Acupuncture ameliorates atopic dermatitis by modulating gut barrier function in a gut microbiota-dependent manner in mice.

OBJECTIVE: Atopic dermatitis (AD) is a chronic inflammatory skin disease that may be linked to changes in the gut microbiome. Acupuncture has been proven to be effective in reducing AD symptoms without serious adverse events, but its underlying mechanism is not completely understood. The purpose of this study was to investigate whether the potential effect of acupuncture on AD is gut microbiota-dependent. METHODS: AD-like skin lesions were induced by applying MC903 topically to the cheek of the mouse. Acupuncture was done at the Gok-Ji (LI11) acupoints. AD-like symptoms were assessed by lesion scores, scratching behavior, and histopathological changes; intestinal barrier function was measured by fecal output, serum lipopolysaccharide levels, histopathological changes, and mRNA expression of markers involved in intestinal permeability and inflammation. Gut microbiota was profiled using 16S rRNA gene sequencing from fecal samples. RESULTS: Acupuncture effectively improved chronic itch as well as the AD-like skin lesions with epidermal thickening, and also significantly altered gut microbiota structure as revealed by ß-diversity indices and analysis of similarities. These beneficial effects were eliminated by antibiotic depletion of gut microbiota, but were reproduced in gut microbiota-depleted mice that received a fecal microbiota transplant from acupuncture-treated mice. Interestingly, AD mice had intestinal barrier dysfunction as indicated by increased intestinal permeability, atrophy of the mucosal structure (reduced villus height and crypt depth), decreased expression of tight junctions and mucus synthesis genes, and increased expression of inflammatory mediators in the ileum. Acupuncture attenuated these abnormalities, which was gut microbiota-dependent. CONCLUSION: Acupuncture ameliorates AD-like phenotypes in a gut microbiota-dependent manner and some of these positive benefits are explained by modulation of the intestinal barrier, providing new perspective for non-pharmacological strategies for modulating gut microbiota to prevent and treat AD. Please cite this article as: Yeom M, Ahn S, Hahm DH, Jang SY, Jang SH, Park SY, Jang JH, Park J, Oh JY, Lee IS, Kim K, Kwon SK, Park HJ. Acupuncture ameliorates atopic dermatitis by modulating gut barrier function in a gut microbiota-dependent manner in mice. J Integr Med. 2024; 22(5): 600-613.

Exploratory Study of Biomechanical Properties and Pain Sensitivity at Back-Shu Points.

OBJECTIVES: Hypersensitive acupoints in specific body areas are associated with corresponding internal or visceral disorders. Back-shu points are clinically significant for the diagnosis of visceral organ disease, according to the biomechanical characteristics of the acupoints. In this study, we assessed the biomechanical characteristics and pain sensitivities of five back-shu points linked to five visceral organs in healthy participants. METHODS: The study included 48 volunteer participants. A myotonometry was used to assess muscle tone and muscle stiffness at five back-shu points associated with visceral organs. Pressure was monitored using a microcontroller and a force sensor. Pain sensitivity was assessed in response to deep pressure pain produced by a constant force. RESULTS: Substantial differences in muscle tone and stiffness were observed at the five back-shu points; muscle tone was highest at BL15, whereas muscle tone and muscle stiffness were lowest at BL23. Moreover, pain sensitivity was significantly different among the acupoints; pain sensitivity was highest at BL23. There was a significant negative correlation between muscle tone and pain sensitivity. CONCLUSIONS: We found significant differences in muscle tone, muscle stiffness, and pain sensitivity among five back-shu points associated with visceral organs, which may be attributable to anatomical variations at each point. Our findings suggest that differences at back-shu points should be considered to ensure the accurate diagnosis of visceral disease.

The multi-herbal decoction SH003 alleviates LPS-induced acute lung injury by targeting inflammasome and extracellular traps in neutrophils.

BACKGROUND: Acute lung injury (ALI) is a devastating condition caused by sepsis, pneumonia, trauma, and more recently, COVID-19. SH003, an herbal formula consisted of Astragalus membranaceus, Angelica gigas and Trichosanthes kirilowii, is known for its effects on cancer and immunoregulation. HYPOTHESIS/PURPOSE: Previous studies show SH003 exerts a promising anti-inflammatory effect. This study investigates the effect of modified SH003 on ALI using in silico, in vivo, and in vitro models. STUDY DESIGN AND METHODS: We performed in silico-based analysis of SH003 on ALI-related pathways. C57BL/6 mice were intraperitoneally subjected to lipopolysaccharide (LPS) to induce septic ALI, followed by oral administration of SH003 for 2 weeks. Dexamethasone was used as the positive control. Human peripheral blood-derived polymorphonuclear neutrophils (PMN) were used to investigate the effect and mechanisms of SH003 on neutrophil extracellular trap (NET) formation. RESULTS: Network pharmacology analysis suggested SH003 regulates lung inflammation by modulating NET formation. SH003 significantly reduced mortality in sepsis in vivo by inhibiting local and systemic inflammation, likely via nuclear factor kappa B and mitogen-activated protein kinase pathways-mediated inflammasome suppression. SH003 also decreased NET-related markers in lung tissues and inhibited LPS- and phorbol myristate acetate-induced NET formation in PMN. Cytometry time-of-flight analysis confirmed regulation of NETosis-related pathways by SH003. CONCLUSION: SH003 effectively inhibits excessive immune responses in the lung by suppressing inflammasome activation and NET formation. These findings suggest SH003 as a potential therapeutic agent for septic ALI.

Revealing the mechanism and efficacy of natural products on treating the asthma: Current insights from traditional medicine to modern drug discovery.

Asthma remains a significant global health challenge, demanding innovative approaches to treatment. Traditional medicine has a rich history of using natural products to alleviate asthmatic symptoms. However, transitioning from these traditional remedies to modern drug discovery approaches has provided fresh insights into the mechanisms and effectiveness of these natural products. This study provides our comprehensive review, which examines the current state of knowledge in the treatment of asthma. It delves into the mechanisms through which natural products ameliorate asthma symptoms, and it discusses their potential in the development of novel therapeutic interventions. Our analysis reveals that natural products, traditionally employed for asthma relief, exhibit diverse mechanisms of action. These include anti-inflammatory, bronchodilatory, immunomodulatory effects, and reducing gene expression. In the context of modern drug discovery, these natural compounds serve as valuable candidates for the development of novel asthma therapies. The transition from traditional remedies to modern drug discovery represents a promising avenue for asthma treatment. Our review highlights the substantial efficacy of natural products in managing asthma symptoms, underpinned by well-defined mechanisms of action. By bridging the gap between traditional and contemporary approaches, we contribute to the growing body of knowledge in the field, emphasizing the potential of natural products in shaping the future of asthma therapy.

Neural Biomarkers for Identifying Atopic Dermatitis and Assessing Acupuncture Treatment Response Using Resting-State fMRI.

Purpose: Only a few studies have focused on the brain mechanisms underlying the itch processing in AD patients, and a neural biomarker has never been studied in AD patients. We aimed to develop a deep learning model-based neural signature which can extract the relevant temporal dynamics, discriminate between AD and healthy control (HC), and between AD patients who responded well to acupuncture treatment and those who did not. Patients and Methods: We recruited 41 AD patients (22 male, age mean ± SD: 24.34 ± 5.29) and 40 HCs (20 male, age mean ± SD: 26.4 ± 5.32), and measured resting-state functional MRI signals. After preprocessing, 38 functional regions of interest were applied to the functional MRI signals. A long short-term memory (LSTM) was used to extract the relevant temporal dynamics for classification and train the prediction model. Bootstrapping and 4-fold cross-validation were used to examine the significance of the models. Results: For the identification of AD patients and HC, we found that the supplementary motor area (SMA), posterior cingulate cortex (PCC), temporal pole, precuneus, and dorsolateral prefrontal cortex showed significantly greater prediction accuracy than the chance level. For the identification of high and low responder to acupuncture treatment, we found that the lingual-parahippocampal-fusiform gyrus, SMA, frontal gyrus, PCC and precuneus, paracentral lobule, and primary motor and somatosensory cortex showed significantly greater prediction accuracy than the chance level. Conclusion: We developed and evaluated a deep learning model-based neural biomarker that can distinguish between AD and HC as well as between AD patients who respond well and those who respond less to acupuncture. Using the intrinsic neurological abnormalities, it is possible to diagnose AD patients and provide personalized treatment regimens.

Role of gut-derived bacterial lipopolysaccharide and peripheral TLR4 in immobilization stress-induced itch aggravation in a mouse model of atopic dermatitis.

Psychological stress and intestinal leakage are key factors in atopic dermatitis (AD) recurrence and exacerbation. Here, we demonstrate the mechanism underlying bacterial translocation across intestinal epithelial barrier damaged due to stress and further aggravation of trimellitic anhydride (TMA)-induced itch, which remain unclear, in AD mice. Immobilization (IMO) stress exacerbated scratching bouts and colon histological damage, and increased serum corticosterone and lipopolysaccharide (LPS). Orally administered fluorescein isothiocyanate (FITC)-dextran and surgically injected (into the colon) Cy5.5-conjugated LPS were detected in the serum and skin after IMO stress, respectively. The relative abundance of aerobic or facultative anaerobic bacteria was increased in the colon mucus layer, and Lactobacillus murinus, E. coli, Staphylococcus nepalensis, and several strains of Bacillus sp. were isolated from the spleens and mesenteric lymph nodes. Oral antibiotics or intestinal permeability blockers, such as lubiprostone (Lu), 2,4,6-triaminopyrimidine (TAP) and ML-7, inhibited IMO stress-associated itch; however, it was reinduced through intradermal or i.p. injection of LPS without IMO stress. I.p. injection of TAK-242 (resatorvid), a TLR4 inhibitor, abrogated IMO stress-associated itch, which was also confirmed in TLR4-KO mice. IMO stress alone did not cause itch in naïve mice. IMO stress-induced itch aggravation in TMA-treated AD mice might be attributed to the translocation of gut-derived bacterial cells and LPS, which activates peripheral TLR4 signaling.

Chronic Gut Inflammation and Dysbiosis in IBS: Unraveling Their Contribution to Atopic Dermatitis Progression.

Emerging evidence suggests a link between atopic dermatitis (AD) and gastrointestinal disorders, particularly in relation to gut microbial dysbiosis. This study explored the potential exacerbation of AD by gut inflammation and microbial imbalances using an irritable bowel syndrome (IBS) mouse model. Chronic gut inflammation was induced in the model by intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), followed by a 4-week development period. We noted significant upregulation of proinflammatory cytokines in the colon and evident gut microbial dysbiosis in the IBS mice. Additionally, these mice exhibited impaired gut barrier function, increased permeability, and elevated systemic inflammation markers such as IL-6 and LPS. A subsequent MC903 challenge on the right cheek lasting for 7 days revealed more severe AD symptoms in IBS mice compared to controls. Further, fecal microbial transplantation (FMT) from IBS mice resulted in aggravated AD symptoms, a result similarly observed with FMT from an IBS patient. Notably, an increased abundance of Alistipes in the feces of IBS mice correlated with heightened systemic and localized inflammation in both the gut and skin. These findings collectively indicate that chronic gut inflammation and microbial dysbiosis in IBS are critical factors exacerbating AD, highlighting the integral relationship between gut and skin health.

Auditory influence on stickiness perception: an fMRI study of multisensory integration.

This study explored how the human brain perceives stickiness through tactile and auditory channels, especially when presented with congruent or incongruent intensity cues. In our behavioral and functional MRI (fMRI) experiments, we presented participants with adhesive tape stimuli at two different intensities. The congruent condition involved providing stickiness stimuli with matching intensity cues in both auditory and tactile channels, whereas the incongruent condition involved cues of different intensities. Behavioral results showed that participants were able to distinguish between the congruent and incongruent conditions with high accuracy. Through fMRI searchlight analysis, we tested which brain regions could distinguish between congruent and incongruent conditions, and as a result, we identified the superior temporal gyrus, known primarily for auditory processing. Interestingly, we did not observe any significant activation in regions associated with somatosensory or motor functions. This indicates that the brain dedicates more attention to auditory cues than to tactile cues, possibly due to the unfamiliarity of conveying the sensation of stickiness through sound. Our results could provide new perspectives on the complexities of multisensory integration, highlighting the subtle yet significant role of auditory processing in understanding tactile properties such as stickiness.

Correction: Prediction of disease severity using serum biomarkers in patients with mild-moderate Atopic Dermatitis: A pilot study.

[This corrects the article DOI: 10.1371/journal.pone.0293332.].

Prediction of disease severity using serum biomarkers in patients with mild-moderate Atopic Dermatitis: A pilot study.

Atopic dermatitis (AD) is an inflammatory skin condition that relies largely on subjective evaluation of clinical signs and symptoms for diagnosis and severity assessment. Using multivariate data, we attempted to construct prediction models that can diagnose the disease and assess its severity. We combined data from 28 mild-moderate AD patients and 20 healthy controls (HC) to create random forest models for classification (AD vs. HC) and regression analysis to predict symptom severities. The classification model outperformed the random permutation model significantly (area under the curve: 0.85 ± 0.10 vs. 0.50 ± 0.15; balanced accuracy: 0.81 ± 0.15 vs. 0.50 ± 0.15). Correlation analysis revealed a significant positive correlation between measured and predicted total SCORing Atopic Dermatitis score (SCORAD; r = 0.43), objective SCORAD (r = 0.53), eczema area and severity index scores (r = 0.58, each p < 0.001), but not between measured and predicted itch ratings (r = 0.21, p = 0.18). We developed and tested multivariate prediction models and identified important features using a variety of serum biomarkers, implying that discovering the deep-branching relationships between clinical measurements and serum measurements in mild-moderate AD patients may be possible using a multivariate machine learning method. We also suggest future methods for utilizing machine learning algorithms to enhance drug target selection, diagnosis, prognosis, and customized treatment in AD.

Graded brain fMRI response to somatic and visual acupuncture stimulation.

Increased stimulation can enhance acupuncture clinical response; however, the impact of acupuncture stimulation as "dosage" has rarely been studied. Furthermore, acupuncture can include both somatic and visual components. We assessed both somatic and visual acupuncture dosage effects on sensory ratings and brain response. Twenty-four healthy participants received somatic (needle inserted, manually stimulated) and visual (needle video, no manual stimulation) acupuncture over the leg at three different dosage levels (control, low-dose, and high-dose) during functional magnetic resonance imaging (fMRI). Participants reported the perceived deqi sensation for each acupuncture dose level. Blood-oxygen-level dependent imaging data were analyzed by general linear model and multivariate pattern analysis. For both somatic and visual acupuncture, reported deqi sensation increased with increased dosage of acupuncture stimulation. Brain fMRI analysis demonstrated that higher dosage of somatic acupuncture produced greater brain responses in sensorimotor processing areas, including anterior and posterior insula and secondary somatosensory cortex. For visual acupuncture, higher dosage of stimulation produced greater brain responses in visual-processing areas, including the middle temporal visual areas (V5/MT+) and occipital cortex. Psychophysical and psychophysiological responses to both somatic and visual acupuncture were graded in response to higher doses. Our findings suggest that acupuncture response may be enhanced by the dosage of needling-specific and nonspecific components, represented by different neural mechanisms.

Acupuncture treatment for functional gastrointestinal disorders: Identification of major acupoints using network analysis.

Background: Using network analysis, we sought to determine the acupoints most commonly used to treat functional gastrointestinal disorders (FGIDs), particularly functional dyspepsia (FD) and irritable bowel syndrome (IBS). Methods: To explore the acupoint patterns used for FGID, data on acupoint combinations for FD and IBS were gathered from systematic reviews. Network analysis was used to determine the degree, closeness centrality, betweenness centrality, and eigenvector centrality of each acupoint. The most common acupoint combinations for FD and IBS were examined based on the eigenvector centrality. Results: Network analysis revealed that CV12, ST25, ST36, CV10, and LR3, which had the highest eigenvector centrality values, were the main acupoints for treating FGID. CV12 was the main acupoint for treating FD, while ST25 was the hub acupoint for treating IBS in the abdomen. ST36, LR3, and PC6 were the key peripheral acupoints for FD and IBS. Conclusions: Using network analysis, we provided data that will aid the selection of both general and specific acupoints for FD and IBS, along with spatial information (i.e., the positions of acupoints on a body map). These findings could be applied in future acupuncture research on therapy for gastrointestinal system dysfunction. They may also help bridge the gap between the traditional meridian theory, which assumes that there is a link between diseases/symptoms and the specific body region being treated, and real-world clinical evidence.

A prospective observational study of optimal acupoint selection on patients with functional gastrointestinal disorders.

INTRODUCTION: Functional gastrointestinal disorders (FGIDs), which include irritable bowel syndrome (IBS) and functional dyspepsia (FD), are common gastrointestinal (GI) diseases that have a large financial impact on patients' quality of life (QoL). Traditional Korean medicine has a particular diagnostic pattern for treating FGIDs. However, FGIDs have not been thoroughly explored because of their complexity. In this proposed study, we will investigate the acupoint selection pattern for FGID patients with various disease patterns, and further determine the best acupoints for treating FGID patients using a machine-learning algorithm. METHODS: We will collect clinical data from 15 multi-center Korean medical clinics that treat FGID as part of an observational study registry. Patients who meet the criteria will be added to the registry after screening. They will receive a maximum 4-week treatment, and they will respond 3 times to a series of questions. We will investigate how doctors of FGID patients with diverse disease patterns choose the acupoints, and we will use a machine learning technique to identify the best acupoints for treating FGID patients. DISCUSSION: This will be the first multi-center observational registry study to assess how traditional Korean medical practitioners diagnose and treat patients in the real world. The findings will shed light on how traditional Korean medicine treats FGIDs and demonstrate the rationale for the diagnostic and acupuncture treatment flow.

Central Regulation of Eating Behaviors in Humans: Evidence from Functional Neuroimaging Studies.

Neuroimaging has great potential to provide insight into the neural response to food stimuli. Remarkable advances have been made in understanding the neural activity underlying food perception, not only in normal eating but also in obesity, eating disorders, and disorders of gut-brain interaction in recent decades. In addition to the abnormal brain function in patients with eating disorders compared to healthy controls, new therapies, such as neurofeedback and neurostimulation techniques, have been developed that target the malfunctioning brain regions in patients with eating disorders based on the results of neuroimaging studies. In this review, we present an overview of early and more recent research on the central processing and regulation of eating behavior in healthy and patient populations. In order to better understand the relationship between the gut and the brain as well as the neural mechanisms underlying abnormal ingestive behaviors, we also provide suggestions for future directions to enhance our current methods used in food-related neuroimaging studies.

Sensory and emotional responses to deep pressure stimulation at myofascial trigger points: a pilot study.

Objective: Although manual pressure, such as that used during a massage, is often associated with pain, it can simultaneously be perceived as pleasant when applied to certain body areas. We hypothesized that stimulation of myofascial trigger points (TPs) leads to simultaneous pain and pleasure. TPs are hyperirritable points located in the taut band of the skeletal muscle. Method: In this study, we measured the muscle tone, muscle stiffness, and pressure pain threshold of TPs and control points in the left brachioradialis muscle of 48 healthy participants. We also applied deep compression to the two points and collected subjective data on pain, pleasantness, unpleasantness, and relief. Result: Greater muscle stiffness was observed in the TPs versus control points (t = 6.55, p < 0.001), and the pain threshold was significantly lower in the TPs (t = -6.21, p < 0.001). Unpleasantness ratings after deep compression were significantly lower in the TPs compared with control points (t = -2.68, p < 0.05). Participants experienced greater relief at the TPs compared with control points (t = 2.01, p < 0.05), although the perceived pain did not differ between the two types of points. Conclusion: We compared the properties of TPs and control points, and found that deep compression at TPs was associated with higher muscle tone and stiffness, lower unpleasantness ratings, and higher relief ratings compared with the control points. These findings suggest that, at least for some TPs, pain and pleasantness are simultaneously elicited by deep pressure stimulation.

Acupuncture and Acupoints for Low Back Pain: Systematic Review and Meta-Analysis.

Acupuncture has been used as a therapeutic intervention for the treatment of numerous diseases and symptoms for thousands of years, and low back pain has been studied and treated the most in acupuncture clinics. Traditional theory strongly suggests that the selection of acupoints will influence their clinical effects and combinations (e.g., the clinical effects of a particular acupoint or combination on reducing pain), but this idea was not considered in earlier systematic reviews and meta-analyses. We performed a systematic review, meta-analysis, and network analysis to evaluate the magnitude of the effects of acupoints used to treat low back pain in randomized controlled clinical trials. We found that acupuncture significantly reduced pain in patients with low back pain compared with the control group. The most frequently prescribed acupoints were BL23, GV3, BL20, BL40, and BL25, whereas the acupoints with the highest average effect size scores were BL20, GV3, GB30, GB34, and BL25. Further, the combinations of BL23-BL40, BL23-B25, and BL23-BL60 were the most frequently prescribed, while BL23-GV3, BL40-GV4, and BL23-BL25 showed the largest average effect size. By calculating clinical outcomes based on average effect sizes, we found that the most popular acupoints might not always be associated with the best results. Although a more thorough investigation is necessary to determine the clinical effects of each acupoint and combination on patients, we suggest that our approach may offer a fresh perspective that will be useful for future research.

Enhanced Empathic Pain by Facial Feedback.

The facial feedback hypothesis states that feedback from cutaneous and muscular afferents affects our emotion. Based on the facial feedback hypothesis, the purpose of this study was to determine whether enhancing negative emotion by activating a facial muscle (corrugator supercilii) increases the intensity of cognitive and emotional components of empathic pain. We also assessed whether the muscle contraction changed the pupil size, which would indicate a higher level of arousal. Forty-eight individuals completed 40 muscular contraction and relaxation trials while looking at images of five male and five female patients with neutral and painful facial expressions, respectively. Participants were asked to rate (1) how much pain the patient was in, and (2) how unpleasant their own feelings were. We also examined their facial muscle activities and changes in pupil size. No significant differences in pain or unpleasantness ratings were detected for the neutral face between the two conditions; however, the pain and unpleasantness ratings for the painful face were considerably higher in the contraction than relaxation condition. The pupils were considerably larger in the contraction than relaxation condition for both the painful and neutral faces. Our findings indicate that, by strengthening the corrugator supercilii, facial feedback can affect both the cognitive evaluative and affective sharing aspects of empathic pain.

Similarities between Ashi acupoints and myofascial trigger points: Exploring the relationship between body surface treatment points.

Although acupuncture points and myofascial trigger points (TPs) are based in different medical fields, the two points share important attributes. We explored the relationship between acupuncture points and TPs based on their characteristics and the results of previous studies. We outlined the relationship between acupuncture points and TPs by examining their similarities and differences. Among the acupuncture point subgroups, TPs mostly corresponded to Ashi points. Based on the common features of TPs and Ashi points, we suggest that TPs are more closely related to Ashi points than to other acupoints. However, TPs also share some features, such as pain indication and location, with classical acupuncture points (CA) and extra acupuncture points (EA), which makes it difficult to elucidate their relationship with other subgroups. Therefore, we suggest to understand the relationship of CAs, EAs, Ashi points, and TPs. In this report, we concluded that concerning muscular pain symptoms Ashi points and TPs are indistinguishable.

Comparison of the acupuncture manipulation properties of traditional East Asian medicine and Western medical acupuncture.

Background: Acupuncture treatments frequently use manipulation techniques. The therapeutic advantages of acupuncture differ depending on the acupuncture manipulation. The purpose of this article was to compare manipulation techniques in traditional East Asian medicine (TEAM) and Western medical acupuncture (WMA). Methods: Manipulation techniques in TEAM and WMA were compared according to purpose, modulating parameters, and indications. The practical understanding of manipulation in terms of acupuncture stimulation intensity was also explored. The TEAM manipulation techniques of twirling and lifting and thrusting are discussed in terms of the objectives of tonification and sedation. Results: The main therapeutic effect of WMA is mediated through activation of the nervous system, which is achieved with adequate intensity of needling. The TEAM tonification and sedation techniques were designed to produce mild or intense stimulation, respectively, to elicit varying degrees of deqi sensation. Conclusions: Further research is needed to clarify the differences between the TEAM and WMA practices, and to determine whether different needling manipulations affect treatment outcomes.