Venkatakrishna Rao Jala, Ph.D.


Lab Staff and Students

Dr. Sweta Ghosh, Post-Doctoral Fellow
Dr. Sobha Bodduluri, Post-Doctoral Fellow
Zachary M Vanwinkle, Technician


Research Interests

Dr. Jala’s research interest is in understanding the regulation and mechanisms of of Inflammation, Microbiota and Microbial Metabolites in inflammatory disorders such as inflammatory bowel diseases (IBD), alcohol liver disease (ALD) and colon cancer. Our laboratory focusses on investigating how gut barrier function and inflammation play a critical role in regulating in pathophysiology of these disorders. The complex nature of the human gut microbiota and its relevance to human health and disease is at a very early stage of investigation. It is becoming very clear that changes in the environment, diet and genetic factors greatly influence human microbiota contributing to the modulation of disease progression. Dr. Jala’s laboratory focuses on determining the role of chemokine receptors, gut microbiota and interaction of microbial metabolites in colon cancer. We utilize several genetically altered transgenic/compound (knockout/conditional expression of interested genes) pre-clinical mouse models, cellular and molecular models and next generation sequencing methods to understand the colon cancer progression.

Impact of gut microbial metabolites on gut barrier function and inflammation: Increased intestinal permeability (leaky gut) and chronic inflammation are key pathogenic events in several gut related disorders including inflammatory bowel diseases (IBD) and alcoholic liver disease (ALD). Leaky gut and increased chronic inflammation are self-perpetuating and promote pathophysiology of disease conditions. Therefore, correcting the gut barrier dysfunction in addition to blocking inflammation, will increase the therapeutic outcomes in these diseases. Thus far, no drugs are available that target to improve the gut epithelial barrier function in order to attenuate gut leakiness. In this context, we identified a microbial metabolite called ‘Urolithin A (UroA)’, derived from dietary polyphenolics of pomegranates/berries that enhances gut barrier function in addition to blocking inflammation. Further, we also developed novel synthetic analogue (UAS03- Patent filed) that exhibited better gut barrier protective and anti-inflammatory activities than its parent compound UroA. Oral treatment with these compounds significantly mitigated colitis (Nature communications 10, 89, (2019)) and ALD in pre-clinical models. We identified unique mechanisms that these compounds exert their activities through aryl hydrocarbon receptor (AhR)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent- pathways to enhance gut barrier function through upregulating and stabilizing tight junction proteins. Our laboratory investigating whether direct consumption of beneficial microbial metabolites and their stable structural analogue improve overall health. Additionally, we focus on unraveling mechanisms of action of these compounds in regulating gut barrier and inflammation to mitigate adverse events. We are also focusing on identifying human bacterial consortium responsible for enhanced gut barrier function and reduce inflammation. We are utilizing germ-free mice, fecal microbiota transplantation (FMT) methodologies and humanized microbiota mice to achieve these objectives.

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. 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.  

Chemokine receptors-Gut microbiota and Colon cancer: The chemokines (chemotactic chemokines) are a family of small proteins or lipids known for their ability to control cell migration in the body. Their receptors belong to the class A subfamily of G protein-coupled receptors (GPCRs). In recent years, chemokines and their receptors have grown their importance, because they are involved in inflammation and autoimmune diseases, includes AIDS, atherosclerosis, arthritis, cancer and asthma etc. Chemokine receptors are some of the most tractable drug targets in the huge battery of molecules that regulate inflammation and immunity. For example, CCR2, a seven transmembrane GPCR, mediates several biological functions including chemotaxis of leukocytes upon binding to its ligand, CCL2 (MCP1). Elevated expression of CCL2 in tumor cells is very well correlated with increased metastasis and poor prognosis in several types of human cancers. We also determined lack of CCR2-CCL2 axis significantly reduce the colon tumorigenesis in mouse models. Dr. Jala’s laboratory investigates the role of CCL2-CCR2 axis in balancing the inter-relationship between immune system and microbiota in colon tumorigenesis. Determining the molecular, cellular mechanisms and complex inter-relationship between immune system-microbiota in the context of cancer will have a strong impact on our basic understanding of intestinal carcinogenesis as well as potential for developing novel therapeutic strategies. In collaboration with Dr. Bodduluri, we also investigate the role of leukotrienes and their receptors (BLT1 and BLT1) and chemokine decoy receptor (ACKR2, also called as D6 or CCBP2 receptor) in colon cancer progression and influence on the microbiota and vice versa.


SELECTED PUBLICATIONS

  1. Jala VR*, Bodduluri SR, Ghosh S, Chheda Z, Singh R, Smith ME, Chilton PM, Fleming CJ, Mathis SP, Sharma RK, Knight R, Yan J, Haribabu B. Absence of CCR2 reduces spontaneous intestinal tumorigenesis in the Apc(Min) (/+) mouse model. Int J Cancer 2021 (In press).
  2. Singh R, Chandrashekharappa S, Vemula PK, Haribabu B, Jala VR*. Microbial Metabolite Urolithin B Inhibits Recombinant Human Monoamine Oxidase A Enzyme. Metabolites 2020;10(6).
  3. Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, Hiwale AA, Saiyed T, Patel P, Vijay-Kumar M, Langille MGI, Douglas GM, Cheng X, Rouchka EC, Waigel SJ, Dryden GW, Alatassi H, Zhang HG, Haribabu B, Vemula PK, Jala VR*. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun 2019;10(1):89.
  4. Jala VR, Bodduluri SR, Satpathy SR, Chheda Z, Sharma RK, Haribabu B.  The Yin and Yang of Leukotriene B4 Mediated Inflammation in Cancer. Seminars in Immunology (2017)  33, 58-64.
  5. Jala VR*, Maturu P*, Bodduluri SR, Krishnan E, Mathis S, Subbarao K, Wang M, Jenson AB, Proctor ML, Rouchka EC, Knight R, Haribabu B. Leukotriene B4-receptor-1 mediated host response shapes gut microbiota and controls colon tumor progression. OncoImmunology. 2017:e1361593. doi: 10.1080/2162402X.2017.1361593. (* equally contributed)
  6. Fleming C, Cai Y, Sun X, Jala VR, Xue F, Morrissey S, Wei YL, Chien YH, Zhang HG, Haribabu B, Huang J, Yan J. Microbiota-activated CD103+ DCs stemming from microbiota adaptation specifically drive γδT17 proliferation and activation. Microbiome. 2017 Apr 24;5(1):46. doi: 10.1186/s40168-017-0263-9.
  7. Vemula PK and Jala VR* (2016). Colonic crypts are natural gatekeepers of microbial metabolites to protect stem cells (Invited commentary). Translational Cancer Research  5(3):S536-S9.
  8. Chheda ZS, Sharma RK, Jala VR, Luster AD, Haribabu B. 2016. Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors. J Immunol 197: 2016-26
  9. Saha P, Yeoh BS, Singh R, Chandrasekar B, Vemula PK, Haribabu B, Vijay-Kumar M*, Jala VR* Gut Microbiota Conversion of Dietary Ellagic Acid into Bioactive Phytoceutical Urolithin A Inhibits Heme Peroxidases. PloS one. 2016;11(6):e0156811. doi: 10.1371/journal.pone.0156811. PubMed PMID: 27254317; PMCID: PMC4890745. (*corresponding author).
  10. Satpathy SR, Jala VR, Bodduluri SR, Krishnan E, Hegde B, Hoyle G, Fraig M. Luster AD, Haribabu B (2015) Crystalline Silica-induced leukotrieneB4-dependent inflammation promotes lung tumor growth. Nature Communications 6:7064. doi: 10.1038/ncomms8064 PMID: 25923988