patients. When a combination of four antibiotics (ampicillin, neomycin, metronidazole, and vancomycin) was administered to mice through their drinking water from 2 weeks before infection until the end of the experiment, approximately 80% of the mice were protected from ECM-associated mortality. Evaluating the blood-brain barrier (BBB) permeability associated with ECM revealed that Evans blue dye leakage was significantly reduced in the antibiotic-administered group. Furthermore, histological evaluation confirmed a mitigation of brain lesions (adhesion of infected erythrocytes, hemorrhaging, and vascular occlusion in the olfactory bulb, cerebellum, and cerebral parenchyma), along with a remarkable reduction in leukocyte infiltration that triggers brain inflammation. These results indicate that antibiotic-induced alteration of the gut microbiota suppresses erythrocyte adhesion and leukocyte infiltration into the brain, ultimately resulting in milder neurological symptoms.

Because mitigation of ECM was observed following the alteration of gut microbiota via the four-antibiotic cocktail, the research team attempted to identify the specific gut bacteria associated with ECM by conducting a comparative microbiota analysis across six groups (the four-antibiotic cocktail group, four single-antibiotic groups administering only one type of antibiotic, and an untreated control group). The results showed that full protection against ECM occurred only with the four-antibiotic cocktail, whereas single-antibiotic treatments yielded only about a 50% protective effect. Through this comparative analysis, they identified candidate bacteria that increased in this combination group, as well as those that decreased exclusively under this treatment.

To rule out any direct effects of the antibiotics on ECM, live bacteria corresponding to the candidate bacterium (ASV1) that increased the most in the combination group and the candidate bacterium (ASV37) whose proportion decreased exclusively in this group were orally administered to germ-free mice to establish colonization (gnotobiotic mice) and assess their effects on ECM. The live bacteria (ASV1 and ASV37) were isolated from mouse feces, exhibiting 100% sequence identity to the V4 region of the 16S rRNA gene identified in the microbiota analysis.

In the gnotobiotic mice colonized with ASV1, the onset and death from ECM were delayed compared to the control group, and parasitemia remained lower throughout the infection period. Conversely, gnotobiotic mice colonized with ASV37 exhibited neurological symptoms earlier than the control group, starting from day 4, and 80% of the mice died by day 7. This result demonstrates that ECM progression is mediated by gut bacteria rather than the antibiotics.

If further research clarifies the mechanism by which gut bacteria influence the onset of cerebral malaria, it will open up new avenues for prevention and diagnosis toward "Zero Malaria," including the development of gut microbiota-based biomarkers and therapies aimed at restoring a healthy microbiota.

Journal Information
Publication: Tropical Medicine and Health
Title: Gut microbiota bidirectionally influences protection and severity in cerebral malaria in mice
DOI: 10.1186/s41182-026-00947-1