Biomedicines

Research

14 pages, 3792 KiB

Open AccessArticle

The Causal Relationship Between Gut Microbiomes, Inflammatory Mediators, and Traumatic Brain Injury in Europeans: Evidence from Genetic Correlation and Functional Mapping Annotation Analyses

by Bingyi Song, Youjia Qiu, Zilan Wang, Yuchen Tao, Menghan Wang, Aojie Duan, Minjia Xie, Ziqian Yin, Zhouqing Chen, Chao Ma and Zhong Wang

Biomedicines 2025, 13(3), 753; https://doi.org/10.3390/biomedicines13030753 - 20 Mar 2025

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Abstract

Background: The gut microbiome (GM) has been reported to play a role in traumatic brain injury (TBI). To investigate the causal relationship between GMs, inflammatory mediators, and TBI, a comprehensive Mendelian randomization (MR) analysis was conducted. Methods: We utilized Genome-Wide Association Study (GWAS) [...] Read more.

Background: The gut microbiome (GM) has been reported to play a role in traumatic brain injury (TBI). To investigate the causal relationship between GMs, inflammatory mediators, and TBI, a comprehensive Mendelian randomization (MR) analysis was conducted. Methods: We utilized Genome-Wide Association Study (GWAS) summary statistics to examine the causal relationships between GM and TBI. To assess the potential causal associations between GM and TBI, we employed the inverse-variance-weighted, MR-Egger, and weighted median methods. Mediation analysis was used to assess the possible mediating factors. Several sensitivity analyses methods were implemented to verify the stability of the results. Additionally, we utilized FUMA GWAS to map single-nucleotide polymorphisms to genes and conduct transcriptomic MR analysis. Results: We identified potential causal relationships between nine bacterial taxa and TBI. Notably, class Methanobacteria, family Methanobacteriaceae, and order Methanobacteriales (p = 0.0003) maintained a robust positive correlation with TBI. This causal association passed false discovery rate (FDR) correction (FDR < 0.05). Genetically determined 1 inflammatory protein, 30 immune cells and 3 inflammatory factors were significantly causally related to TBI. None of them mediated the relationship between GMs and TBI. The outcome of the sensitivity analysis corroborated the findings. Regarding the mapped genes of significant GMs, genes such as CLK4, MTRF1, NAA16, SH3BP5, and ZNF354A in class Methanobacteria showed a significant causal correlation with TBI. Conclusions: Our study reveals the potential causal effects of nine GMs, especially Methanogens on TBI, and there was no link between TBI and GM through inflammatory protein, immune cells, and inflammatory factors, which may offer fresh insights into TBI biomarkers and therapeutic targets through specific GMs. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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16 pages, 4255 KiB

Open AccessArticle

Gut Microbiota in Different Treatment Response Types of Crohn’s Disease Patients Treated with Biologics over a Long Disease Course

by Xiaolei Zhao, Jun Xu, Dong Wu, Ning Chen and Yulan Liu

Biomedicines 2025, 13(3), 708; https://doi.org/10.3390/biomedicines13030708 - 13 Mar 2025

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Abstract

Background and Aims: Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) with a globally increasing prevalence, partially driven by alterations in gut microbiota. Although biological therapy is the first-line treatment for CD, a significant proportion of patients experience a primary non-response [...] Read more.

Background and Aims: Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) with a globally increasing prevalence, partially driven by alterations in gut microbiota. Although biological therapy is the first-line treatment for CD, a significant proportion of patients experience a primary non-response or secondary loss of response over time. This study aimed to explore the differences in gut microbiota among CD patients with divergent long-term responses to biological therapy, focusing on a long disease course. Methods: Sixteen CD patients who applied the biological agents for a while were enrolled in this study and were followed for one year, during which fecal specimens were collected monthly. Metagenomic analysis was used to determine the microbiota profiles in fecal samples. The response to biological therapy was evaluated both endoscopically and clinically. Patients were categorized into three groups based on their response: R (long-term remission), mA (mild active), and R2A group (remission to active). The differences in the gut microbiota among the groups were analyzed. Results: Significant differences in fecal bacterial composition were observed between the groups. The R2A group exhibited a notable decline in gut microbial diversity compared to the other two groups (p < 0.05). Patients in the R group had higher abundances of Akkermansia muciniphila, Bifidobacterium adolescentis, and Megasphaera elsdenii. In contrast, Veillonella parvula, Veillonella atypica, and Klebsiella pneumoniae were higher in the R2A group. Conclusions: Gut microbial diversity and specific bacterial significantly differed among groups, reflecting distinct characteristics between responders and non-responders. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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16 pages, 1172 KiB

Open AccessArticle

Effects of In Vitro Fermented Pleurotus eryngii on Intestinal Barrier Integrity and Immunomodulation in a Lipopolysaccharide-Induced Colonic Model

by Evangelia N. Kerezoudi, Georgia Saxami, Georgios I. Zervakis, Vasiliki Pletsa, Robert J. Brummer, Adamantini Kyriacou and Ignacio Rangel

Biomedicines 2025, 13(2), 430; https://doi.org/10.3390/biomedicines13020430 - 11 Feb 2025

Cited by 1 | Viewed by 1056

Abstract

Background: This study investigates the impact of fermentation supernatants (FSs) from Pleurotus eryngii whole mushrooms (PEWS), as well as its subcomponents, digested (PEWSD) and extracted (PEWSE) forms, on intestinal barrier function and immune modulation in lipopolysaccharide (LPS) -stimulated Caco-2 cells. Methods: [...] Read more.

Background: This study investigates the impact of fermentation supernatants (FSs) from Pleurotus eryngii whole mushrooms (PEWS), as well as its subcomponents, digested (PEWSD) and extracted (PEWSE) forms, on intestinal barrier function and immune modulation in lipopolysaccharide (LPS) -stimulated Caco-2 cells. Methods: Gene expression of tight junction (TJs) genes, cytokines, and key immune/metabolic receptors was assessed via qRT-PCR, while cytokine protein levels were measured using ELISA to explore post-transcriptional regulation. Results: LPS challenge significantly downregulated TJs zonula occludens-1 (ZO-1,) occludin, and claudin-1, compromising epithelial integrity. Treatment with FS-PEWS notably restored ZO-1 and occludin expression, outperforming FS-PEWSD and FS-PEWSE, which only partially mitigated the LPS-induced damage. FS-PEWS further demonstrated potent immunomodulatory effects, upregulating anti-inflammatory IL-10 and pro-inflammatory cytokines such as IL-8 and TNF-α. The activation of key receptors like TLR-2 and mTOR suggests that FS-PEWS modulates critical immune and metabolic pathways, such as NF-kB signaling, to maintain immune homeostasis. Although mRNA expression of pro-inflammatory cytokines was altered, no corresponding protein release was detected, suggesting potential post-transcriptional regulation. Conclusions: FS-PEWS preserves intestinal barrier integrity and modulates immune responses, particularly in low-grade inflammation, highlighting the whole food matrix’s role in enhancing its bioactivity and functional food potential. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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20 pages, 4831 KiB

Open AccessArticle

Probiotic-Derived Metabolites from Lactiplantibacillus plantarum OC01 Reprogram Tumor-Associated Macrophages to an Inflammatory Anti-Tumoral Phenotype: Impact on Colorectal Cancer Cell Proliferation and Migration

by Beatrice Garavaglia, Letizia Vallino, Alessandra Ferraresi, Angela Amoruso, Marco Pane and Ciro Isidoro

Biomedicines 2025, 13(2), 339; https://doi.org/10.3390/biomedicines13020339 - 3 Feb 2025

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Abstract

Background: Tumor-associated macrophages (TAMs) are key players in the colorectal cancer (CRC) tumor microenvironment (TME), representing the most abundant immune cells within it. The interplay between the intestinal microbiota, macrophages, and cancer cells significantly impacts tumor progression by driving macrophage polarization. Particularly, the [...] Read more.

Background: Tumor-associated macrophages (TAMs) are key players in the colorectal cancer (CRC) tumor microenvironment (TME), representing the most abundant immune cells within it. The interplay between the intestinal microbiota, macrophages, and cancer cells significantly impacts tumor progression by driving macrophage polarization. Particularly, the polarization into the pro-tumoral M2-like TAM phenotype promotes the extracellular matrix remodeling, cancer cell proliferation, metastasis, immune suppression, and therapy resistance. Probiotic metabolites can disrupt this crosstalk, possibly reverting the TAM polarization toward a pro-inflammatory anti-tumoral phenotype, thus potentially benefiting the intestinal mucosa and opposing CRC progression. Previously, we showed that Lactiplantibacillus plantarum OC01 metabolites counter interleukin (IL)-6-induced CRC proliferation and migration. Methods: Here, we explore how probiotics affect CRC secretome and how this influences TAM polarization, which then impacts CRC malignancy. Results: The conditioning medium (CM) from CRC cells indeed promoted the polarization of macrophage toward the M2-like phenotype, whereas the CM from CRC pre-treated with L. plantarum OC01 metabolites induced a pro-inflammatory macrophage phenotype, characterized by NLRP3 inflammasome activation and reactive oxygen species (ROS) production, and by decreased expression of the M2 phenotype markers CD206 and CD163. Consistently, the expression of tumor growth factor (TGF)-β, a promoter of M2 macrophage polarization, was reduced in CRC cells treated with L. plantarum OC01. The pro-inflammatory macrophages inhibited CRC proliferation and migration. Conclusions: Overall, our study highlights the potential of metabolites from L. plantarum OC01 to reprogram the metabolism in cancer cells and thus reshape the TME by shifting TAMs toward a more inflammatory and anti-tumoral phenotype, emphasizing the promise of probiotics in advancing novel therapeutic approaches for CRC. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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17 pages, 559 KiB

Open AccessArticle

Role of Vitamin D Status and Alterations in Gut Microbiota Metabolism in Fibromyalgia-Associated Chronic Inflammatory Pain

by Caterina Saija, Maria Paola Bertuccio, Alberto Scoglio, Vincenzo Macaione, Francesco Cacciola, Giuseppe Micalizzi, Daniela Caccamo, Carolina Muscoli and Monica Currò

Biomedicines 2025, 13(1), 139; https://doi.org/10.3390/biomedicines13010139 - 9 Jan 2025

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Abstract

Background/Objectives: Several studies suggest gut microbiota metabolites as important immuno-modulators in inflammatory pain. We aimed to investigate the relationship between vitamin D status and gut dysbiosis markers in fibromyalgia (FM)-associated chronic inflammation. Methods: Blood samples were collected from sixty-eight female FM [...] Read more.

Background/Objectives: Several studies suggest gut microbiota metabolites as important immuno-modulators in inflammatory pain. We aimed to investigate the relationship between vitamin D status and gut dysbiosis markers in fibromyalgia (FM)-associated chronic inflammation. Methods: Blood samples were collected from sixty-eight female FM patients (49.9 ± 12.35 years). Pain intensity was assessed by FIQ-R. The serum levels of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, IL-17, IFN-γ, as well as those of vitamin D (25(OH)D3) and the kynurenine/tryptophan ratio (Kyn/Trp) were determined by ELISA and HPLC, respectively. The plasma levels of the SCFAs acetate, butyrate, and propionate were detected by GC-MS. Results: A mean FIQ-R score indicated that the patients could be classified as having moderate FM. The mean levels of all cytokines, but IL-6 and IL-1β, were higher than the normal reference values. The highest concentrations of cytokines were observed in patients showing the highest FIQ-R scores and the lowest 25(OH)D3 levels. Deficient levels of acetate were found paralleled by an increase in Kyn/Trp. The highest acetate concentrations were detected in patients with the lowest FIQ-R scores and 25(OH)D3 levels. Significantly negative correlations were found between 25(OH)D3 concentrations and FIQ-R scores (p = 0.007) as well as IL-17 levels (p = 0.002) and between acetate and TNF-α (p = 0.040) as well as FIQ-R scores (p = 0.028), while significantly positive correlations were observed between Kyn/Trp and IL-17 (p = 0.027) as well as IFN-γ (p = 0.003). Conclusions: Our preliminary data suggest that the vitamin D status along with altered gut microbiota metabolism plays a major role in FM-related inflammatory pain. Replication of these findings in a larger cohort is required to provide additional insights. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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20 pages, 5518 KiB

Open AccessArticle

Butyric Acid Modulates Gut Microbiota to Alleviate Inflammation and Secondary Bone Loss in Ankylosing Spondylitis

by Ke You, Lianjun Yang, Zhihai Su, Jun Shen, Xinyang Fan, Yuanqing Guo, Zhen Yuan and Hai Lu

Biomedicines 2025, 13(1), 9; https://doi.org/10.3390/biomedicines13010009 - 24 Dec 2024

Viewed by 1477

Abstract

Background: Ankylosing spondylitis (AS) is a chronic inflammatory and autoimmune disease that primarily affects the sacroiliac joints and axial skeleton. While the exact pathogenetic mechanism of AS remains unclear, previous reports have highlighted the involvement of genetic factors, immune responses, and gut microbiota [...] Read more.

Background: Ankylosing spondylitis (AS) is a chronic inflammatory and autoimmune disease that primarily affects the sacroiliac joints and axial skeleton. While the exact pathogenetic mechanism of AS remains unclear, previous reports have highlighted the involvement of genetic factors, immune responses, and gut microbiota dysregulation in the development of this condition. Short-chain fatty acids (SCFAs), which are microbial fermentation products derived from sugar, protein, and dietary fibers, play a role in maintaining the intestinal barrier function and reducing inflammatory responses. The aim of this study was to investigate the therapeutic potential of butyric acid (BA), an important SCFA, in the treatment of AS. Methods: To evaluate the anti-inflammatory and anti-bone loss effects of BA, a murine AS model was established using proteoglycan and dimethyl dioctadecyl ammonium (DDA) adjuvants. Various techniques, including an enzyme-linked immunosorbent assay (ELISA), magnetic resonance imaging (MRI), micro-CT, histology, quantitative PCR (qPCR) for intestinal tight junction protein expression, and 16S rDNA sequencing to analyze gut microbiota abundance, were employed to assess the inflammation and bone health in the target tissues. Results: The results indicated that BA demonstrated potential in alleviating the inflammatory response in the peripheral joints and the axial spine affected by AS, as evidenced by the reductions in inflammatory infiltration, synovial hyperplasia, and endplate erosion. Furthermore, BA was found to impact the intestinal barrier function positively. Notably, BA was associated with the downregulation of harmful inflammatory factors and the reversal of bone loss, suggesting its protective effects against AS. Conclusions: These beneficial effects were attributed to the modulation of gut microbiota, anti-inflammatory properties, and the maintenance of skeletal metabolic homeostasis. This study contributes new evidence supporting the relationship between gut microbiota and bone health. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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20 pages, 3836 KiB

Open AccessArticle

Taurine Supplementation Alleviates Blood Pressure via Gut–Brain Communication in Spontaneously Hypertensive Rats

by Qing Su, Xiong-Feng Pan, Hong-Bao Li, Ling-Xiao Xiong, Juan Bai, Xiao-Min Wang, Xiao-Ying Qu, Ning-Rui Zhang, Guo-Quan Zou, Yang Shen, Lu Li, Li-Li Huang, Huan Zhang and Meng-Lu Xu

Biomedicines 2024, 12(12), 2711; https://doi.org/10.3390/biomedicines12122711 - 27 Nov 2024

Cited by 1 | Viewed by 2229

Abstract

Objects: Taurine exhibits protective effects in the context of cardiovascular pathophysiology. A range of evidence suggests that hypertension activates inflammatory responses and oxidative stress in the paraventricular nucleus (PVN), elevating the arterial tone and sympathetic activity, while it induces gut–brain axis dysfunction in [...] Read more.

Objects: Taurine exhibits protective effects in the context of cardiovascular pathophysiology. A range of evidence suggests that hypertension activates inflammatory responses and oxidative stress in the paraventricular nucleus (PVN), elevating the arterial tone and sympathetic activity, while it induces gut–brain axis dysfunction in the context of hypertension. However, the mechanism underlying taurine’s anti-hypertensive effects via the gut–brain axis remains unclear. Method: Male spontaneously hypertensive rats (SHRs) were administered 3% taurine in their drinking water for eight weeks, with their arterial pressure measured weekly. Molecular techniques were employed to investigate taurine’s effects on the hypertensive gut and PVN. Additionally, 16S rRNA gene sequencing was used to analyze the gut microbiota composition, and untargeted metabolomics was applied to assess the fecal metabolites following taurine supplementation. Results: Taurine supplementation not only reduced the blood pressure, sympathetic activity, and inflammatory and oxidative stress in the PVN but also improved the cardiac pathology and microbiota composition while alleviating gut inflammation in hypertensive rats. The untargeted metabolite analysis indicated that the primary effect of the taurine intervention in SHRs was exerted on tryptophan metabolism. The levels of serum metabolites such as kynurenine, L-tryptophan, serotonin (5-HT), and 5-hydroxyindole-3-acetic acid (5-HIAA) were altered in hypertensive rats following taurine treatment. Conclusions: Taurine supplementation restored the microbiota balance, strengthened the mucosal barrier, reduced intestinal inflammation, and stimulated tryptophan metabolism. The metabolites derived from the gut microbiota likely crossed the brain barrier and reached the paraventricular nucleus, thereby reducing the inflammatory responses and oxidative stress in the PVN via gut–brain communication, leading to decreased sympathetic nerve activity and blood pressure in the studied hypertensive rats. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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28 pages, 5189 KiB

Open AccessArticle

Characteristics of the Gut Microbiota Composition of the Arctic Zone Residents in the Far Eastern Region

by Alexandra I. Nekrasova, Irina G. Kalashnikova, Anna V. Korobeynikova, German A. Ashniev, Maria M. Bobrova, Sirozhdin Yu. Bakoev, Ekaterina S. Petryaikina, Alexander S. Nekrasov, Angelika V. Zagainova, Mariya V. Lukashina, Larisa R. Tolkacheva, Igor P. Bobrovnitskii, Vladimir S. Yudin, Anton A. Keskinov, Valentin V. Makarov and Sergey M. Yudin

Biomedicines 2024, 12(11), 2472; https://doi.org/10.3390/biomedicines12112472 - 28 Oct 2024

Cited by 1 | Viewed by 1243

Abstract

Background. In many studies over the past decade, scientists have made a connection between the composition of gut microbiota and human health. A number of publications have shown that gut bacteria are involved in many metabolic and physiological processes of the organism. [...] Read more.

Background. In many studies over the past decade, scientists have made a connection between the composition of gut microbiota and human health. A number of publications have shown that gut bacteria are involved in many metabolic and physiological processes of the organism. The composition of the gut microbiome is unique for each person and is formed under the influence of various factors associated with both the individual characteristics of the body and the characteristics of the environment. Different regional characteristics make it necessary for the body to adapt to certain conditions, including temperature fluctuations. Living in areas with low temperatures, such as the Arctic zone, dictates the need for increased energy consumption, which affects the composition of the gut microbiome. Methods. In our study, an extensive questionnaire was conducted among the participants, where many questions were included about the dietary preferences of the study participants, which allowed them us to further divide them into groups according to their diets. Stool samples were collected from participants from 3 groups: Arctic native, Arctic newcomer and the control group. The next step was the isolation of bacterial DNA and sequencing the 16S rRNA gene. The analysis of the results of the diversity of the intestinal microbiota was carried out both with and without taking into account the dietary preferences of the participants. Results. As a result of comparing the intestinal microbiota obtained from residents of the Arctic zone with the gut microbiota of residents of other regions with a milder climate, significant differences are found. These differences may be related to limited food resources and a reduction in the variety of food products characteristic of this Arctic region. t was also found that representatives of the bacterial families Christensenellaceae and Muribaculaceae dominated the control group, both with traditional nutrition and with a dairy-free diet in comparison with the Arctic groups. The control group was dominated by representatives of the Prevotellaceae, Enterobacteriaceae and Comamonadaceae families compared to the Arctic group (with a traditional diet). The results also show that the number of representatives of the families Desulfovibrionaceae (with traditional diet) and Enterobacteriaceae (with milk-free diet) is growing in the Arctic group. Conclusions. In the course of this work, bacterial families characteristic of people living in the Arc-tic zone of the Far Eastern region of the Russian Federation were identified. Poor diet, difficult climatic conditions, and problems with logistics and medical care can have a strong impact on the health of this population. The main type of diet for the inhabitants of the Arctic is the traditional type of diet. They consume a large number of low-cost products, obtainget animal protein from poultry and canned food, and also eat a small number of fresh vegetables and fruits. Such a diet is due to the social status of the study participants and the climatic and geographical features of the region (difficulties in agriculture). With such a diet, we observe a decrease in representatives of the Christensenellaceae, Muribaculaceae, Eubacteriaceae, and Prevotellaceae families and an increase in representatives of the Enterobacteriaceae and Desulfovibrionaceae families among Arctic residents. This imbalance in the futuremay cause, this population may to develop various diseases in the future, including chronic diseases such as obesity, intestinal dysbiosis, inflammatory bowel diseases, and type 2 diabetes. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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22 pages, 3201 KiB

Open AccessArticle

The Association between Gut Microbiota and Serum Biomarkers in Children with Atopic Dermatitis

by Irina G. Kalashnikova, Alexandra I. Nekrasova, Anna V. Korobeynikova, Maria M. Bobrova, German A. Ashniev, Sirozhdin Yu. Bakoev, Angelica V. Zagainova, Mariya V. Lukashina, Larisa R. Tolkacheva, Ekaterina S. Petryaikina, Alexander S. Nekrasov, Sergey I. Mitrofanov, Tatyana A. Shpakova, Lidiya V. Frolova, Natalya V. Bulanova, Ekaterina A. Snigir, Vladimir E. Mukhin, Vladimir S. Yudin, Valentin V. Makarov, Anton A. Keskinov and Sergey M. Yudin Show full author list Hide full author list

Biomedicines 2024, 12(10), 2351; https://doi.org/10.3390/biomedicines12102351 - 15 Oct 2024

Cited by 1 | Viewed by 1305

Abstract

Background. Currently, it is known that the gut microbiota plays an important role in the functioning of the immune system, and a rebalancing of the bacterial community can arouse complex immune reactions and lead to immune-mediated responses in an organism, in particular, the [...] Read more.

Background. Currently, it is known that the gut microbiota plays an important role in the functioning of the immune system, and a rebalancing of the bacterial community can arouse complex immune reactions and lead to immune-mediated responses in an organism, in particular, the development of atopic dermatitis (AD). Cytokines and chemokines are regulators of the innate and adaptive immune response and represent the most important biomarkers of the immune system. It is known that changes in cytokine profiles are a hallmark of many diseases, including atopy. However, it remains unclear how the bacterial imbalance disrupts the function of the immune response in AD. Objectives. We attempted to determine the role of gut bacteria in modulating cytokine pathways and their role in atopic inflammation. Methods. We sequenced the 16S rRNA gene from 50 stool samples of children aged 3–12 years who had confirmed atopic dermatitis, and 50 samples from healthy children to serve as a control group. To evaluate the immune status, we conducted a multiplex immunofluorescence assay and measured the levels of 41 cytokines and chemokines in the serum of all participants. Results. To find out whether changes in the composition of the gut microbiota were significantly associated with changes in the level of inflammatory cytokines, a correlation was calculated between each pair of bacterial family and cytokine. In the AD group, 191 correlations were significant (Spearman’s correlation coefficient, p ≤ 0.05), 85 of which were positive and 106 which were negative. Conclusions. It has been demonstrated that intestinal dysbiosis is associated with alterations in cytokine profiles, specifically an increase in proinflammatory cytokine concentrations. This may indicate a systemic impact of these conditions, leading to an imbalance in the immune system’s response to the Th2 type. As a result, atopic conditions may develop. Additionally, a correlation between known AD biomarkers (IL-5, IL-8, IL-13, CCL22, IFN-γ, TNF-α) and alterations in the abundance of bacterial families (Pasteurellaceae, Barnesiellaceae, Eubacteriaceae) was observed. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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Review

Jump to: Research, Other

20 pages, 1406 KiB

Open AccessReview

Cytokines Meet Phages: A Revolutionary Pathway to Modulating Immunity and Microbial Balance

by Rossella Cianci, Mario Caldarelli, Paola Brani, Annalisa Bosi, Alessandra Ponti, Cristina Giaroni and Andreina Baj

Biomedicines 2025, 13(5), 1202; https://doi.org/10.3390/biomedicines13051202 - 15 May 2025

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Abstract

Bacteriophages are a unique and fascinating group of viruses, known for their highly specific ability to infect and replicate within bacterial cells. While their potential as antibacterial agents has been recognized for decades, recent research has revealed complex interactions between phages and the [...] Read more.

Bacteriophages are a unique and fascinating group of viruses, known for their highly specific ability to infect and replicate within bacterial cells. While their potential as antibacterial agents has been recognized for decades, recent research has revealed complex interactions between phages and the human immune system, offering new insights into their role in immune modulation. New evidence reveals a dynamic and intricate relationship between phages and cytokines, suggesting their ability to regulate inflammation, immune tolerance, and host–pathogen interaction. Herein, we review how phages affect the production of cytokines and the behavior of immune cells indirectly by lysis of bacterium or directly on mammalian cells. Phages have been shown to induce both pro- and anti-inflammatory responses and recently, they have been explored in personalized immunotherapy, cancer immunotherapy, and microbiome modulation, which are the focus of this review. Several challenges remain despite significant progress, including practical obstructions related to endotoxins along with host microbiome variability and regulatory issues. Nevertheless, the potential of bacteriophages to modulate immune responses makes them attractive candidates for the future of precision medicine. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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25 pages, 1673 KiB

Open AccessReview

Gut Microbiota in Heart Failure—The Role of Inflammation

by Petros N. Fountoulakis, Panagiotis Theofilis, Panayotis K. Vlachakis, Paschalis Karakasis, Konstantinos Pamporis, Marios Sagris, Yannis Dimitroglou, Panagiotis Tsioufis, Evangelos Oikonomou, Konstantinos Tsioufis and Dimitris Tousoulis

Biomedicines 2025, 13(4), 911; https://doi.org/10.3390/biomedicines13040911 - 9 Apr 2025

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Abstract

Heart failure (HF) has become an immense health concern affecting almost 1–2% of the population globally. It is a complex syndrome characterized by activation of the sympathetic nervous system and the Renin–Angiotensin–Aldosterone (RAAS) axis as well as endothelial dysfunction, oxidative stress, and inflammation. [...] Read more.

Heart failure (HF) has become an immense health concern affecting almost 1–2% of the population globally. It is a complex syndrome characterized by activation of the sympathetic nervous system and the Renin–Angiotensin–Aldosterone (RAAS) axis as well as endothelial dysfunction, oxidative stress, and inflammation. The recent literature points towards the interaction between the intestinal flora and the heart, also called the gut–heart axis. The human gastrointestinal tract is naturally inhabited by various microbes, which are distinct for each patient, regulating the functions of many organs. Alterations of the gut microbiome, a process called dysbiosis, may result in systemic diseases and have been associated with heart failure through inflammatory and autoimmune mechanisms. The disorder of intestinal permeability favors the translocation of microbes and many metabolites capable of inducing inflammation, thus further contributing to the deterioration of normal cardiac function. Besides diet modifications and exercise training, many studies have revealed possible gut microbiota targeted treatments for managing heart failure. The aim of this review is to demonstrate the impact of the inflammatory environment induced by the gut microbiome and its metabolites on heart failure and the elucidation of these novel therapeutic approaches. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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15 pages, 861 KiB

Open AccessReview

The Covert Side of Ascites in Cirrhosis: Cellular and Molecular Aspects

by Carlo Airola, Simone Varca, Angelo Del Gaudio and Fabrizio Pizzolante

Biomedicines 2025, 13(3), 680; https://doi.org/10.3390/biomedicines13030680 - 10 Mar 2025

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Abstract

Ascites, a common complication of portal hypertension in cirrhosis, is characterized by the accumulation of fluid within the peritoneal cavity. While traditional theories focus on hemodynamic alterations and renin–angiotensin–aldosterone system (RAAS) activation, recent research highlights the intricate interplay of molecular and cellular mechanisms. [...] Read more.

Ascites, a common complication of portal hypertension in cirrhosis, is characterized by the accumulation of fluid within the peritoneal cavity. While traditional theories focus on hemodynamic alterations and renin–angiotensin–aldosterone system (RAAS) activation, recent research highlights the intricate interplay of molecular and cellular mechanisms. Inflammation, mediated by cytokines (interleukin-1, interleukin-4, interleukin-6, tumor necrosis factor-α), chemokines (chemokine ligand 21, C-X-C motif chemokine ligand 12), and reactive oxygen species (ROS), plays a pivotal role. Besides pro-inflammatory cytokines, hepatic stellate cells (HSCs), sinusoidal endothelial cells (SECs), and smooth muscle cells (SMCs) contribute to the process through their activation and altered functions. Once activated, these cell types can worsen ascites accumulationthrough extracellular matrix (ECM) deposition and paracrine signals. Besides this, macrophages, both resident and infiltrating, through their plasticity, participate in this complex crosstalk by promoting inflammation and dysregulating lymphatic system reabsorption. Indeed, the lymphatic system and lymphangiogenesis, essential for fluid reabsorption, is dysregulated in cirrhosis, exacerbating ascites. The gut microbiota and intestinal barrier alterations which occur in cirrhosis and portal hypertension also play a role by inducing inflammation, creating a vicious circle which worsens portal hypertension and fluid accumulation. This review aims to gather these aspects of ascites pathophysiology which are usually less considered and to date have not been addressed using specific therapy. Nonetheless, it emphasizes the need for further research to understand the complex interactions among these mechanisms, ultimately leading to targeted interventions in specific molecular pathways, aiming towards the development of new therapeutic strategies. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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27 pages, 1137 KiB

Open AccessReview

Microbiome Integrity Enhances the Efficacy and Safety of Anticancer Drug

by Alice N. Mafe and Dietrich Büsselberg

Biomedicines 2025, 13(2), 422; https://doi.org/10.3390/biomedicines13020422 - 10 Feb 2025

Cited by 4 | Viewed by 1516

Abstract

The intricate relationship between anticancer drugs and the gut microbiome influences cancer treatment outcomes. This review paper focuses on the role of microbiome integrity in enhancing the efficacy and safety of anticancer drug therapy, emphasizing the pharmacokinetic interactions between anticancer drugs and the [...] Read more.

The intricate relationship between anticancer drugs and the gut microbiome influences cancer treatment outcomes. This review paper focuses on the role of microbiome integrity in enhancing the efficacy and safety of anticancer drug therapy, emphasizing the pharmacokinetic interactions between anticancer drugs and the gut microbiota. It explores how disruptions to microbiome composition, or dysbiosis, can alter drug metabolism, immune responses, and treatment side effects. By examining the mechanisms of microbiome disruption caused by anticancer drugs, this paper highlights specific case studies of drugs like cyclophosphamide, 5-fluorouracil, and irinotecan, and their impact on microbial diversity and clinical outcomes. The review also discusses microbiome-targeted strategies, including prebiotics, probiotics, postbiotics, and fecal microbiota transplantation (FMT), as promising interventions to enhance cancer treatment. Furthermore, the potential of microbiome profiling in personalizing therapy and integrating these interventions into clinical practice is explored. Finally, this paper proposes future research directions, including developing novel biomarkers and a deeper comprehension of drug–microbiome interactions, to respond to current gaps in knowledge and improve patient outcomes in cancer care. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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25 pages, 1395 KiB

Open AccessReview

The Interplay of Nutrition, the Gut Microbiota and Immunity and Its Contribution to Human Disease

by Samantha L. Dawson, Emma Todd and Alister C. Ward

Biomedicines 2025, 13(2), 329; https://doi.org/10.3390/biomedicines13020329 - 31 Jan 2025

Cited by 1 | Viewed by 2075

Abstract

Nutrition, the gut microbiota and immunity are all important factors in the maintenance of health. However, there is a growing realization of the complex interplay between these elements coalescing in a nutrition–gut microbiota–immunity axis. This regulatory axis is critical for health with disruption [...] Read more.

Nutrition, the gut microbiota and immunity are all important factors in the maintenance of health. However, there is a growing realization of the complex interplay between these elements coalescing in a nutrition–gut microbiota–immunity axis. This regulatory axis is critical for health with disruption being implicated in a broad range of diseases, including autoimmune disorders, allergies and mental health disorders. This new perspective continues to underpin a growing number of innovative therapeutic strategies targeting different elements of this axis to treat relevant diseases. This review describes the inter-relationships between nutrition, the gut microbiota and immunity. It then details several human diseases where disruption of the nutrition–gut microbiota–immunity axis has been identified and presents examples of how the various elements may be targeted therapeutically as alternate treatment strategies for these diseases. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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27 pages, 1649 KiB

Open AccessReview

Gut Microbiota as Emerging Players in the Development of Alcohol-Related Liver Disease

by Wei Li, Wenkang Gao, Shengqi Yan, Ling Yang, Qingjing Zhu and Huikuan Chu

Biomedicines 2025, 13(1), 74; https://doi.org/10.3390/biomedicines13010074 - 31 Dec 2024

Viewed by 1233

Abstract

The global incidence and mortality rates of alcohol-related liver disease are on the rise, reflecting a growing health concern worldwide. Alcohol-related liver disease develops due to a complex interplay of multiple reasons, including oxidative stress generated during the metabolism of ethanol, immune response [...] Read more.

The global incidence and mortality rates of alcohol-related liver disease are on the rise, reflecting a growing health concern worldwide. Alcohol-related liver disease develops due to a complex interplay of multiple reasons, including oxidative stress generated during the metabolism of ethanol, immune response activated by immunogenic substances, and subsequent inflammatory processes. Recent research highlights the gut microbiota’s significant role in the progression of alcohol-related liver disease. In patients with alcohol-related liver disease, the relative abundance of pathogenic bacteria, including Enterococcus faecalis, increases and is positively correlated with the level of severity exhibited by alcohol-related liver disease. Supplement probiotics like Lactobacillus, as well as Bifidobacterium, have been found to alleviate alcohol-related liver disease. The gut microbiota is speculated to trigger specific signaling pathways, influence metabolite profiles, and modulate immune responses in the gut and liver. This research aimed to investigate the role of gut microorganisms in the onset and advancement of alcohol-related liver disease, as well as to uncover the underlying mechanisms by which the gut microbiota may contribute to its development. This review outlines current treatments for reversing gut dysbiosis, including probiotics, fecal microbiota transplantation, and targeted phage therapy. Particularly, targeted therapy will be a vital aspect of future alcohol-related liver disease treatment. It is to be hoped that this article will prove beneficial for the treatment of alcohol-related liver disease. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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12 pages, 1657 KiB

Open AccessReview

The Gut Microbiome’s Influence on Incretins and Impact on Blood Glucose Control

by Ajay S. Dulai, Mildred Min and Raja K. Sivamani

Biomedicines 2024, 12(12), 2719; https://doi.org/10.3390/biomedicines12122719 - 27 Nov 2024

Viewed by 1689

Abstract

Obesity and type 2 diabetes mellitus (T2DM) have been increasing in prevalence, causing complications and strain on our healthcare systems. Notably, gut dysbiosis is implicated as a contributing factor in obesity, T2DM, and chronic inflammatory diseases. A pharmacology exists which modulates the incretin [...] Read more.

Obesity and type 2 diabetes mellitus (T2DM) have been increasing in prevalence, causing complications and strain on our healthcare systems. Notably, gut dysbiosis is implicated as a contributing factor in obesity, T2DM, and chronic inflammatory diseases. A pharmacology exists which modulates the incretin pathway to improve glucose control; this has proven to be beneficial in patients with obesity and T2DM. However, it is unclear how the gut microbiome may regulate insulin resistance, glucose control, and metabolic health. In this narrative review, we aim to discuss how the gut microbiome can modulate incretin pathways and related mechanisms to control glucose. To investigate this, Google Scholar and PubMed databases were searched using key terms and phrases related to the microbiome and its effects on insulin and glucose control. Emerging research has shown that several bacteria, such as Akkermansia and MN-Gup, have GLP-1-agonistic properties capable of reducing hyperglycemia. While more human research is needed to prove clinical benefit and identify long-term implications on health, the usage of pre-, pro-, and postbiotics has the potential to improve glucose control. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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11 pages, 3732 KiB

Open AccessCase Report

Involvement of Pruritus, Gut Dysbiosis and Histamine-Producing Bacteria in Paraneoplastic Syndromes

by Doina Georgescu, Daniel Lighezan, Mihai Ionita, Paul Ciubotaru, Gabriel Cozma, Alexandra Faur, Ioana Suceava, Oana Elena Ancusa and Roxana Buzas

Biomedicines 2025, 13(5), 1036; https://doi.org/10.3390/biomedicines13051036 - 25 Apr 2025

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Abstract

Background/Objectives: Paraneoplastic syndromes (PNS), characterized by a large diversity of symptoms, may sometimes be the first clinical feature of a severe underlying disorder such as cancer. Methods: We report the case of a middle-aged male patient with no significant previous medical history, a [...] Read more.

Background/Objectives: Paraneoplastic syndromes (PNS), characterized by a large diversity of symptoms, may sometimes be the first clinical feature of a severe underlying disorder such as cancer. Methods: We report the case of a middle-aged male patient with no significant previous medical history, a nonsmoker or alcohol heavy drinker, complaining about generalized, recently onset itch. Given no reasonable explanation of pruritus after dermatological consultation and the unsatisfactory response to treatment, the patient was referred to gastroenterology with the suspicion of a cholestatic liver disease. Results: The abdominal ultrasound examination revealed gallstones and no dilation of the biliary tree. Numerous tests were run and came out negative, except for the slight elevation of C-reactive protein, mild dyslipidemia, and positivity for H. pylori antigen. The gut microbiota displayed important dysbiosis with a significant increase in the histamine-producing bacteria. Given this chronic pruritus became suspicious, thorax and abdominal CT were recommended and performed soon after. A large right mid-thoracic tumor image was found. Bronchoscopy came out negative for a tumor. After the CT-guided biopsy, the tumor turned out not to be a lymphoma, but a non-small cell lung carcinoma (NSCLC). Conclusions: Chronic pruritus was not associated with cholestasis in a patient with gallstone disease, but rather with a PNS, as the first clinical manifestation of NSCLC, triggering many diagnostic and therapeutic challenges. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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34 pages, 1915 KiB

Open AccessSystematic Review

The Immune Environment in Colorectal Adenoma: A Systematic Review

by Ugne Silinskaite, Jurate Valciukiene, Matas Jakubauskas and Tomas Poskus

Biomedicines 2025, 13(3), 699; https://doi.org/10.3390/biomedicines13030699 - 12 Mar 2025

Viewed by 846

Abstract

Background/Objectives: Research on colorectal adenoma is significantly less comprehensive compared to studies on colorectal carcinoma. Although colorectal adenoma is a precursor of the majority of sporadic colorectal cancers, not all adenomas develop into carcinomas. The complex interaction of immune responses in the premalignant [...] Read more.

Background/Objectives: Research on colorectal adenoma is significantly less comprehensive compared to studies on colorectal carcinoma. Although colorectal adenoma is a precursor of the majority of sporadic colorectal cancers, not all adenomas develop into carcinomas. The complex interaction of immune responses in the premalignant tumor microenvironment might be a factor for that. Methods: In this systematic review, we aim to provide a thorough analysis of the current research examining the immune infiltration patterns in sporadic colorectal adenoma tissues in the context of immune cell-based, cytokine-based, and other immunological factor-related changes along the conventional adenoma–carcinoma sequence. The articles included in the review extend up to December 2024 in PubMed and Web of Science databases. Results: Most included studies have shown significant differences in immune cell counts, densities, and cytokine expression levels associated with premalignant colorectal lesions (and/or colorectal cancer). No consensus on the immune-related tendencies concerning CD4+T cells and CD8+T cells was reached. Decreasing expression of mDCs and plasma and naïve B cells were detected along the ACS. The increased density of tissue eosinophils in the adenoma tissue dramatically diminishes after the transition to carcinoma. As the adenoma progresses, the increasing expression of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-21, IL-23, IL-33, and TGF-β and decreasing levels of IL-12A, IL-18, IFN—γ, and TNFα cytokines in the invasive carcinoma stage is being detected. The over-expression of COX-2, PD-1/PD-L1, CTLA-4, and ICOS/ICOSLG in the colorectal adenomatous and cancerous tissues was also observed. Conclusions: Further studies are needed for a better understanding of the whole picture of colorectal adenoma-associated immunity and its impact on precancerous lesion’s potential to progress. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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