The Miraculous Effectiveness of Probiotic Intervention in Traumatic Brain Injury

Traumatic brain injury (TBI) is harmful and lacks effective treatments, and the neuroinflammation it causes interacts with gut flora dysbiosis. Researchers conducted a study on the effects of probiotic therapy on the inflammatory response to TBI and found that probiotics regulate flora, reduce inflammation, improve function, and that there are gender differences.

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Overview

Head trauma poses a major threat to human health, with TBI receiving much attention due to its potential long-term harm. As a major cause of death and disability worldwide, TBI not only causes immediate damage, but also significantly increases the risk of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The challenge facing the medical community today is the lack of effective therapies to promote neuroprotection or brain tissue regeneration in both acute and chronic phases.

In terms of pathological mechanisms, neuroinflammation triggered by TBI is the core of the deterioration of the disease. The activation of microglia, macrophages, neutrophils and other immune cells at the site of injury releases a large number of inflammatory mediators, and this excessive immune response not only directly causes secondary brain damage, but also triggers systemic effects through the "brain-gut axis". Recent studies have found that gut flora disruption caused by TBI exacerbates central neuroinflammation, while dysregulated gut microbes in turn affect microglia, creating a self-reinforcing vicious cycle. This bidirectional mechanism of action explains why some patients experience persistent cognitive and motor dysfunction.

A team of researchers at the Houston Methodist Research Institute conducted an innovative exploration of this complex pathologic network. They focused on the role of probiotic intervention in modulating the inflammatory response in the acute and chronic phases of TBI, and their findings have been published in the Journal of Neuroinflammation. This study provides a theoretical basis for breaking the "brain-gut vicious cycle" through the regulation of intestinal flora, and also opens up a new direction for the development of novel neuroprotective strategies.

Findings of the Study

The researchers used a variety of key technical methods. First, they established a mouse TBI model, using a controlled cortical impact (CCI) injury system to model moderate to severe TBI in mice. Then, they prepared a probiotic (Pan-probiotic, PP) mixture containing multiple Lactobacillus strains and gave it to mice orally. They also used 16S rRNA V1-V3 sequencing analysis to evaluate the taxonomic characteristics of the microbiota in fecal samples. Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS) was used to measure the level of short-chain fatty acids (SCFAs). Immunohistochemistry, in situ hybridization, and histological analysis were used to evaluate neuroinflammation after TBI. Behavioral assessments were used to detect the sensorimotor and cognitive functions of mice.

• Modulation of Gut Microbiota Diversity

The impact of the probiotic preparation (PP) treatment on gut microbial diversity manifested in a manner dependent on both sex and time post-intervention. Specifically, within the female cohort subjected to Traumatic Brain Injury (TBI), PP administration yielded a significant elevation in alpha diversity, as measured by the Simpson's index, at the 7-week time point. Furthermore, an earlier significant increase in microbial richness (Chao1 index) was observed at 2 weeks in these PP-treated TBI females. Analysis of beta diversity, reflecting overall community structure, revealed significant distinctions between the PP-treated TBI group and control females at both 2 and 7 weeks.

Conversely, male mice exhibited a differential response profile. Following TBI, PP treatment did not elicit statistically significant alterations in the assessed alpha diversity indices (Simpson, Chao1) at either the 2-week or 7-week evaluations. Investigation of beta diversity did, however, identify a significant divergence between the PP-treated sham-operated male group and their corresponding controls, although this effect was confined to the 7-week assessment point.

• Impact on Gut Microbiota Composition

Significant shifts in the relative abundance of specific bacterial taxa were induced by PP treatment, with patterns varying according to sex and injury condition. In sham-operated animals (lacking TBI), PP administration led to a significant increase in the relative abundance of Lactiplantibacillus and Limosilactobacillus within male mice. Sham-operated females receiving PP demonstrated significantly elevated levels of Lactiplantibacillus and Lacticaseibacillus.

Subsequent to TBI induction, PP treatment continued to drive taxonomic changes. Male mice subjected to TBI and receiving PP exhibited significantly augmented relative abundances of Lactiplantibacillus and the genus designated Lactobacillaceae HT002. In the corresponding female TBI cohort treated with PP, a significant increase was specifically documented for the relative abundance of Lactobacillaceae HT002.

• Effects on Levels of SCFAs

The effects of PP treatment on levels of SCFAs were also sex- and time-dependent. At 35 days, isobutyric acid, 2-methylbutyric acid, valeric acid, and hexanoic acid levels were significantly increased in PP-treated male mice, and 2-methylbutyric acid and hexanoic acid were higher in PP-treated male mice than in female mice.

• Effects on Injury and Cell Death

At 3 days, PP treatment significantly reduced injury volume and apoptotic cell death in male mice but not in females; at 35 days, PP treatment had no significant effect on injury volume in either male or female mice.

• Effects on Neuroinflammatory Response

PP treatment significantly decreased the density of Iba1⁺ cells and reduced the neuroinflammatory response in male but not in female mice at both 3 and 35 days.

• Effects on Locomotor Function and Depression-like Behavior

In male mice, PP treatment improved locomotor performance after TBI; in female mice, PP treatment significantly reduced immobility time after TBI, with an antidepressant-like effect.

Taken together, this study demonstrates the potential of PP supplementation to modulate the gut microbiota, metabolic profile, and inflammation, providing neuroprotective and behavioral improvement benefits in mice following TBI. This research highlights the importance of gut-brain axis interactions and sex-specific responses, provides a theoretical basis for the use of probiotics in clinical TBI rehabilitation, and points the way to more in-depth research and personalized approaches to TBI rehabilitation.

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Reference

1. Holcomb, M., Marshall, A.G., Flinn, H. et al. Probiotic treatment induces sex-dependent neuroprotection and gut microbiome shifts after traumatic brain injury. J Neuroinflammation 22, 114 (2025). Distributed under Open Access license CC BY 4.0, without modification.