Directory Entry For: Venkatakrishna Jala

Biography

Research Interests

Dr. Jala’s research interest is in understanding the regulation and mechanisms of Inflammation, Microbiota and Microbial Metabolites (e.g., urolithins) in inflammatory disorders such as colorectal cancer (CRC), inflammatory bowel diseases (IBD) and alcohol associated liver disease (ALD). Environmental factors, diet, and host genetics are increasingly recognized as key modulators of the human microbiota, thereby shaping disease progression. To dissect these complex interactions, Dr. Jala’s team employs a multifaceted strategy that integrates genetically engineered transgenic and compound mouse models (knockout and conditional expression systems) with cellular and molecular approaches. In parallel, advanced next-generation sequencing technologies are applied to uncover the diverse roles of microbiota and their metabolites in human pathophysiology.

Area 1: Impact of gut microbial metabolites on gut barrier function and inflammation:  Increased intestinal permeability, commonly referred to as "leaky gut," and chronic inflammation play pivotal roles in the pathogenesis of various gastrointestinal disorders, including inflammatory bowel diseases (IBD) and alcohol-associated liver disease (AALD). The interplay between leaky gut and chronic inflammation creates a self-perpetuating cycle that exacerbates the pathophysiology of these conditions. Therefore, addressing both gut barrier dysfunction and inflammation is crucial for enhancing therapeutic outcomes in these diseases. Unfortunately, currently available drugs do not specifically target the improvement of gut epithelial barrier function to mitigate gut leakiness. In this context, our research has made significant advancements. We demonstrated that oral treatment with microbial metabolite, urolithin A (UroA) and its analogue (UAS03) significantly mitigated colitis (Singh et al Nature communications 10, 89, (2019)) as well as attenuated AALD (Under review) in pre-clinical models. This breakthrough suggests a promising avenue for intervention.

Mechanistically, we will be investigating how intestinal epithelial cells (enterocytes, goblet cells, Paneth cells, stem cells) interact with microbiota/metabolites and mucosal immune system to regulate gut barrier functions. In this context, we focused on xenobiotic-inflammasome pathways that regulate mucus secretion and junctional proteins expression.

Furthermore, our focus extends to identifying a human bacterial consortium capable of producing UroA to enhance gut barrier function and reducing inflammation, with applications across various disorders involving gut barrier dysfunction. To achieve this, we employ a comprehensive approach involving germ-free mice, fecal microbiota transplantation (FMT) methodologies, and humanized microbiota mice as well as human and mouse intestinal organoid systems. These innovative strategies aim to uncover novel therapeutic interventions for conditions characterized by compromised gut barrier integrity.

Area 2: Microbial Metabolites enhance efficacies of chemotherapy and immunotherapy: Numerous studies focused on establishing the differential microbiota populations and their associations with cancer using high throughput sequencing methods. However, there is significant knowledge gap in determining cause and consequence relationships especially identifying the diet associated microbial metabolites and their effects on cancer development and therapies. In this regard, our laboratory tested the hypothesis that UroA and UAS03 act as chemosensitizing adjuvants in 5-FU therapies through regulation of drug transporters and cancer stemness. The focus of this study is to identify molecular target of these compounds, determining the mechanisms and therapeutic effects of UroA and its potent analogue, UAS03 on 5FU therapies utilizing pre-clinical colon cancer mouse models and establishing UroA and UAS03 as therapeutic chemosensitizing adjuvants in 5FU therapies. Immunotherapy: The remarkable success of immune checkpoints blockade therapies suggest that cancer immunotherapeutic approaches will likely become standard of care for many cancers. Two immune checkpoint targets [anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4 or ipilimumab) and anti-programmed cell-death (anti-PD1 or pembrolizumab/nivolumab)] are approved by the FDA. Despite impressive success of immunotherapy, a large cohort of patients do not respond to these therapies and responsive population develop whole spectrum of severe immune-related adverse events (irAE) such as diarrhea and colitis.  Immune check point inhibitor-induced colitis: Since, UroA and UAS03 mitigated colitis by enhancing gut barrier function, as a future goal, we are planning to develop these immunotherapy models to test whether treatment with UroA/UAS03 protects from irAEs as well as enhance efficacy of immunotherapy by activating immune system.  

Area 3: Effects of Microbial products against arsenic-induced gut barrier dysfunction: Inorganic Arsenic (iAs) ranks first on the United States Environmental Protection Agency Priority List of Hazardous Substances. About 225 million people in over 70 countries in the world are chronically exposed to toxic levels of arsenic making it an environmental health crisis with no known treatment. Chronic exposure to iAs leads to a multiple organ injury (including, liver, kidney, bladder, skin, intestines and central nervous system) in a condition referred as ‘arsenicosis’. Although association of microbial dysbiosis has been reported in arsenicosis, it is unclear how microbiota and their metabolites influence the outcomes of arsenic toxicity and attenuate arsenicosis. Recently, we published that treatment with UroA protects against arsenic-induced gut barrier damage and inflammation in human colon organoids model systems. Mechanistically, UroA blocks arsenic-induced oxidative stress and gut barrier permeability. The goal of this project is to test the beneficial effects and molecular mechanisms of selected gut microbiota and their metabolites against As-induced adverse events on gut and inflammatory bowel diseases (IBD) using pre-clinical models.

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