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New research sheds light on the intricate connection between the gut microbiome and the brain, suggesting that a prebiotic diet might boost brain GABA (gamma-aminobutyric acid) levels, a key neurotransmitter associated with calming effects and neurological health.

GABA is an amino acid functioning as the principal inhibitory neurotransmitter that can act on the brain to slow or stop the reception of certain signals to the brain, leading to a calmer and more relaxed state.

Low GABA levels in the brain have been associated with neurological disorders and diseases like depression, Alzheimer’s, or epilepsy.

“Our study suggests that prebiotics have the ability to prevent or treat those brain diseases by increasing brain GABA levels via promoting gut GABA production through modulating gut microbiota,” details study corresponding author Thunatchaporn Kumrungsee, associate professor at Hiroshima University’s Graduate School of Integrated Sciences for Life.

Dietary interventions on GABA

Recently, there has been a push towards understanding more about the gut’s influence on mood, behavior, and mental health, as well as what foods might fuel or hinder a healthy mind.

The study authors aimed to assess how information directly passes between these two systems, asking: “Can an increase in gut-derived GABA directly cause an increase in the levels of brain GABA?”

The researchers set to work on determining whether brain GABA levels can be increased through dietary additions with the aim of modulating the gut bacteria present in an individual to bypass the blood-brain barrier — through which research has not yet proven GABA can pass.

Through trials on mice, researchers confirmed a “direct association” between gut GABA, brain GABA, and the gut microbiota.

There are still no solid results on whether or not gut microbiota-derived GABA can cross the blood-brain barrier and directly increase brain GABA. However, the research team claims further studies indicate a potential for other pathways to cause an increase in brain GABA elevation, such as stimulation through the vagus nerve or hormonal pathways.

Prebiotics that elevate GABA

In trials conducted on mice, researchers identified fructo-oligosaccharides (FOS), non-digestible oligosaccharides, and Aspergillus-derived enzymes, lipase and protease, as prebiotics effective in elevating brain GABA through their influence on the gut. FOS significantly increased brain GABA in the mice’s cortex and hippocampus — regions where GABA acts to reduce excitability and induce calmness.

Additionally, FOS and enzyme supplementation also raised homocarnosine levels in the hippocampus.

“Food factors such as prebiotics and fungi-derived enzymes with prebiotic-like effects have an ability to increase brain GABA and homocarnosine, a GABA-containing brain-specific peptide, which can possibly in turn enhance brain health through gut microbiota modulation,” adds Kumrungsee.

Homocarnosine has also been linked to certain brain diseases, with a previous study by Kumrungsee showing that homocarnosine-deficient mice were more prone to exhibiting depression-like behaviors and instances of hyperactivity.

Despite the lack of confirmed data on a direct increase in brain GABA derived from gut microbiota, the study provides strong indications that prebiotic consumption may indeed increase the brain’s GABA levels.

Future research will focus on unraveling the precise mechanisms by which the gut influences the brain and identifying the specific pathways involved. Once clarified, the next objective will be to determine if the prebiotic treatments used in this study can be further employed to treat GABA-related diseases, such as epilepsy or depression.

The study is published in npj Science of Food.

Gut-brain axis research highlights

As interest in the human gut-brain axis picks up, the US FDA formally acknowledged the safety of Lactobacillus plantarum DR7 — a patented probiotic strain developed by Kaneka Probiotics and AB-Biotics. One study found DR7 modulated enzymes linked to neurotransmitter production, suggesting a role in supporting healthy serotonin and dopamine levels, two key chemicals that influence mood, cognition, and emotional well-being.

In May, a clinical study suggested that a combined intervention of a synbiotic and “gut-directed” hypnotherapy significantly reduces gastrointestinal discomfort, irritability, and anxiety symptoms in autistic children.

Meanwhile, in botanical innovations, a recent clinical paper in Nutrients demonstrated that ZenGut, a natural microalgae extract developed by Microphyt, relieves digestive discomfort while enhancing mood and mental well-being in healthy adults.

Introduction

Human immunodeficiency virus (HIV) is the causative agent of acquired immune deficiency syndrome (AIDS), which induces the progressive depletion of CD4⁺ T cells in humans.¹ Infection with HIV can result in life-threatening opportunistic infections and may progress to AIDS. Since the start of the HIV epidemic, approximately 88.4 million people have been infected and 42.3 million people have died from AIDS-related illnesses.² The Joint United Nations Programme on HIV/AIDS estimates that, in 2023, there were 39.9 million people living with HIV (PLWH), 1.3 million new infections, and 630,000 deaths from AIDS-related illnesses globally.² Antiretroviral therapy (ART) is an effective therapeutic approach for preventing and treating HIV, thereby promoting a healthy lifespan.³ However, many individuals struggle with adherence to ART because of side effects, pill fatigue or aversion, and stigma.⁴ Therefore, it is necessary to find new drugs or treatments, such as traditional Chinese medicine (TCM).

TCM formulations have been used to treat AIDS in China since 2004. A national trial was conducted in the 19 major provinces to investigate the effects of TCM on AIDS, in addition to a series of research studies funded by the National Natural Science Foundation of China.⁵ Consequently, multiple TCM preparations have been developed to treat AIDS, many of which have demonstrated effectiveness.⁶ The Shuyu pill is a classic Chinese herbal formula for the treatment of Xu Lao for more 1800 years. Yiaikang(YAK) capsules, a modified form of Shuyu pills for the treatment of AIDS, which has antiviral and immune activities and improves the level of clinical application of symptoms and signs (eg, weakness, shortness of breath, spontaneous sweating, and diarrhea) in China.⁷ The main active components of YAK capsules, which are derived from the TCM prescription known as “Shuyu-Wan”, have been identified.⁸ Although YAK contains a total of 22 Chinese herbs, we summarize here the six key herbs and 11 bioactive ingredients that are used to treat AIDS, with a focus on their main target pathways, mechanisms, and therapeutic effects (Table 1). Among the active ingredients, Astragaloside IV combined Ginsenoside Rg1 have synergitic inhibition on autophagy injury.⁹

Table 1 Active Ingredients, Targets/Pathways, Mechanisms, and Therapeutic Effects of the Six Major Chinese Herbs of Yiaikang (YAK) Capsules Against Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS)

Mechanisms of YAK in HIV Treatment

According to recent research,^21–27 the functions and mechanisms of YAK include the following: blocking virus binding to its receptor, increasing the CD4⁺ T-cell count, regulating cytokine and chemokine responses, regulating the balance of T helper (Th)17 cells and regulatory T cells (Tregs), increasing the cytotoxic function of natural killer (NK) cells and maintaining the integrity of the intestinal mucosal barrier (Figure 1). According to previous studies, long-term application of Yiaikang is both safety and efficacy.²⁸ YAK combined with LPV/r can alleviate liver injury caused by LPV/r and combined with FTC+PMPA+RAL has no significant effect on the routine blood parameters in the treatment of SIVmac239 infected rhesus monkey AIDS model.²⁹ Studies shown that YAK combined with LPV/r in the treatment of SIVmac239 infected rhesus can maintain the stability of blood biochemical levels, reduce thrombocytopenia caused by ART, alleviate the side effects caused by LPV/r, and increase the efficacy of ART.³⁰

Figure 1 Therapeutic actions of Yiaikang (YAK) capsules. (A) YAK inhibits the viral Tat and Rev proteins as well as host intercellular adhesion molecule 1 (ICAM-1), assisting with the replication of HIV. YAK also increases CD4+ T-cell counts, possibly by restoring the expression of C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4), as well as T-cell activation levels. YAK significantly inhibits interleukin (IL)-13, increases the IL-2 and interferon (IFN)-γ cytokine response, and enhances host antiviral defense. (B) YAK significantly promotes the proliferation of natural killer (NK) cells and increases secretion of IFN-γ, enhancing immune function. (C) YAK regulates the imbalance in T helper 17 (Th17) cell/ regulatory T cell (Treg) imbalance by increasing RORγt expression and reducing FoxP3 expression, enhancing host antiviral defense. (D) YAK maintains the integrity of the intestinal mucosal barrier through inhibition of the expression of tight junction proteins ZO-1, Claudin-1, and Claudin-5, and chemokines. Created in BioRender. Xue, D. (2025) https://BioRender.com/l95e206.

Inhibition of Viral Replication

The HIV-1 envelope consists of two noncovalently associated fragments: gp120 and gp41. During infection, gp120 binds to the CD4 receptor on the surface of the host cell, interacting through its V3 ring with a coreceptor (eg, C-C chemokine receptor type 5 [CCR5] or C-X-C chemokine receptor type 4 [CXCR4]). This induces a conformational change that activates gp41, leading to the insertion of its viral fusion peptide to promote fusion of the viral and host cell membranes.³¹ The main target cells of HIV invasion and replication are CD4⁺ T lymphocytes,³² which are destroyed, thereby damaging the immune system.³³

The HIV genome contains two regulatory genes (trans-activator of transcription [tat] and rev), three structural genes (gag, pol, and env), and four accessory genes (nef, vpr, vpu, and vif). HIV-1 gene expression and replication largely depend on the Tat and Rev regulatory proteins.³⁴ Viral mRNA transcription is driven by the long terminal repeat, regulated by Tat and several host factors. Rev is transported to the infected host cell nucleus via its nuclear localization signal, where it binds to the Rev response element on viral RNA, accelerating viral mRNA transport outside of the nucleus.³⁵ Li et al³⁶ found that tat/rev expression and HIV-1 load in venous blood decreased significantly in the group that administration with YAK for 6 months compared with that in the control group, which suggesting that YAK may inhibit replication of HIV-1 by reducing the expression of Tat/Rev (mRNA level).

The levels of intercellular adhesion molecule 1 (ICAM-1), a glycoprotein that participates in immune responses, are abnormally increased on the surface of various cells following HIV infection, even under ART. ICAM-1 expression exhibits rapid upregulation in response to stimulation by cytokines, including interferon (IFN)-γ.³⁷ High levels of cell-surface ICAM-1 promote HIV production and virus spread,³⁸ and are positively correlated with HIV disease progression. ICAM-1 binds to the integrin lymphocyte function-associated antigen (LFA)-1, thereby stimulating HIV-infected dendritic cells and T cells and promoting viral spread.³⁹ Inhibition of ICAM-1/LFA-1 reduces HIV replication and transmission in vitro, suggesting the potential of ICAM-1 as a therapeutic target in HIV infection. Yue et al⁴⁰ observed an elevation in CD4⁺ T cells in YAK+ART group, with significantly decreased expression of ICAM-1/LFA-1 in CD4⁺ T cells following 6 months of YAK administration compared with ART controls. These results suggest that YAK directly affects the immune response in PLWH by decreasing the expression of ICAM-1 and LFA-1.

Improvement of Immune Response

CD4⁺ T-cell depletion is key to disease progression in PLWH. HIV-1 infection occurs when the virus binds to chemokine receptors and CD4 molecules on the surface of T cells. As the first recognition sites for HIV on the host cell surface, chemokine receptors CCR5 and CXCR4 are crucial in HIV infection.^41,42 Targeting these receptors is an attractive strategy for blocking HIV entry into host cells.⁴³

The active ingredients and other components of YAK regulate T cells through multiple targets and pathways, increasing the number of CD4⁺ T cells (Figure 1A). Liu et al⁴⁴ found that anticoagulant whole blood collected from PLWH at 6 months of YAK treatment exhibited restoration of CCR5 and CXCR4 expression, an increased number of CD4⁺ T cells, and a decreased HIV-1 load compared with that from healthy controls. Such findings suggest that YAK may restore coreceptor and T-cell activation levels to reverse the virus-induced immune damage in PLWH.

Regulation of Cytokine and Chemokine Responses

HIV infection of the human body activates T cells, which rapidly proliferate and secrete high levels of two inflammatory markers: interleukin (IL)-6 and sCD14.⁴⁵ IL-6 and sCD14 predict disease progression and are associated with increased risks of HIV/AIDS and death.⁴⁶ Th1 cells produce IL-2, triggering IFN-γ expression to activate NK cells and leading to apoptosis of HIV-1-infected T cells, which may be critical for controlling HIV-1.^47,48 Cytokine IL-13 has received considerable attention as the regulator of CD4⁺ Th2 immunity,⁴⁹ with inhibition of IL-13 expression increasing the activity of CD8⁺ T cells and protecting against viral infection.⁵⁰

Li et al⁵¹ collected the venous blood of PLWH to screen for HIV-1 load and cytokines at 6 months and 12 months of YAK treatment. They found improvements in the levels of IL-2, IL-13, and IFN-γ, number of CD4⁺ T cells, and anti-HIV activity at 12 months, suggesting that YAK may improving the immune status of PLWH by increasing cytokines and inhibiting HIV-1 (Figure 1A).

Increased Proliferation of NK Cells

HIV infection changes the distribution and functions of the NK cell subpopulation, even after ART.⁵² NK cells are important in HIV-1 infection, inhibiting viral entry into CD4⁺ T cells and preventing HIV-1 transmission.⁵³ IFN-γ (also known as immune IFN) is produced by T cells and is involved in immune regulation, activating NK cells and increasing their cytotoxic capabilities.⁵⁴ Targeting NK cells to restore their residual functionality can bolster their antiviral effects.

YAK was shown to significantly increase the proliferation and cytotoxic function of the human NK cell line NK-92MI⁵⁵ (Figure 1B). Qian et al⁵⁵ cultured NK-92MI cells in blank control and YAK-containing serum (4%, 8%, 15%, 25%) in vitro. Compared with the control, NKG2A expression was downregulated and IFN-γ secretion was upregulated at 6 hours of culture (P < 0.05). Thus, YAK significantly increased the proliferation and cytotoxicity of NK-92MI by inhibiting NKG2A receptors and increasing secretion of IFN-γ.

Regulation of Th17/Treg Balance

An altered Th17/Treg ratio, indicative of rapid depletion of Th17 cells and increased frequency of Tregs, is a hallmark of HIV infection and a marker of disease progression. This imbalance contributes to immune dysfunction and microbial translocation, which leads to chronic immune activation/inflammation and disease progression.⁵⁶ Th17 cells and Tregs are important gatekeepers of mucosal interfaces, with transcriptional profiles that are controlled by the lineage transcription factors RORγt/RORC2 and FOXP3, respectively.⁵⁷ HIV-1 infection can modify the mRNA expression of these transcription factors, which may decrease the immune response of Tregs and Th17 cells.⁵⁸

YAK regulates Th17/Treg imbalance by increasing the level of Th17 cells and decreasing the level of Tregs (Figure 1C). Huang⁵⁹ found that, compared with healthy control, 6 months of YAK treatment led to increases in the proportion of Th17 cells and the expression of RORγt mRNA, alongside reduced levels of Tregs and mRNA expression of Foxp3, in peripheral blood mononuclear cells. Therefore, YAK appears to increase CD4⁺ T cell counts by regulating the Th17/Treg ratio.

Maintenance of the Intestinal Mucosal Barrier

HIV-1 infection disrupts gut-associated lymphatic tissue, leading to loss of intestinal integrity, translocation of pathological microorganisms across the compromised gastrointestinal barrier, and systemic immune activation, even after ART.⁶⁰ CD4⁺ memory T cells in the gut carry higher levels of HIV DNA compared with blood.⁶¹ Virus-induced changes in microbial translocation and damage to the intestinal barrier contribute to inflammation and immune activation, induces apoptosis of CD4+T cells, and aggravates immune failure.⁶² The homing of lymphocytes from the bloodstream to the intestine is a prerequisite for establishing the immune barrier of the intestinal mucosa. This occurs through binding of the homing receptors on the surface of lymphocytes to specific ligands in the intestinal mucosal tissue.⁶³ Maintaining the integrity of intestinal mucosa and the balance of intestinal flora is crucial in the pathogenesis of HIV infection.

YAK reduces the permeability of the intestinal mucosal barrier, maintaining its integrity, through inhibition of the expression of tight junction (TJ) proteins (Figure 1D). Li et al⁶⁴ found that two ingredients of astragalus polysaccharide and ginseng stem saponin in YAK, significantly upregulated expression of the chemokines CCL25 and CCL28, chemokine receptors CCR9 and CCR10, CD80, CD86, major histocompatibility complex II (MHC-II), Toll-like receptor 4 (TLR4), and nuclear factor (NF)-ĸB p65 in intestinal mucosal tissue. These changes promoted the homing of intestinal lymphocytes and stimulated the activation of other immune cells (T and B cells), thereby enhancing intestinal mucosal immunity.

To simulate the intestinal mucosal injury induced by HIV-1, Sang et al⁶⁵ stimulated monolayers of Caco-2 human epithelial cells with IFN-γ. They then examined changes in membrane electrical impedance, fluorescein sodium transmittance, and mRNA expression of genes encoding TJ proteins at different time points following treatment with YAK or blank control group. YAK reduced the permeability of the simulated intestinal mucosal barrier and maintained its integrity, which was found to be related to inhibition of the expression of proteins ZO-1, Claudin-1, and Claudin-5.

Traditional Chinese medicine has unique advantages in regulating the abundance of flora and restoring immune reconstitution. YAK can regulates the intestinal flora, improves intestinal homeostasis, promotes immune reconstitution, and enhances immune function. YAK combined with ART has a certain clinical effect on PLWH, which can improve the proportion of protective factors of intestinal mucosa bacteria (such as Streptococcus, Macromonas, Wesneria, Streptococcus lactis).⁶⁶ YAK decreased the abundance of Lachnoclostridium, Muribaculaceae, Lactobacillaceae, Alphaproteobacteria, Aeromonadales and Prevotella and increase the abundance of Fusobacteriota and Lachnospiraceae and enhance body immunity in HIV/AIDS patients with poor immune reconstitution.⁶⁷

Regulation of Abnormal Lipid Metabolism of HIV

HIV-1 infection, chronic inflammation, and ART therapy are all related to changes in lipid metabolism, posing risk factors for cardiovascular and cerebrovascular diseases among PLWH.^68,69

Shen et al⁷⁰ used the 3-(4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and fluorogenic quantitative PCR to examine the effects of a range of concentrations of YAK-containing serum and ritonavir at different time points on the proliferation of human hepatoma Hep G2 cells and the expression of genes related to lipid metabolism, respectively. Compared with the blank control, the ritonavir + YAK treatment group inhibited cell viability at 24 and 48 hours, while the YAK group upregulated the expression of CYP7A1 and downregulated that of HMG-CoA reductase and peroxisome proliferator-activated receptor (PPAR)α at 48 hours. The role of YAK in lipid lowering may involve inhibition of endogenous cholesterol, promotion of fatty acid transport, and removal of lipids from. Baicalin, a compound present in YAK, has metabolic effects exerted through increasing the activation of brown and white adipose tissue via the AMPK/PGC1α pathway.^71,72

Clinical Applications of YAK in AIDS

Impacts on Clinical Manifestations, Quality of Life (QoL), Survival Rate, Anemia, and Lung Infections

YAK can be used to improve the clinical symptoms of HIV/AIDS. Clinical trials showed that patients receiving YAK had significantly improved clinical manifestations of AIDS compared with combination therapy of YAK and ART has been shown to benefit AIDS patients. China National Knowledge Infrastructure, Wanfang, Chinese Biomedicine Literature Database, PubMed, Embase and Medline were searched for studies on the effect of YAK on HIV/AIDS published up to February 2025. Data was presented in the Table 2.

Table 2 Studies Showing the Benefits of Yiaikang (YAK) Capsules in Combination with Antiretroviral Therapy for the Treatment of Acquired Immunodeficiency Syndrome (AIDS)

The prevalence of anemia and lung infections among PLWH is high,^82,83 but can be prevented using YAK. In a cross-sectional analysis of 8632 PLWH, patients receiving YAK therapy had a lower prevalence of anemia than those who did not.⁸² In addition, a randomized placebo-controlled trial performed in Henan Province, China, found that 4.9% of PLWH in the treatment group experienced a lung infection, compared with 6.0% of PLWH in the control group.⁸⁴

Survival rate is an indicator of the effectiveness of AIDS management. Jin et al reported a retrospective cohort study that compared the survival rate of HIV infection in patients with and without YAK treatment. A total of 3229 HIV-infected patients were followed for 21,876 person-years, showing 8-year cumulative survival rates of 78.5% in the YAK group (n = 1442) and 74.0% in the non-YAK group (n = 1787). The follow-up studies also showed that YAK increased the survival rate and increased lifetime in HIV-infected patients.^85,86

QoL refers to awareness and satisfaction with social status and living conditions. PLWH often face both physical and psychological stress, and thus require greater attention to their QoL. In a cross-sectional study of 275 PLWH, mean QoL scores (excluding spirituality/personal beliefs) were significantly higher in the YAK + ART group than in the ART group (P < 0.05).⁸⁷

Adjuvant Drugs for Common AIDS-Related Conditions

As an adjuvant medicine, YAK can improve the efficacy of the primary treatment for many of the symptoms and illnesses common in PLWH. It has been widely used to treat abnormal lipid metabolism, diarrhea, anxiety/depression, ulcers, cough, and HIV/hepatitis C with hepatic fibrosis (Table 3).

Table 3 Illnesses and Symptoms Treated with Yiaikang (YAK) Capsule Therapy in Patients with Human Immunodeficiency Virus (HIV) Infection

Improvement in Clinical Symptoms of Abnormal Lipid Metabolism

Yu et al⁹⁵ performed a clinical trial with 40 PLWH who took YAK + ART. After 6 months of YAK treatment, patients experience alleviation of clinical symptoms (asthma, spontaneous sweating, chest tightness, fatigue, and palpitation), achieved through regulation of phosphatidylcholine, phosphatidylethanolamine, cholesterol ester, and sphingomyelin, along with improvements in lipid metabolism and decreased vascular endothelial injury.

Conclusions

The therapeutic effects and mechanisms of action of YAK in the treatment of patients with AIDS have become a focus of TCM research.⁹⁶ By outlining these mechanisms and progress in clinical research on YAK in HIV/AIDS, this review has highlighted novel therapeutic targets and effective complementary approaches to ART. The key actions of YAK include the following: blocking virus–receptor binding, elevating CD4⁺ T-cell counts, regulating cytokine/chemokine responses, regulating Th17/Treg balance, enhancing NK cytotoxicity, and maintaining the integrity of the intestinal mucosal barrier. These effects are mediated through a number of pathological pathways involving NF-ĸB, PPAR, PD-1, transforming growth factor (TGF)-β/Smad, T-cell receptors (TCRs), and TLRs. Clinical studies have demonstrated the therapeutic efficacy of YAK in terms of improvements in clinical symptoms and QoL, longer survival times, and reduced mortality in patients with AIDS. As an herbal medicine, YAK is complementary to ART. However, there is limited clinical trial data on the effects of YAK in AIDS. Firstly, its pharmacology and therapeutic mechanism have not been extensively explored, necessitating further research to optimize its clinical application. Secondly, due to limited number and quality of clinical studies included in the analysis, further research is needed. Lately, we support large-scale clinical trials to evaluate the protective efficacy of YAK in AIDS, as well as single-cell and spatial multi-omics studies of its mechanisms of action. YAK shows great promise as a complementary treatment to ART and warrants further exploration.

Funding

This work was supported by the Zhengzhou Medical and Health Science and Technology Innovation Guidance Program (2024YLZDJH134), Henan Province Pilot Project of Treating AIDS with Traditional Chinese Medicine(No. 2004ZYA109), Henan Province Key Research and Development and Promotion Project (252102310488) and Traditional Chinese Medicine Research Project of Henan Province (2025ZKY016).

Disclosure

The authors report no conflicts of interest in this work.

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