Mouse model of NASH that replicates key features of the human disease and progresses to fibrosis stage 3
St Rose, Kristy; Yan, Jun; Xu, Fangxi; Williams, Jasmine; Dweck, Virginia; Saxena, Deepak; Schwabe, Robert; Caviglia, Jorge Matias
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and the world; with no Food and Drug Administration-approved pharmacological treatment available, it remains an area of unmet medical need. In nonalcoholic steatohepatitis (NASH), the most important predictor of clinical outcome is the fibrosis stage. Moreover, the Food and Drug Administration recommends that clinical trials for drugs to treat this disease include patients with fibrosis stage 2 or greater. Therefore, when using animal models for investigating the pathophysiology of NAFLD and for the preclinical evaluation of new drugs, it is important that the animals develop substantial fibrosis. The aim of this study was to develop a mouse model of NAFLD that replicated the disease in humans, including obesity and progressive liver fibrosis. Agouti yellow mutant mice, which have hyperphagia, were fed a Western diet and water containing high-fructose corn syrup for 16â€‰weeks. Mice became obese and developed glucose intolerance. Their gut microbiota showed dysbiosis with changes that replicate some of the changes described in humans with NASH. They developed NASH with activity scores of 5-6 and fibrosis, which was stage 1 after 16â€‰weeks, and stage 3 after 12â€‰months. Changes in liver gene expression assessed by gene-set enrichment analysis showed 90% similarity with changes in human patients with NASH. Conclusion: Ay mice, when fed a Western diet similar to that consumed by humans, develop obesity and NASH with liver histology, including fibrosis, and gene expression changes that are highly similar to the disease in humans.
The tumor mycobiome: A paradigm shift in cancer pathogenesis
Li, Xin; Saxena, Deepak
Distinct fungal communities or "mycobiomes" have been found in individual tumor types and are known to contribute to carcinogenesis. Two new studies present a comprehensive picture of the tumor-associated mycobiomes from a variety of human cancers. These studies reveal that fungi, although in low abundance, are ubiquitous across all major human cancers and that specific mycobiome types can be predictive of survival.
Targeting the succinate receptor effectively inhibits periodontitis
Guo, Yuqi; Xu, Fangxi; Thomas, Scott C; Zhang, Yanli; Paul, Bidisha; Sakilam, Satish; Chae, Sungpil; Li, Patty; Almeter, Caleb; Kamer, Angela R; Arora, Paramjit; Graves, Dana T; Saxena, Deepak; Li, Xin
Periodontal disease (PD) is one of the most common inflammatory diseases in humans and is initiated by an oral microbial dysbiosis that stimulates inflammation and bone loss. Here, we report an abnormal elevation of succinate in the subgingival plaque of subjects with severe PD. Succinate activates succinate receptor-1 (SUCNR1) and stimulates inflammation. We detected SUCNR1 expression in the human and mouse periodontium and hypothesize that succinate activates SUCNR1 to accelerate periodontitis through the inflammatory response. Administration of exogenous succinate enhanced periodontal disease, whereas SUCNR1 knockout mice were protected from inflammation, oral dysbiosis, and subsequent periodontal bone loss in two different models of periodontitis. Therapeutic studies demonstrated that a SUCNR1 antagonist inhibited inflammatory events and osteoclastogenesis inÂ vitro and reduced periodontal bone loss inÂ vivo. Our study reveals succinate's effect on periodontitis pathogenesis and provides a topical treatment for this disease.
The Antimicrobial Properties of Cannabis and Cannabis-Derived Compounds and Relevance to CB2-Targeted Neurodegenerative Therapeutics
Hong, HeeJue; Sloan, Lucy; Saxena, Deepak; Scott, David A
Cannabinoid receptor 2 (CB2) is of interest as a much-needed target for the treatment or prevention of several neurogenerative diseases. However, CB2 agonists, particularly phytocannabinoids, have been ascribed antimicrobial properties and are associated with the induction of microbiome compositional fluxes. When developing novel CB2 therapeutics, CB2 engagement and antimicrobial functions should both be considered. This review summarizes those cannabinoids and cannabis-informed molecules and preparations (CIMPs) that show promise as microbicidal agents, with a particular focus on the most recent developments. CIMP-microbe interactions and anti-microbial mechanisms are discussed, while the major knowledge gaps and barriers to translation are presented. Further research into CIMPs may proffer novel direct or adjunctive strategies to augment the currently available antimicrobial armory. The clinical promise of CIMPs as antimicrobials, however, remains unrealized. Nevertheless, the microbicidal effects ascribed to several CB2 receptor-agonists should be considered when designing therapeutic approaches for neurocognitive and other disorders, particularly in cases where such regimens are to be long-term. To this end, the potential development of CB2 agonists lacking antimicrobial properties is also discussed.
Intrahepatic microbes govern liver immunity by programming NKT cells
Leinwand, Joshua C; Paul, Bidisha; Chen, Ruonan; Xu, Fangxi; Sierra, Maria A; Paluru, Madan M; Nanduri, Sumant; Alcantara Hirsch, Carolina G; Shadaloey, Sorin Aa; Yang, Fan; Adam, Salma A; Li, Qianhao; Bandel, Michelle; Gakhal, Inderdeep; Appiah, Lara; Guo, Yuqi; Vardhan, Mridula; Flaminio, Zia J; Grodman, Emilie R; Mermelstein, Ari; Wang, Wei; Diskin, Brian; Aykut, Berk; Khan, Mohammed; Werba, Gregor; Pushalkar, Smruti; McKinstry, Mia; Kluger, Zachary; Park, Jaimie J; Hsieh, Brandon; Dancel-Manning, Kristen; Liang, Feng-Xia; Park, James S; Saxena, Anjana; Li, Xin; Theise, Neil D; Saxena, Deepak; Miller, George
The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically Bacteroidetes species. Targeting Bacteroidetes with oral antibiotics reduced hepatic immune cells by ~90%, prevented APC maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of Bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial - glycosphingolipid - NKT - CCL5 axis that underlies hepatic immunity.
Electronic cigarette use enriches periodontal pathogens
Xu, Fangxi; Pushalkar, Smruti; Lin, Ziyan; Thomas, Scott C; Persaud, Julia Kishanie; Sierra, Maria A; Vardhan, Mridula; Vasconcelos, Rebeca; Akapo, Adenike; Guo, Yuqi; Gordon, Terry; Corby, Patricia M; Kamer, Angela R; Li, Xin; Saxena, Deepak
The effect of electronic cigarette (e-cigarette) smoking, especially its long-term impact on oral health, is poorly understood. Here, we conducted a longitudinal clinical study with two study visits, 6 months apart, to investigate the effect of e-cigarette use on the bacterial community structure in the saliva of 101 periodontitis patients. Our data demonstrated that e-cigarette use altered the oral microbiome in periodontitis patients, enriching members of the Filifactor, Treponema, and Fusobacterium taxa. For patients at the same periodontal disease stage, cigarette smokers and e-cigarette smokers shared more similarities in their oral bacterial composition. E-cigarette smoking may have a similar potential as cigarette smoking at altering the bacterial composition of saliva over time, leading to an increase in the relative abundance of periodontal disease-associated pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum. The correlation analysis showed that certain genera, such as Dialister, Selenomonas, and Leptotrichia in the e-cigarette smoking group, were positively correlated with the levels of proinflammatory cytokines, including IFN-Î³, IL-1Î², and TNF-Î±. E-cigarette use was also associated with elevated levels of proinflammatory cytokines such as IFN-Î³ and TNF-Î±, which contribute to oral microbiome dysbiosis and advanced disease state. This article is protected by copyright. All rights reserved.
Electronic Cigarette Use Promotes a Unique Periodontal Microbiome
Thomas, Scott C; Xu, Fangxi; Pushalkar, Smruti; Lin, Ziyan; Thakor, Nirali; Vardhan, Mridula; Flaminio, Zia; Khodadadi-Jamayran, Alireza; Vasconcelos, Rebeca; Akapo, Adenike; Queiroz, Erica; Bederoff, Maria; Janal, Malvin N; Guo, Yuqi; Aguallo, Deanna; Gordon, Terry; Corby, Patricia M; Kamer, Angela R; Li, Xin; Saxena, Deepak
Electronic cigarettes (e-cigs) have become prevalent as an alternative to conventional cigarette smoking, particularly in youth. E-cig aerosols contain unique chemicals which alter the oral microbiome and promote dysbiosis in ways we are just beginning to investigate. We conducted a 6-month longitudinal study involving 84 subjects who were either e-cig users, conventional smokers, or nonsmokers. Periodontal condition, cytokine levels, and subgingival microbial community composition were assessed, with periodontal, clinical, and cytokine measures reflecting cohort habit and positively correlating with pathogenic taxa (e.g., Treponema, Saccharibacteria, and Porphyromonas). Î±-Diversity increased similarly across cohorts longitudinally, yet each cohort maintained a unique microbiome. The e-cig microbiome shared many characteristics with the microbiome of conventional smokers and some with nonsmokers, yet it maintained a unique subgingival microbial community enriched in Fusobacterium and Bacteroidales (G-2). Our data suggest that e-cig use promotes a unique periodontal microbiome, existing as a stable heterogeneous state between those of conventional smokers and nonsmokers and presenting unique oral health challenges. IMPORTANCE Electronic cigarette (e-cig) use is gaining in popularity and is often perceived as a healthier alternative to conventional smoking. Yet there is little evidence of the effects of long-term use of e-cigs on oral health. Conventional cigarette smoking is a prominent risk factor for the development of periodontitis, an oral disease affecting nearly half of adults over 30â€‰years of age in the United States. Periodontitis is initiated through a disturbance in the microbial biofilm communities inhabiting the unique space between teeth and gingival tissues. This disturbance instigates host inflammatory and immune responses and, if left untreated, leads to tooth and bone loss and systemic diseases. We found that the e-cig user's periodontal microbiome is unique, eliciting unique host responses. Yet some similarities to the microbiomes of both conventional smokers and nonsmokers exist, with strikingly more in common with that of cigarette smokers, suggesting that there is a unique periodontal risk associated with e-cig use.
The mycobiome-immune axis: The next frontier in pancreatic cancer
Li, Xin; Saxena, Deepak
In this issue of Cancer Cell, Aftab etÂ al. identify a pro-inflammatory cytokine, IL-33, that is released as a chemoattractant for type 2 immune cells in response to the intratumoral mycobiome. Depletion of fungi or deletion of IL-33 in cancer cells significantly decreases pancreatic ductal adenocarcinoma (PDAC) tumor progression and increases survival.
The Gut Microbiome, Metformin, and Aging
Induri, Sri Nitya Reddy; Kansara, Payalben; Thomas, Scott C; Xu, Fangxi; Saxena, Deepak; Li, Xin
Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Interaction of toxic metals with the gut microbiome
Chapter by: Yan, Wenbo; Saxena, Deepak
in: Handbook on the Toxicology of Metals by
[S.l.] : Elsevier, 2021