Faecalibacterium prausnitzii and Akkermansia muciniphila: driving the multiple sclerosis-a systematic review.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally. Most patients present with late diagnosis, leading to poor prognosis. This narrative review explores novel biomarkers for early HCC detection. We conducted a comprehensive literature review analyzing protein, circulating nucleic acid, metabolite, and quantitative proteomics-based biomarkers, evaluating the advantages and limitations of each approach. While established markers like alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, and AFP-L3 remain relevant, promising candidates include circulating tumor DNA, microRNAs, long noncoding RNAs, extracellular vesicle, and metabolomic biomarkers. Multi-biomarker panels like the GALAD score, Oncoguard, and Helio liver test show promise for improved diagnostic accuracy. Non-invasive approaches like urine and gut microbiome analysis are also emerging possibilities. Integrating these novel biomarkers with current screening protocols holds significant potential for earlier HCC detection and improved patient outcomes. Future research should explore multi-biomarker panels, omics technologies, and artificial intelligence to further enhance early HCC diagnosis and management.

The present review provides a comprehensive examination of the intricate dynamics between α-synuclein, a protein crucially involved in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and multiple system atrophy, and endogenously-produced bioactive lipids, which play a pivotal role in neuroinflammation and neurodegeneration. The interaction of α-synuclein with bioactive lipids is emerging as a critical factor in the development and progression of neurodegenerative and neuroinflammatory diseases, offering new insights into disease mechanisms and novel perspectives in the identification of potential biomarkers and therapeutic targets. We delve into the molecular pathways through which α-synuclein interacts with biological membranes and bioactive lipids, influencing the aggregation of α-synuclein and triggering neuroinflammatory responses, highlighting the potential of bioactive lipids as biomarkers for early disease detection and progression monitoring. Moreover, we explore innovative therapeutic strategies aimed at modulating the interaction between α-synuclein and bioactive lipids, including the development of small molecules and nutritional interventions. Finally, the review addresses the significance of the gut-to-brain axis in mediating the effects of bioactive lipids on α-synuclein pathology and discusses the role of altered gut lipid metabolism and microbiota composition in neuroinflammation and neurodegeneration. The present review aims to underscore the potential of targeting α-synuclein-lipid interactions as a multifaceted approach for the detection and treatment of neurodegenerative and neuroinflammatory diseases.

Multiple sclerosis (MS) is a well-known, chronic autoimmune disorder of the central nervous system (CNS) involving demyelination and neurodegeneration. Research previously conducted in the area of the gut microbiome has highlighted it as a critical contributor to MS pathogenesis. Changes in the commensal microbiota, or dysbiosis, have been shown to affect immune homeostasis, leading to elevated levels of pro-inflammatory cytokines and disruption of the gut–brain axis. In this review, we provide a comprehensive overview of interactions between the gut microbiota and MS, especially focusing on the immunomodulatory actions of microbiota, such as influencing T-cell balance and control of metabolites, e.g., short-chain fatty acids. Various microbial taxa (e.g., Prevotella and Faecalibacterium) were suggested to lay protective roles, whereas Akkermansia muciniphila was associated with disease aggravation. Interventions focusing on microbiota, including probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary therapies to normalize gut microbial homeostasis, suppress inflammation and are proven to improve clinical benefits in MS patients. Alterations in gut microbiota represent opportunities for identifying biomarkers for early diagnosis, disease progression and treatment response monitoring. Further studies need to be conducted to potentially address the interplay between genetic predispositions, environmental cues, and microbiota composition to get the precise mechanisms of the gut–brain axis in MS. In conclusion, the gut microbiota plays a central role in MS pathogenesis and offers potential for novel therapeutic approaches, providing a promising avenue for improving clinical outcomes in MS management.

Multiple sclerosis (MS) is a complex autoimmune disease in which both the roles of genetic susceptibility and environmental/microbial factors have been investigated. More than 200 genetic susceptibility variants have been identified along with the dysbiosis of gut microbiota, both independently have been shown to be associated with MS. We hypothesize that MS patients harboring genetic susceptibility variants along with gut microbiome dysbiosis are at a greater risk of exhibiting the disease. We investigated the genetic risk score for MS in conjunction with gut microbiota in the same cohort of 117 relapsing remitting MS (RRMS) and 26 healthy controls. DNA samples were genotyped using Illumina’s Infinium Immuno array-24 v2 chip followed by calculating genetic risk score and the microbiota was determined by sequencing the V4 hypervariable region of the 16S rRNA gene. We identified two clusters of MS patients, Cluster A and B, both having a higher genetic risk score than the control group. However, the MS cases in cluster B not only had a higher genetic risk score but also showed a distinct gut microbiome than that of cluster A. Interestingly, cluster A which included both healthy control and MS cases had similar gut microbiome composition. This could be due to (i) the non-active state of the disease in that group of MS patients at the time of fecal sample collection and/or (ii) the restoration of the gut microbiome post disease modifying therapy to treat the MS. Our study showed that there seems to be an association between genetic risk score and gut microbiome dysbiosis in triggering the disease in a small cohort of MS patients. The MS Cluster A who have a higher genetic risk score but microbiome profile similar to that of healthy controls could be due to the remitting phase of the disease or due to the effect of disease modifying therapies.

Lymphocyte calcium influx characteristics and its modulation by Kv1.3 and IKCa1 potassium channel inhibitors in multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation and neurodegeneration. Emerging evidence links gut microbiota dysbiosis to immune dysregulation and MS progression. While extensive research has been conducted in Western populations, region-specific studies are needed to assess the influence of local genetic and environmental factors. This study investigates gut microbiota alterations in Egyptian MS patients using Oxford Nanopore sequencing to identify microbial signatures associated with disease progression. Fecal samples from 33 newly diagnosed MS patients (20 with relapsing–remitting MS [RRM] and 13 with Progressive MS [PMS]) and 10 healthy controls were analyzed using long-read Oxford Nanopore sequencing of the full 16S rRNA gene. MS patients exhibited increased microbial richness but reduced evenness, with distinct gut microbiome profiles. Progressive MS was characterized by an abundance of pro-inflammatory bacteria (e.g., Enterococcus faecium and Romboutsia timonensis) and a depletion of short-chain fatty acid (SCFA)–producing species (Ruminococcus bromii and Faecalibacterium duncaniae), potentially contributing to heightened neuroinflammation and disease progression. Relapsing MS exhibited microbial shifts indicative of immune dysregulation, including increased Clostridium saudiense and decreased levels of the gut-protective Faecalibacterium butyricigenerans. Functional analysis linked these microbial alterations to oxidative stress, neurotransmitter imbalance, and suppressed lipid and carbohydrate metabolism. These findings underscore the role of gut microbiota dysbiosis in MS pathogenesis and, by focusing on an underexplored Egyptian cohort, highlight region-specific microbial shifts that may inform targeted therapeutic strategies for both Progressive and Relapsing forms of MS.

The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota have also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.

The number of colorectal cancer (CRC) patients is steadily growing worldwide, particularly in developing nations. Nonetheless, recent advances in early detection studies and therapy alternatives have reduced CRC mortality in affluent countries, despite rising incidence. Gut microbiota and their metabolites may contribute to tumor growth and reduced therapeutic efficacy. This preliminary study sought to uncover metabolic fingerprints in colorectal cancer patients. It also emphasizes the correlation between the gut microbiome, microbial metabolism, and altered metabolites in CRC. In this study, stool samples from 20 CRC patients and matched healthy controls were enrolled. Untargeted metabolomics approach based on an ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-MS/MS) were applied. Statistical approaches, pathway enrichment analysis, and network analysis were employed to unleash CRC perturbed metabolic pathways and putative biomarkers. The study identified a distinct manually curated metabolite profile that is substantially linked to CRC. The steroidogenesis, aspartate, tryptophan (Trp), and urea cycle were the most significant pathways that concurrently contributed to CRC.Prominently, among other pathways, Trp metabolism was identified as a critical pathway, indicating a possible connection between the development of CRC and gut microbiota. In a nutshell the notable resulted metabolites reveal auspicious biomarkers for the initial diagnosis as well as surveilling of CRC progression. This preliminary study highlights the potential involvement that gut bacteria may contribute in CRC patients. Further investigation into the composition of the gut microbiome associated with this metabolic profile may lead to the identification of novel biomarkers for early detection and possible targets for treatment.

Background Breast cancer is a heterogeneous disease with different molecular pathological types and different clinical manifestations. Liquid-based analysis of tumor heterogeneity in circulating tumor DNA (ctDNA) can be used for cancer detection, monitoring disease progression, etc. The gut microbiome has emerged as an important mediating factor of breast cancer. Dysbiosis may contribute to the development of breast cancer. In this study, we aimed to identify risk-associated microbiome and whether some of specific microbiomes correlate with tumor-specific mutation burdens and disease progression in Taiwan breast cancer patients. Methods A total of 141 normal female subjects and 52 breast cancer patients were enrolled randomly. The study was approved from the Internal Review Board of Kaohsiung Medical University Hospital and informed consents were obtained from each subject. The Oncomine™ breast cfDNA assays with 10-gene panel of 152-associated mutational hotspot loci was performed to detect circulating breast tumor-derived DNA (ctDNA). The microbiota composition in fecal samples was analyzed using 16S ribosome RNA gene (V3-V4 region) amplicon sequencing on Illumina Miseq platform. 16S rRNA sequencing data were analyzed using CLC genomics workbench (Qiagen, Germany) and MeTaxon software (DNArails Co., Ltd, Taipei, Taiwan, ROC). Results Multiple logistic regression was used to compare the differences of druggable gene mutations and 59.2% of patients harbored at least one somatic mutation. Compared to TP53, the odds of mutations of PIK3CA, ERBB2, AKT, KRAS, and SF3B1 were 94.4%, 98.5%, 99.3%, 99.3%, and 99.7% were significantly lower than those of TP53 (all p<0.001), after adjusting for tumor staging. As compared with stage I&II, the risk of harboring gene mutations was significantly higher in stage III (OR=9.519; 95% CI: 2.862-31.661), after adjusting for the effect of mutation type. Further investigation of the gut microbiota in breast cancer patients and normal controls showed that patients had an increased fecal microbiota composition (β-diversity) (ANOSIM, R2=0.0799, p=0.01 for Bray Curtis distances) but a lower α-diversity (pChao1=0.02) when compared with control women. Patients in stage I&II group had higher relative abundance of Streptococcus, Pasteurellaceae, Klebsiella pneumoniae, Blautia and Lachnospiraceae, as compared with control (p=0.003, <0.001, 0.001, <0.001 and 0.01).The ratio of increased microbial group (Streptococcus, Pasteurellaceae, Klebsiella pneumoniae, and Blautia) to decreased one (Sphingobacteriaceae and Akkermansia muciniphila) could obtain a score to discriminate stage I&II from normal control (AUC=0.783, p<0.001). Intriguingly, Lachnospiraceae wasincreased along with stage progression. In addition, the patients with TP53 mutations had higher levels of Klebsiella and those ones with PIK3CA mutations had higher levels of Lachnospiraceae and Sphingobacteriaceae. Blautia was increased when patients presented with both TP53 and PIK3CA mutations. More importantly, the proportion of TP53 mutations was higher and specially enriched with Klebsiella pneumoniae. Conclusion Our results showed that several microbiomes were significantly changed in breast cancer patients and the ratio of increased microbial group to decreased one could discriminate stage I&II from normal control. In addition, these microbiomes were correlated to specific ctDNA mutation patterns. Mutations of TP53 was associated with the enrichment of Klebsiella pneumoniae which was highly represented in breast cancer. Dysbiosis of specific gut microbiome may serve as novel biomarkers for early detection and prevention of breast cancer. The mechanisms underlying specific association between gut microbiome and gene mutations require further investigations. Citation Format: Ming-Feng Hou, Chih-Po Chiang, Chuan-Hsin Chang, Wei-Ting Lien, Ming-Je Yang, Yao-Tsung Yeh. TP53 mutations in circulating tumor DNA associate with klebsiella pneumoniae inbreast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-03-05.

Background: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs, including joints. The co-occurrence of osteoarthritis (OA) in SLE patients, termed lupus-associated osteoarthritis (LAO), presents unique challenges in diagnosis and management due to overlapping symptoms and accelerated joint degradation. Purpose: This review aims to explore the emerging landscape of novel biomarkers for early detection and monitoring of LAO, addressing the limitations of current biomarkers in capturing the unique pathophysiology of this condition. Main Body: The pathophysiology of LAO involves a complex interplay between autoimmune inflammation and degenerative processes. Key molecular pathways include pro-inflammatory cytokines (TNF-α, IL-1, IL-6), matrix metalloproteinases, and oxidative stress mechanisms. Current biomarkers for OA (e.g., CTX-II, COMP) and SLE (e.g., anti-dsDNA, complement proteins) lack specificity for LAO. Emerging biomarker strategies encompass genomics, proteomics, and metabolomics approaches, aiming to distinguish between inflammatory lupus arthritis, typical OA, and LAO. These novel biomarkers could potentially revolutionize early detection, disease progression tracking, and personalized therapeutic interventions. Conclusion: The development of LAO-specific biomarkers is crucial for improving early diagnosis and monitoring. Future research should focus on validating these biomarkers and translating them into clinical practice, potentially transforming the management of LAO in SLE patients.

TPS500 Background: It is estimated that by 2030 pancreatic cancer will be the second leading cause of cancer deaths in the US. Currently, only 9% of newly diagnosed pancreatic cancer is localized and 5-year survival is 7%. Due to most pancreatic cancers (PC) presenting at a later stage with poor overall survival, early detection methods must be implemented to improve treatment outcomes. Yet, effective early screening guidelines do not exist for pancreatic cancer. Our Early Detection Program (EDP) provides personalized early detection including risk assessment, screening, and genetic testing. We aim to evaluate risk assessment criteria, establish a database to delineate a pattern of characteristics, and utilize a biospecimen repository and molecular based technologies to map novel biomarkers for early detection. Methods: The EDP screens those with a family history or germline mutation consistent with potential increased risk for developing PC. Patients are eligible based on risk assessment and stratified into 3 groups based on the CAPS Consortium criteria (average, moderate, and high risk). Screenings may include genetic testing for germline mutations, blood testing including Hemoglobin A1C (HgBA1C), complete blood count (CBC), complete metabolic profile (CMP), cancer antigen 19-9 (CA 19-9), vitamin D 25-OH, lipid panel, and thyroid stimulating hormone (TSH). Serum and urine collection will be offered for banking for future studies. Patients have yearly screenings including thorough history and physical exam and cases are discussed at a multi-disciplinary pancreatic tumor board. If indicated, patients undergo MRI/MRCP abdomen, GI consult and EUS. Study participants also complete a cancer anxiety index. The EDP is still recruiting patients. Next-generation sequencing and molecular based technologies are being explored for mapping novel biomarkers for early detection. The Institute is expanding to include those at risk for breast and ovarian cancer. We are evaluating risk assessment criteria and are developing a valid and reliable EDP index (EDP-I) anxiety instrument.

Introduction: It is estimated that by 2030 pancreatic cancer will be the second leading cause of cancer deaths in the US. Currently, only 9% of newly diagnosed pancreatic cancer is localized and 5-year survival is 7%. Due to most pancreatic cancers (PC) presenting at a later stage with poor overall survival, early detection methods must be implemented to improve treatment outcomes. Yet, effective early screening guidelines do not exist for pancreatic cancer. Our Early Detection Program (EDP) provides personalized early detection including risk assessment, screening, and genetic testing. We aim to evaluate risk assessment criteria, establish a database to delineate a pattern of characteristics, and utilize a biospecimen repository and molecular based technologies to map novel biomarkers for early detection. Methods: This is a prospective study for individuals with a family history or a germline mutation consistent with risk for developing PC. Patients are eligible based on risk assessment criteria and stratified into 3 groups as defined by best available evidence based upon the CAPS Consortium and a prior prospective screening study. Patients are assessed at initial visit, have yearly screenings, and each case is discussed at a multi-disciplinary pancreatic tumor board. At the initial visit, patients undergo a thorough history and physical exam, genetic testing for germline mutations, routine blood tests along with Ca19-9 tumor marker and if indicated, MRI/MRCP abdomen, GI consult and EUS. Patients defined as average risk have one family member diagnosed with PC above the age of 55 years. Those at moderate risk are individuals with two or more first, second, third degree relatives with PC or one first degree relative with PC diagnosed < 55 years. Those at high risk have three or more first, second, or third degree relatives with pancreatic cancer, two or more first degree relatives with pancreatic cancer, one first and one second degree relative with pancreatic cancer if one of the relatives was < 55 years old at diagnosis, or have a genetic syndrome associated with pancreatic cancer. Study participants also complete a cancer anxiety index. Results: Since the inception of the EDP (IRB approved November 2015), there have been no PC cases identified. Current participants include individuals age 34 to 79 with a mean age of 59. According to the current risk criteria 22% have a low PC risk, 26% have a moderate risk, and 52% have a high PC risk. All were advised a genetic assessment. Of the current sample, 36% were male and 64% were female, 55% used tobacco in the past, and 9% currently use tobacco. The BMI average is 26.85 (overweight), 2 participants have Type 2 diabetes, and several have had other types of cancer such as: 5% breast, 2% colon, 2% ovarian, 1% thyroid, and 38% had basal cell skin cancer. 26% had germline mutations and 10% with intraductal papillary mucinous neoplasm (IPMN). Initial results reveal there is a level of anxiety associated with PC risk and some indicate their chance to develop cancer is high (M = 5.05, SD = 1.80). Compared to other people, participants stated their chance of getting cancer sometime in their life is a little higher (M = 4.10, SD = .85), and their ability to exercise control over their cancer risk was moderate (M = 2.6, SD .93). Conclusions: Although the EDP is still recruiting patients, the effectiveness of our screening for PC has revealed some encouraging outcomes. Next-generation sequencing (NGS) and molecular based technologies will be explored for mapping novel biomarkers for early detection in a clinical study. The Institute is expanding to also include those at risk for breast and ovarian cancer. We will be evaluating risk assessment criteria and also current anxiety scales. A product of this study will be the development of a valid and reliable EDP index (EDP-I) anxiety instrument. Citation Format: Courtney Snyder, Susan G. Haag, Nickie Adams, Jade Hess, Breann Paskett, Erkut Borazanci. Improving pancreatic cancer risk prediction through early detection. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B18.

Management of neurodegenerative disease can be challenging when there is limited access to effective treatment options. Recent studies indicate that human gut microbiota may influence neurodegenerative diseases and the aging process. Gut microbiota dysbiosis is one of the exacerbating factors associated with the interrupted gut-brain axis and neurodegenerative diseases. According to preclinical evidence, targeting gut microbiota by probiotic Lactiplantibacillus plantarum (LBP) may be a promising approach to improve altered gut microbiota and several neurodegenerative hallmarks. LBP has been a popular probiotic model but its psychobiotic potential is little understood so far. LBP can modulate altered gut microbiota and maintain intestinal homeostasis, resulting in induced levels of SCFAs, GABA, and other neurotransmitter. LBP-associated signaling agents induce the gut-brain axis (GBA) and stimulate intracellular antioxidant and anti-inflammatory pathways in the nerve cells. LBP-based probiotic supplements may reduce various neurodegenerative hallmarks such as β-amyloid formation, tau phosphorylation, microgliosis, infiltrated blood-brain barrier, neuroinflammation, and influence the morphology of grey matter in several neurodegenerative animal models such as Alzheimer’s disease, autism spectrum disorder, multiple sclerosis, and Parkinson’s disease. This review suggests LBP may be an important psychobiotic agent to modulate perturbed gut microbiota associated neurodegenerative disease. LBP administration may enhance the existed neurodegenerative treatment, especially associated with gut microbiota dysbiosis and geriatric conditions.

The gut microbiota (GM) has emerged as an important element in the management of host metabolism, immune functions, and overall metabolic well-being. This review consolidates contemporary research regarding the intricate relationship between GM and diabetes mellitus, focusing on the mechanisms by which microbial composition and activity affect the development of both Type 1 (T1D) and Type 2 diabetes (T2D). Dysbiosis-characterized by diminished microbial diversity, a modified Firmicutes/Bacteroidetes ratio, and a reduction in advantageous SCFA-producing bacteria-has been significantly associated with disrupted glucose metabolism, insulin resistance, and persistent inflammation. Additionally, the review discusses the potential for microbial signatures and metabolites, such as SCFAs, lipopolysaccharides (LPS), and trimethylamine N-oxide (TMAO), to serve as novel biomarkers for early detection and risk evaluation. Moreover, it investigates therapeutic approaches designed to reestablish microbial balance through the use of probiotics, prebiotics, dietary changes, fecal microbiota transplantation (FMT), and microbiome engineering. By integrating findings from recent research, this paper emphasizes the groundbreaking possibilities of microbiome-centric diagnostics and treatments in individualized diabetes care.

Thyroid cancer is a common endocrine malignancy associated with various inflammatory factors. This research aimed to explore the causal relationships between 41 inflammatory factors and the risk of thyroid cancer using Mendelian randomisation (MR) analysis. MR analysis was performed using genetic data from two publicly available European genome-wide association studies (GWAS). Instrumental variables were selected based on single-nucleotide polymorphisms significantly associated with cytokine levels. Causal relationships were assessed using the inverse variance weighted method, with sensitivity analyses to evaluate heterogeneity and pleiotropy. The results suggest that interleukin-1 receptor antagonist (IL-1RA) and β-nerve growth factor (B-NGF) are risk factors for thyroid cancer, while macrophage colony-stimulating factor (M-CSF) has a protective effect. IL-1RA, B-NGF, and M-CSF play a key role in regulating the tumour microenvironment compared with 38 other inflammatory factors that do not show a clear correlation. IL-1RA may promote cancer cell proliferation by activating pro-inflammatory signalling pathways, while B-NGF may enhance angiogenesis and immune escape, accelerating tumour progression. Conversely, M-CSF may reduce thyroid cancer risk by enhancing the anti-tumour immune response. Additionally, single-nucleotide polymorphism survival prognostic analysis showed that specific genetic variants associated with IL-1RA, B-NGF, and M-CSF may influence overall survival (OS) and cancer-specific survival (CSS) in patients with thyroid cancer, further supporting their potential value in thyroid cancer management. These findings suggest that IL-1RA and B-NGF could serve as novel biomarkers for early detection and disease monitoring of thyroid cancer, while M-CSF could be a potential therapeutic target, providing theoretical support for personalised intervention strategies. The results provide a new direction for precision medicine research in thyroid cancer.