Melatonin restores DNFB-induced dysbiosis of skin microbiota in a mouse model of atopic dermatitis.

BACKGROUND: The epidermic microbiota plays crucial roles in the pathogenesis of atopic dermatitis (AD), a common inflammatory skin disease. Melatonin (MLT) has been shown to ameliorate skin damage in AD patients, yet the underlying mechanism is unclear. METHODS: Using 2,4-dinitrofluorobenzene (DNFB) to induce an AD model, MLT intervention was applied for 14 days to observe its pharmaceutical effect. Skin lesions were observed using HE staining, toluidine blue staining and electron microscopy. Dermal proinflammatory factor (IL-4 and IL-13) and intestinal barrier indices (ZO1 and Occludin) were assessed by immunohistochemistry and RT-qPCR, respectively. The dysbiotic microbiota was analyzed using 16S rRNA sequencing. RESULTS: MLT significantly improved skin lesion size; inflammatory status (mast cells, IgE, IL-4, and IL-13); and the imbalance of the epidermal microbiota in AD mice. Notably, Staphylococcus aureus is the key bacterium associated with dysbiosis of the epidermal microbiota and may be involved in the fine modulation of mast cells, IL-4, IL-13 and IgE. Correlation analysis between AD and the gut revealed that intestinal dysbiosis occurred earlier than that of the pathological structure in the gut. CONCLUSION: Melatonin reverses DNFB-induced skin damage and epidermal dysbiosis, especially in S. aureus.

Herbal medicine and gut microbiota: exploring untapped therapeutic potential in neurodegenerative disease management.

The gut microbiota that exists in the human gastrointestinal tract is incredibly important for the maintenance of general health as it contributes to multiple aspects of host physiology. Recent research has revealed a dynamic connection between the gut microbiota and the central nervous system, that can influence neurodegenerative diseases (NDs). Indeed, imbalances in the gut microbiota, or dysbiosis, play a vital role in the pathogenesis and progression of human diseases, particularly NDs. Herbal medicine has been used for centuries to treat human diseases, including NDs. These compounds help to relieve symptoms and delay the progression of NDs by improving intestinal barrier function, reducing neuroinflammation, and modulating neurotransmitter production. Notably, herbal medicine can mitigate the progression of NDs by regulating the gut microbiota. Therefore, an in-depth understanding of the potential mechanisms by which herbal medicine regulates the gut microbiota in the treatment of NDs can help explain the pathogenesis of NDs from a novel perspective and propose novel therapeutic strategies for NDs. In this review, we investigate the potential neuroprotective effects of herbal medicine, focusing on its ability to regulate the gut microbiota and restore homeostasis. We also highlight the challenges and future research priorities of the integration of herbal medicine and modern medicine. As the global population ages, access to this information is becoming increasingly important for developing effective treatments for these diseases.

Effect of chronic low-dose treatment with chitooligosaccharides on microbial dysbiosis and inflammation associated chronic ulcerative colitis in Balb/c mice.

The study aimed to investigate the potential of low dose chitooligosaccharide (COS) in ameliorating dextran sodium sulfate (DSS) induced chronic colitis by regulating microbial dysbiosis and pro-inflammatory responses. Chronic colitis was induced in BALB/c mice by DSS (4% w/v, 3 cycles of 5 days) administration. The mice were divided into four groups: vehicle, DSS, DSS + mesalamine and DSS+COS. COS and mesalamine were administered orally, daily once, from day 1 to day 30 at a dose of 20 mg/kg and 50 mg/kg respectively. The disease activity index (DAI), colon length, histopathological score, microbial composition, and pro-inflammatory cytokine expression were evaluated. COS (20 mg/kg, COSLow) administration reduced the disease activity index, and colon shortening, caused by DSS significantly. Furthermore, COSLow restored the altered microbiome in the gut and inhibited the elevated pro-inflammatory cytokines (IL-1 and IL-6) in the colon against DSS-induced chronic colitis in mice. Moreover, COSLow treatment improved the probiotic microflora thereby restoring the gut homeostasis. In conclusion, this is the first study where microbial dysbiosis and pro-inflammatory responses were modulated by chronic COSLow treatment against DSS-induced chronic colitis in Balb/c mice. Therefore, COS supplementation at a relatively low dose could be efficacious for chronic inflammatory bowel disease.

The Use of Microbial Modifying Therapies to Prevent Psoriasis Exacerbation and Associated Cardiovascular Comorbidity.

Psoriasis has emerged as a systemic disease characterized by skin and joint manifestations as well as systemic inflammation and cardiovascular comorbidities. Many progresses have been made in the comprehension of the immunological mechanisms involved in the exacerbation of psoriatic plaques, and initial studies have investigated the mechanisms that lead to extracutaneous disease manifestations, including endothelial disfunction and cardiovascular disease. In the past decade, the involvement of gut dysbiosis in the development of pathologies with inflammatory and autoimmune basis has clearly emerged. More recently, a major role for the skin microbiota in establishing the immunological tolerance in early life and as a source of antigens leading to cross-reactive responses towards self-antigens in adult life has also been evidenced. Gut microbiota can indeed be involved in shaping the immune and inflammatory response at systemic level and in fueling inflammation in the cutaneous and vascular compartments. Here, we summarized the microbiota-mediated mechanisms that, in the skin and gut, may promote and modulate local or systemic inflammation involved in psoriatic disease and endothelial dysfunction. We also analyze the emerging strategies for correcting dysbiosis or modulating skin and gut microbiota composition to integrate systemically existing pharmacological therapies for psoriatic disease. The possibility of merging systemic treatment and tailored microbial modifying therapies could increase the efficacy of the current treatments and potentially lower the effect on patient's life quality.

The microbiome in the pathogenesis of lung cancer: The role of microbiome in lung cancer pathogenesis.

As one of the malignant tumors with high incidence rate and high mortality, lung cancer seriously threatens the life safety of patients. Research shows that microorganisms are closely related to lung cancer. The microbiome is symbiotic with the host and plays a vital role in the functions of the human body. Microbiota dysbiosis is correlated with development of lung cancer. However, the underlying mechanisms are poorly understood. This paper summarizes the composition characteristics of the gut-lung axis microbiome and intratumoral microbiome in patients with lung cancer. We then expound five potential carcinogenic mechanisms based on microorganisms, such as genotoxicity, metabolism, inflammation, immune response, and angiogenesis. Next, we list three high-throughput sequencing methods, and finally looks forward to the prospect of microorganisms as novel targets for early diagnosis and treatment of lung cancer.

Targeting Gut Dysbiosis and Microbiome Metabolites for the Development of Therapeutic Modalities for Neurological Disorders.

The gut microbiota, composed of numerous species of microbes, works in synergy with the various organ systems in the body to bolster our overall health and well-being. The most well-known function of the gut microbiome is to facilitate the metabolism and absorption of crucial nutrients, such as complex carbohydrates, while also generating vitamins. In addition, the gut microbiome plays a crucial role in regulating the functioning of the central nervous system (CNS). Host genetics, including specific genes and single nucleotide polymorphisms (SNPs), have been implicated in the pathophysiology of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD). The gut microbiome dysbiosis also plays a role in the pathogenesis of these neurodegenerative disorders, thus perturbing the gut-brain axis. Overproduction of certain metabolites synthesized by the gut microbiome, such as short-chain fatty acids (SCFAs) and p-cresyl sulfate, are known to interfere with microglial function and trigger misfolding of alpha-synuclein protein, which can build up inside neurons and cause damage. By determining the association of the gut microbiome and its metabolites with various diseases, such as neurological disorders, future research will pave the way for the development of effective preventive and treatment modalities.

Structural characterization of a polysaccharide from Alhagi honey and its protective effect against inflammatory bowel disease by modulating gut microbiota dysbiosis.

The Alhagi honey polysaccharide (AHP) exhibits notable anti-inflammatory, antioxidant, and immunomodulatory properties, positioning it as a promising candidate in traditional Chinese medicine. In this investigation, we successfully isolated and purified a neutral AHP, designated AHPN50-1a, subsequently elucidating its structural attributes. AHPN50-1a was found to have a molecular weight of 1.756 × 106 Da, featuring a structural motif characterized by a recurring (1→6)-α-GlcP linker. To comprehensively evaluate its therapeutic potential, we explored the protective effects of AHPN50-1 in a murine model of dextran sodium sulfate-induced colitis. Administration of AHPN50-1 at doses of 200 and 400 mg/kg/day resulted in improved food intake, increased body weight, and increased colon length in mice with acute colitis. Simultaneously, a reduction in the disease activity index and histological scores was observed. AHPN50-1 effectively mitigated colon tissue damage, down-regulated the expression levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α) in colon tissue, restored intestinal microbiota diversity, and concentrations of short-chain fatty acids (SCFAs) of gut microbiota metabolites, thus alleviating intestinal inflammation in mice. In summary, our findings underscore the promise of AHPN50-1 as a valuable nutritional or dietary supplement for the treatment and prevention of inflammatory bowel disease.

Prebiotics and Probiotics: Therapeutic Tools for Nonalcoholic Fatty Liver Disease.

Alterations in the gut-liver axis and changes in the gut microbiome are among the risk factors for the pathogenesis of non-alcoholic fatty liver disease (NAFLD). These patients show increased bacterial overgrowth in the small intestine and impaired intestinal permeability. Therefore, therapeutic options such as probiotics or prebiotics have been investigated to modulate intestinal microbiota composition to improve NAFLD. Most in vivo and in vitro probiotic studies have focused on reducing hepatic fat accumulation. The beneficial effects of probiotics on NAFLD have been demonstrated in animal models, and the most widely used microorganisms are those of the Lactobacillus and Bifidobacterium genera. In animal models, probiotics help restore the intestinal microbiota and improve the integrity of the intestinal barrier. This narrative review summarizes published evidence and the likely benefits of probiotics and prebiotics as a therapeutic option for patients with NAFLD.

Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis.

Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production. There are some similarities in changes of microflora from insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, fails to suppress HCC in the male STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which show dysbiosis and impaired gut barrier function. Furthermore, male ieIRKO mice are prone to develop HCC merely on HFD. These data suggest that impaired gut insulin signaling increases the risk of HCC, which can be countered by restoration of insulin action in diabetes.

Fungal dysbiosis and decreased tear mucin at the conjunctiva in patients with conjunctival mucosa-associated lymphoid tissue lymphoma.

OBJECTIVE: This study aimed to examine the differences in the fungal microbiome between patients with conjunctival mucosa-associated lymphoid tissue (MALT) and healthy controls using metagenomic analysis. METHODS AND ANALYSIS: This case-control study was conducted at Osaka University Hospital in Osaka, Japan, from April 2015 to March 2022. Twenty-five consecutive patients with conjunctival MALT lymphoma and 25 healthy volunteers were included. Metagenomic analysis using Internal Transcribed Spacer (ITS)1 deep sequencing and hierarchical clustering was performed to investigate differences in the fungal microbiome. To assess tear environmental change, we measured tear mucin concentrations using ELISA. RESULTS: Detailed analyses showed fungal dysbiosis and changes in ß-diversity within the conjunctiva of patients with conjunctival MALT lymphoma. Hierarchical clustering revealed that the participants could be divided into three clusters according to the Malassezia abundance: cluster I (Malassezia abundance above 70%), cluster II (Malassezia abundance 25%-70%) and cluster II (Malassezia abundance below 25%). Most patients were included in cluster I, whereas most of healthy controls were included in cluster III. The differences were significant. Tear mucin concentrations were significantly lower in patients with MALT compared with healthy controls. CONCLUSION: The metagenomic analysis using ITS1 deep sequencing was useful for identifying the differences in commensal fungi between patients with MALT lymphoma and healthy individuals. The increased prevalence of the Malassezia genus and the decreased levels of tear mucin can lead to an allergic response of the conjunctiva, resulting in the pathogenesis associated with conjunctival MALT lymphoma. Therefore, it may be beneficial to initiate treatment when a high abundance Malassezia is detected.

Laser Capture Microdissection, Culture Analysis, and Bacterial Sequencing to Evaluate the Microbiota of Focal Duodenal Necrosis in Egg Layers.

Focal duodenal necrosis (FDN) is a common intestinal disease of table egg layers. In this research we aimed to identify the bacteria commonly found in FDN lesions as seen with histopathological analysis. Fifty-nine ethanol-fixed duodenum samples were collected from egg layers on eight FDN-affected farms, and 42 samples had typical FDN lesions. Excision of bacteria-containing lesions using laser capture microdissection was performed, followed by 16S rRNA gene sequencing of extracted DNA for bacterial identification. Bacterial sequencing analysis revealed no consistent bacterial species identified from samples with FDN. However, analysis of the relative phylum abundance revealed differences in the duodenal microbiota between layers with FDN and healthy birds. There were differences in the abundance of Proteobacteria, Firmicutes, and Actinobacteria between FDN-positive and FDN-negative control samples compatible with intestinal dysbiosis. In addition, 10 duodenal samples with FDN lesions were collected for bacteriological analysis, yielding 47 colonies on tryptone soy agar, MacConkey agar, and blood agar plates. Using 16S rRNA gene PCR, 39/47 (53.8%) colonies were identified as Escherichia coli. PCR for E. coli virulence genes identified 21/39 (53.8%) E. coli isolates as avian pathogenic E. coli-like. PCR analysis for 19 E. coli virulence genes associated with intestinal disease strains including inflammatory bowel disease found 11/39 (28.2%) isolates containing more than 10 of these virulence genes. In conclusion, FDN appears to be a multifactorial inflammatory intestinal disease associated with intestinal dysbiosis, and Gram-negative bacteria including E. coli may contribute to the pathogenesis of this disease.

Microdisección por captura láser, análisis de cultivos y secuenciación bacteriana para evaluar la microbiota de la necrosis duodenal focal en aves de postura de huevo comercial. La necrosis duodenal focal (FDN) es una enfermedad intestinal común en las gallinas de postura de huevo comercial. En esta investigación, el objetivo fue identificar las bacterias que se encuentran comúnmente en las lesiones provocadas por la necrosis duodenal focal tal como se aprecian con el análisis histopatológico. Se recolectaron 59 muestras de duodeno fijadas con etanol de gallinas de postura de ocho granjas afectadas por necrosis duodenal focal, y 42 muestras tenían lesiones típicas de dicha enfermedad. Se realizó la escisión de las lesiones que contenían bacterias mediante microdisección por captura láser, seguida de la secuenciación del gene 16S rRNA del ADN extraído para la identificación bacteriana. El análisis de secuenciación bacteriana no reveló especies bacterianas consistentes identificadas a partir de muestras con necrosis duodenal focal. Sin embargo, el análisis de la abundancia relativa del phylum reveló diferencias en el microbiota duodenal entre gallinas de postura con necrosis duodenal focal y aves sanas. Hubo diferencias en la abundancia de Proteobacteria, Firmicutes y Actinobacteria entre las muestras controles positivas y negativas para la necrosis duodenal focal compatibles con disbiosis intestinal. Además, se recolectaron 10 muestras duodenales con lesiones de la necrosis duodenal focal para análisis bacteriológico, lo que produjo 47 colonias en placas de agar triptona soya, agar MacConkey y agar sangre. Utilizando un método de PCR para el gene 16S rRNA, 39/47 (53.8 %) colonias se identificaron como Escherichia coli. El método de PCR para genes de virulencia de E. coli identificó 21/39 (53.8 %) aislados de E. coli como similares a E. coli patogénica aviar. El análisis de PCR para 19 genes de virulencia de E. coli asociados con cepas que provocan enfermedades intestinales, incluida la enfermedad inflamatoria intestinal, detectó 11/39 (28.2 %) aislados que contenían más de 10 de estos genes de virulencia. En conclusión, la necrosis duodenal focal parece ser una enfermedad intestinal inflamatoria multifactorial asociada con disbiosis intestinal, y las bacterias Gramnegativas, incluida E. coli, pueden contribuir a la patogenia de esta enfermedad.

Wild mouse gut microbiota limits initial tuberculosis infection in BALB/c mice.

Mouse models are critical tools in tuberculosis (TB) research. Recent studies have demonstrated that the wild mouse gut microbiota promotes host fitness and improves disease resistance. Here we examine whether the wild mouse gut microbiota alters the immunopathology of TB in BALB/c mice. Conventional BALB/c mice (LabC) and mice born to germ-free BALB/c mothers reconstituted with the wild mouse gut microbiota (WildR) were used in our studies. WildR mice controlled initial TB infection better than LabC mice. The microbial gut communities of LabC mice and WildR mice had similar richness but significantly different composition prior to infection. TB reduced the gut community richness in both cohorts while differences in community composition remained indicating a general TB-induced dysbiosis. The wild mouse gut microbiota did not alter the typical lung histopathology of TB in the BALB/c model that includes unstructured immune cell infiltrates with infected foamy macrophages invading alveolar spaces. Animals of both cohorts mounted robust T cell responses in lungs and spleen with lower absolute counts of CD4 and CD8 T cells in lungs of WildR mice during acute infection, corresponding with observed differences in pathogen load. In summary, LabC mice and WildR mice showed largely overlapping TB immunopathology and pathogen kinetics, with WildR mice controlling early acute infection better than LabC mice.

Genesis of clinical and subclinical endometritis in dairy cows.

In brief: Clinical and subclinical endometritis are different manifestations of reproductive tract inflammatory disease in dairy cows. This review addresses the genesis of clinical and subclinical endometritis considering metabolic stress, innate immune dysfunction, and shifts in the composition of the uterine microbiota in the postpartum period. Abstract: Up to half of dairy cows may develop one or more types of reproductive tract inflammatory disease within 5 weeks after calving. Clinical endometritis (CE) results from uterine bacterial dysbiosis with increased relative abundance of pathogenic bacteria associated with luminal epithelial damage. These bacteria cause endometrial stromal cell lysis, followed by massive polymorphonuclear neutrophil (PMN) migration, and pyogenesis. CE is defined as endometrial inflammation accompanied by purulent discharge. Purulent discharge is not always accompanied by uterine inflammation (being (rarely) vaginitis or (commonly) cervicitis), hence referred to as purulent vaginal discharge (PVD). Subclinical endometritis (SCE) is an asymptomatic uterine disease defined by a threshold of PMN on cytology that is associated with worse reproductive performance; it has not been linked with bacterial dysbiosis. Current evidence suggests that SCE is a result of metabolic and inflammatory dysfunction that impairs innate immune function and the ability of endometrial PMN to undergo apoptosis, necrosis, and ultimately achieve resolution of inflammation. CE and SCE are diagnosed between 3 and 5 weeks postpartum and commonly overlap, but they are considered distinct manifestations of reproductive tract inflammatory disease. This review addresses the genesis of CE and SCE in postpartum dairy cows considering metabolic stress, innate immune dysfunction, and shifts in the composition of the uterine microbiota.

Type 2 Diabetes Mellitus and Liver Disease: Across the Gut-Liver Axis from Fibrosis to Cancer.

Type 2 diabetes mellitus is a widespread disease worldwide, and is one of the cornerstones of metabolic syndrome. The existence of a strong relationship between diabetes and the progression of liver fibrosis has been demonstrated by several studies, using invasive and noninvasive techniques. Patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) show faster progression of fibrosis than patients without diabetes. Many confounding factors make it difficult to determine the exact mechanisms involved. What we know so far is that both liver fibrosis and T2DM are expressions of metabolic dysfunction, and we recognize similar risk factors. Interestingly, both are promoted by metabolic endotoxemia, a low-grade inflammatory condition caused by increased endotoxin levels and linked to intestinal dysbiosis and increased intestinal permeability. There is broad evidence on the role of the gut microbiota in the progression of liver disease, through both metabolic and inflammatory mechanisms. Therefore, dysbiosis that is associated with diabetes can act as a modifier of the natural evolution of NAFLD. In addition to diet, hypoglycemic drugs play an important role in this scenario, and their benefit is also the result of effects exerted in the gut. Here, we provide an overview of the mechanisms that explain why diabetic patients show a more rapid progression of liver disease up to hepatocellular carcinoma (HCC), focusing especially on those involving the gut-liver axis.

Gut microbiome and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease globally and imposed a heavy economic burden on society and individuals. To date, the pathological process of NAFLD is not yet fully elucidated. Compelling evidences have demonstrated the pivotal role of gut microbiota in the pathogenesis of NAFLD, and gut dysbiosis has been commonly observed in patients with NAFLD. Gut dysbiosis impairs gut permeability, allowing the translocation of bacterial products such as lipopolysaccharides (LPS), short-chain fatty acids (SCFAs), and ethanol to the liver via portal blood flow. This review aimed to shed light on the underlying mechanisms by which gut microbiota influences the development and progression of NAFLD. In addition, the potential application of gut microbiome as a non-invasive diagnostic tool and a novel therapeutical target was reviewed.

The Crosstalk between Gut Microbiota and Nervous System: A Bidirectional Interaction between Microorganisms and Metabolome.

Several studies have shown that the gut microbiota influences behavior and, in turn, changes in the immune system associated with symptoms of depression or anxiety disorder may be mirrored by corresponding changes in the gut microbiota. Although the composition/function of the intestinal microbiota appears to affect the central nervous system (CNS) activities through multiple mechanisms, accurate epidemiological evidence that clearly explains the connection between the CNS pathology and the intestinal dysbiosis is not yet available. The enteric nervous system (ENS) is a separate branch of the autonomic nervous system (ANS) and the largest part of the peripheral nervous system (PNS). It is composed of a vast and complex network of neurons which communicate via several neuromodulators and neurotransmitters, like those found in the CNS. Interestingly, despite its tight connections to both the PNS and ANS, the ENS is also capable of some independent activities. This concept, together with the suggested role played by intestinal microorganisms and the metabolome in the onset and progression of CNS neurological (neurodegenerative, autoimmune) and psychopathological (depression, anxiety disorders, autism) diseases, explains the large number of investigations exploring the functional role and the physiopathological implications of the gut microbiota/brain axis.

Urolithin C reveals anti-NAFLD potential via AMPK-ferroptosis axis and modulating gut microbiota.

The pharmacology of urolithin C (UroC) on non-alcoholic fatty liver disease (NAFLD) is largely undetermined. We sought to investigate the potential for NAFLD improvement by administration of UroC and the underlying mechanisms. We verified the therapeutic effect of UroC on choline-deficient amino acid-defined high fat diet (CDAHFD) induced NAFLD mice via evaluating NAFLD activity score (NAS), AST, ALT, hepatic phosphorylated AMPK, and 4-hydroxynonenal. Oleic acid-induced AML12 cell was appraised by oil red staining and western blotting to explore the effect and mechanism of UroC in vitro. Transcriptional regulation of UroC was explored by liver RNA sequencing, gut microbiota composition was explored by 16SrRNA sequencing, and colorectal tight junctional proteins were detected by western blotting and immunohistochemistry. The detrimental effects of CDAHFD included the increased liver index, AST, ALT, hepatic 4-hydroxynonenal, impaired intestinal mucosal barrier, and most importantly, pathological damage in liver. Oral administration of UroC largely protected against these harmful alterations. Remarkably, both RNA sequencing and western blotting results indicated an activation in hepatic AMPK signaling pathway which was thought to inhibit ferroptosis response to UroC in vivo, while no change were found in AMPK-ferroptosis axis response to UroC in oleic acid-induced AML12 cells, hinted an indispensable linkage between UroC and hepatic AMPK, presumably the gut-liver axis. Furthermore, UroC could neither alleviate lipid deposition nor inhibit ferroptosis in vitro. The 16SrRNA showed UroC partially counteracted the dysbiosis induced by CDAHFD. Specifically, UroC reversed the elevated proportion of Firmicutes/Bacteroidota and enhanced the level of Parabacteroides goldsteinii and Lactobacillus vaginalis, which played a beneficial role in metabolic disorders. Oral administration of Urolithin C protected against the detrimental impact of CDAHFD via regulating AMPK-ferroptosis axis, maintaining intestinal mucosal barrier and counteracting gut dysbiosis.

Role of the Gut-Liver Axis in the Pathobiology of Cholangiopathies: Basic and Clinical Evidence.

The "Gut-Liver Axis" refers to the physiological bidirectional interplay between the gut and its microbiota and the liver which, in health, occurs thanks to a condition of immune tolerance. In recent years, several studies have shown that, in case of a change in gut bacterial homeostasis or impairment of intestinal barrier functions, cholangiocytes, which are the epithelial cells lining the bile ducts, activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Intestinal dysbiosis or impaired intestinal barrier functions cause cholangiocytes to be exposed to an increasing amount of microorganisms that can reactivate inflammatory responses, thus inducing the onset of liver fibrosis. The present review focuses on the role of the gut-liver axis in the pathogenesis of cholangiopathies.

Decreased Paneth cell α-defensins promote fibrosis in a choline-deficient L-amino acid-defined high-fat diet-induced mouse model of nonalcoholic steatohepatitis via disrupting intestinal microbiota.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fibrosis that develops from fatty liver. Disruption of intestinal microbiota homeostasis, dysbiosis, is associated with fibrosis development in NASH. An antimicrobial peptide α-defensin secreted by Paneth cells in the small intestine is known to regulate composition of the intestinal microbiota. However, involvement of α-defensin in NASH remains unknown. Here, we show that in diet-induced NASH model mice, decrease of fecal α-defensin along with dysbiosis occurs before NASH onset. When α-defensin levels in the intestinal lumen are restored by intravenous administration of R-Spondin1 to induce Paneth cell regeneration or by oral administration of α-defensins, liver fibrosis is ameliorated with dissolving dysbiosis. Furthermore, R-Spondin1 and α-defensin improved liver pathologies together with different features in the intestinal microbiota. These results indicate that decreased α-defensin secretion induces liver fibrosis through dysbiosis, further suggesting Paneth cell α-defensin as a potential therapeutic target for NASH.

Microbiome Dysbiosis: A Pathological Mechanism at the Intersection of Obesity and Glaucoma.

The rate at which obesity is becoming an epidemic in many countries is alarming. Obese individuals have a high risk of developing elevated intraocular pressure and glaucoma. Additionally, glaucoma is a disease of epidemic proportions. It is characterized by neurodegeneration and neuroinflammation with optic neuropathy and the death of retinal ganglion cells (RGC). On the other hand, there is growing interest in microbiome dysbiosis, particularly in the gut, which has been widely acknowledged to play a prominent role in the etiology of metabolic illnesses such as obesity. Recently, studies have begun to highlight the fact that microbiome dysbiosis could play a critical role in the onset and progression of several neurodegenerative diseases, as well as in the development and progression of several ocular disorders. In obese individuals, gut microbiome dysbiosis can induce endotoxemia and systemic inflammation by causing intestinal barrier malfunction. As a result, bacteria and their metabolites could be delivered via the bloodstream or mesenteric lymphatic vessels to ocular regions at the level of the retina and optic nerve, causing tissue degeneration and neuroinflammation. Nowadays, there is preliminary evidence for the existence of brain and intraocular microbiomes. The altered microbiome of the gut could perturb the resident brain-ocular microbiome ecosystem which, in turn, could exacerbate the local inflammation. All these processes, finally, could lead to the death of RGC and neurodegeneration. The purpose of this literature review is to explore the recent evidence on the role of gut microbiome dysbiosis and related inflammation as common mechanisms underlying obesity and glaucoma.