About
Malathi Shivaji Rao is an Assistant Professor of Neurology at the University of Chicago. Her clinical interests include Botox therapy, epilepsy, general neurology, headaches, migraine headaches, and seizures. She is affiliated with the Biological Sciences Division and the University of Chicago Medicine, contributing to the academic and clinical community through her expertise in neurology. Her contact information is provided for professional and patient engagement, and she is involved in research and clinical practice within her specialized fields.
Research topics
- Biology
- Immunology
- Sociology
- Pathology
- Neuroscience
- Genetics
- Evolutionary biology
- Ecology
- Computational biology
- Medicine
- Endocrinology
- Bioinformatics
- Internal medicine
- Cell biology
Selected publications
Gastroenterology · 2025-06-02
editorialOpen accessPhysiology · 2024-05-01
articleBA-associated diarrhea (BAD) occurs in ~1% of the population, where high [BA] alter the gut microbiota and epithelial barrier function. Probiotics are used to help restore the microbiome and alleviate diarrheal symptoms in these patients. Using T84 cells, we showed that the primary BA, chenodeoxycholic acid (CDCA; 500μM) increased apoptosis, oxidative stress (ROS) and proinflammatory cytokine IL-8 to disrupt tight junctions while its secondary BA, lithocholic acid (LCA), did not. We also showed that probiotics reversed the effects of CDCA in T84 cells (Physiol. 2023, 38, S1). In this study, we examined the dose-dependent effects of di-hydroxy (OH) BAs, CDCA, its 7-OH epimer ursodeoxycholic acid (UDCA) and its mono-OH BA, LCA, on microbial and epithelial cell function. We hypothesize that the differences in the -OH position (3, 7, or 12) and stereochemistry (α or β) will result in varied dose-dependent effects of these BAs. Probiotic strains in Up & Up supplement (30 billion CFUs of 10 strains) were grown in T84 cell culture media ± BA (50 - 500μM) in anaerobic conditions (37°C, 48h). The effect of BAs (50-500μM, 0–18h) on barrier function was studied in confluent T84 cells (TransEpithelial Resistance, TER >1000 Ω.cm2) as follows: i) apoptosis (Annexin-V, flow cytometry); ii. mitochondrial and nuclear ROS production (CellRox, flow cytometry) and iii) paracellular permeability (TER and FITC-10kD dextran fluxes (F10D)). The predominant bacterial species (Control media, CFU x 10 8 : 7.5 ± 1) was Lactobacillus fermentum (L f) (16S rRNA sequencing). CDCA caused a dose-dependent (μM) reduction in growth rate (50: 0.6±0.2; 250: 0.06±0.04; 500: 0.05±0.01; p<0.01, n=3) and changed the predominant species to L. plantarum (L p). UDCA and LCA (50-500μM) alone had no effect but reversed the actions of CDCA on bacterial growth (only 50 LCA/UDCA ± 500 CDCA are shown; CFU x 10 8 : LCA: 7±1; CDCA+LCA: 6.7±0.8; UDCA: 6.2±0.5; UDCA + CDCA: 6.5±1, n=3) and changed the predominant species to L f. In T84 cells, apical exposure of CDCA caused a dose-dependent increase in apoptosis while UDCA or LCA at any dose had no effect (% Annexin V + cells, 18 H: DMSO: 10±1; CDCA 50: 14±2; CDCA 250: 20±2; CDCA 500: 25±2; UDCA 500: 13±4; LCA 500: 9±2; n=3). CDCA increased ROS starting at 50μM (% CellRox+ cells: DMSO: 12±0.5; CDCA 50: 25±0.1; CDCA 250: 30±0.1; CDCA 500: 36±2). UDCA and LCA (50-500μM) had no effect. Time- and dose-dependent studies show that CDCA decreased TER (% decrease: CDCA 50: 50±5, CDCA 250: 63±7; CDCA 500: 71±8) and increased F10D fluxes (apparent permeability (x 10 −9 ) cm/sec: Control: 8±1; CDCA 50: 35±5; CDCA 250: 78±10; CDCA 500: 90±20). In contrast, UDCA and LCA alone (50-500μM) had no effect on paracellular permeability but restored CDCA-induced barrier dysfunction (apparent permeability (x 10 −9 ) cm/sec: Control: 8±1; CDCA 50: 35±5; CDCA 250: 78±10; CDCA 500: 90±20; UDCA 500: 13±2; CDCA 500+UDCA: 41±12; LCA 500: 15±2; CDCA 500+LCA: 38±2, n>3). Comparing the effects of hydrophobic CDCA with that of its hydrophilic 7-b isomer, UDCA, highlighted the importance of stereochemistry of -OH groups in BA action. CDCA’s deleterious effects on microbiota and epithelia started as low as 50μM, while UDCA, like LCA, restores the microbiota and barrier function. Understanding and targeting the interplay of BA, microbiota and epithelia may open up new therapeutic avenues for the treatment of diarrheal diseases. Supported by Funds from UGSRF, APS to ZF, NSSRP Funds, BenU to ER, AL, MN, MP and JS, UIC Funds to MR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Gut microbes and the liver circadian clock partition glucose and lipid metabolism
Journal of Clinical Investigation · 2023 · 43 citations
- Biology
- Endocrinology
- Internal medicine
Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we showed hierarchical, bidirectional communication among the liver circadian clock, gut microbes, and glucose homeostasis in mice. To assess this relationship, we utilized mice with liver-specific deletion of the core circadian clock gene Bmal1 via Albumin-cre maintained in either conventional or germ-free housing conditions. The liver clock, but not the forebrain clock, required gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expanded proportions and abundances of oscillating microbial features by 2-fold relative to that in controls. The liver clock was the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provided secondary cues that dampened these rhythms, resulting in reduced lipid fuel utilization relative to carbohydrates. All together, the liver clock transduced signals from gut microbes that were necessary for regulating glucose and lipid metabolism and meeting energy demands over 24 hours.
Physiology · 2023-05-01
articleHigh colonic BAs play a role in pathogenesis of diarrheal diseases in ~1% of the population. Probiotic supplements are often used to help alleviate the symptoms. We have previously reported that the primary BA, chenodeoxycholic acid (CDCA; 500μM), alters the pore and leak functions of TJs and disrupts barrier integrity in T84 cells, while its derivative, lithocholic acid (LCA; 50μM), did not; CDCA action involved reactive oxygen species, the proinflammatory cytokine IL-8, and apoptosis. Further, probiotics±LCA ameliorated CDCA-induced apoptosis and oxidative stress (FASEB J, 36, R5817, 2022). In the present study, we hypothesize that probiotics could ameliorate CDCA-induced cytokine release, barrier disruption and increases in paracellular permeability in T84 cells.Probiotics in Up & Up TM extra strength supplement ( B. bacterium and L. bacillus strains; 30 billion CFUs) were grown in T84 cell culture media±BA under anaerobic conditions at 37°C and sterile filtered to obtain conditioned media (CM), which was used in subsequent experiments. T84 cells grown to confluency in 12-well plates or Transwells to a Trans Epithelial Resistance (TER) of >1KΩ.cm 2 were treated with CM±BA. Following 0.5, 1, 2, 3, 4, 6 and 18 hours (h) incubation: IL-8 released in the media was measured with a sandwich ELISA (pg/ml); TJ pore function measured as TER (Ω.cm2) and TJ leak function measured as FITC-10 kDa dextran flux (F10D; μg). *, p≤0.05 different from control (CTL); #, p≤0.05 different from treatment with only CM.CDCA increased IL-8 release over time, with significant increases starting at 6h (pg/ml; CTL:320±20; CDCA:1524±180*; n=4) and being maintained up to 18h (CTL:700±40; CDCA:3760±350*; +ve CTL: TNFα (100 ng/ml):2600±170*; n≥6; other time points not shown). As previously shown, LCA reduced basal and CDCA-induced IL-8 release (18h, LCA:348±50*; CDCA+LCA:752±30*; n≥4). Probiotic CM±LCA also significantly decreased basal and CDCA-induced IL-8 release (18h, CM:335±50*; CM+CDCA:810±43 # ; CM+LCA:155±15 # ; CM+CDCA+LCA:280±102 # ; n≥4).In terms of TJ pore function, CDCA caused a dramatic reduction in TER in 1 hr and LCA had no effect (% decrease vs CTL;1h, CDCA:88±9*; LCA:2±3; CDCA+LCA:88±5*; n=3). Similarly, probiotic CM did not alter CDCA±LCA-induced decreases in TER (CM+CDCA: 83±8*; CM+LCA: 3±7, CM+CDCA+LCA: 85±9*; n=4). In contrast, probiotic CM reduced the effects of CDCA on the leak function by 60% (18h, F10D flux, μg: CTL:5±1; CDCA:97±5*; CM:6±1; CM+CDCA:36±7 # ; n=3). LCA decreased CDCA’s effect by 40%, which was further attenuated by CM (18h (μg): LCA:11±7; CM+LCA:8±1; CDCA+LCA:51±3 # ; CM+CDCA+LCA:18±3 # ; n≥3). In summary, probiotics and LCA mitigate CDCA-induced inflammation by decreasing IL-8 release and TJ dysfunction by decreasing leak, but not pore function in T84 cells. Understanding the mechanism by which probiotics restore barrier integrity will help identify novel therapeutic strategies to target symptoms in patients with BA associated diarrhea. JS & MP, Institutional funds, Benedictine Univ; HD, EK, IN, FA, & YN: NSSRP, Benedictine Univ. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Gut Microbes and the Liver Circadian Clock Partition Glucose and Lipid Metabolism
bioRxiv (Cold Spring Harbor Laboratory) · 2022-05-25 · 2 citations
preprintOpen accessSummary Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes also exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we show hierarchical, bi-directional communication between the liver circadian clock, gut microbes, and glucose homeostasis in mice. The liver clock, but not the forebrain clock, requires gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expands proportions and abundances of oscillating microbial features by two-fold relative to controls. The liver clock is the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provide secondary cues that dampen these rhythms, resulting in reduced utilization of lipids as fuel relative to carbohydrates. Together, the liver clock transduces signals from gut microbes necessary to regulate glucose and lipid metabolism and meet energy demands over 24 hours. Highlights The liver circadian clock is autonomous from the central clock in metabolic regulation Liver clock and gut microbes interact to direct hepatic glucose and lipid metabolism Reciprocating host-microbe interactions drive rhythmic hepatic transcription Perturbed liver Bmal1 results in chaotic downstream oscillators and metabolism
Gut microbiota as a transducer of dietary cues to regulate host circadian rhythms and metabolism
Nature Reviews Gastroenterology & Hepatology · 2021 · 179 citations
- Biology
- Neuroscience
- Ecology
The FASEB Journal · 2020-04-01
articleBile acid‐associated diarrhea and epithelial barrier dysfunction are common occurrences in patients with inflammatory bowel diseases. There are very few studies that compare the effects of the dihydroxy bile acids (BAs), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), on barrier function, although they are known for their prosecretory properties. We have reported that CDCA induced apoptosis, released reactive oxygen species (ROS), nitrogen species (NO 2 /NO 3 ) and the pro‐inflammatory cytokine IL‐8, to disrupt tight junctions, while its monohydroxy derivative, lithocholic acid (LCA) did not (FASEB J 2019 33:711.1). In this study, we examined the effects of dihydroxy BAs, DCA, CDCA, and ursodeoxycholic acid (UDCA, 7‐OH epimer of CDCA), on barrier function in human colon carcinoma cells (T84). We hypothesize that the effect of dihydroxy BAs on barrier function will be varied owing to the subtle differences in the position (3, 7, or 12) and stereochemistry (α or β) of the hydroxyl group. Confluent T84 cells (Trans Epithelial Resistance, TER >1000 Ω.cm 2 ) were treated overnight (O/N) with 500μM of CDCA, DCA and UDCA and the effects on barrier function were studied as follows: i) apoptosis (Annexin‐V, flow cytometry), ii) mitochondrial and nuclear ROS production (CellRox, flow cytometry), iii) [NO 2 /NO 3 ] (Griess Assay, Colorimetry), iv) IL‐8 release (ELISA) and v) paracellular permeability (TER and FITC‐10kD dextran fluxes (F10D)). Apical exposure of CDCA and DCA induced apoptosis while UDCA did not alter cell viability (% Annexin V + cells, 18 hr: DMSO, 10±3; CDCA: 25±2*; DCA: 26±2*; UDCA: 13±4; n=4, *p<0.05, compared to control). CDCA and DCA increased ROS (% CellRox + cells: DMSO: 12±0.5; CDCA: 32±0.1; DCA: 36±2, p<0.05) and [NO 2 /NO 3 ] (μmol/mg protein: control: 68±6; CDCA: 170±18; DCA: 249±28). UDCA alone had no effect, but it attenuated CDCA’s action (% CellRox + cells: UDCA: 14±0.5; CDCA+UDCA: 12±0.3; [NO 2 /NO 3 ] UDCA: 65±12; CDCA+UDCA: 48±30; n=4, p<0.05). Similarly, CDCA and DCA increased IL‐8 release (ng/ml: Control: 78±4; CDCA: 578±86*; DCA: 789±98*), while UDCA decreased basal and CDCA induced IL‐8 release (UDCA: 20±5; CDCA+UDCA: 26±4; n=6, p<0.05). Time‐dependent studies (0.5–18 hr) show that CDCA and DCA decreased TER by 70% and 62%, respectively and increased F10D fluxes. In contrast, UDCA alone had no effect on paracellular permeability but restored CDCA‐ and DCA‐induced barrier dysfunction (18 hr, apparent permeability (x 10 −9 ) cm/sec: Control: 6±1; CDCA: 96±10; DCA: 120±20; UDCA: 13±2; CDCA+UDCA: 41±12; DCA+UDCA: 18±2; n≥3, *p<0.05). Comparing the effects of hydrophobic CDCA and DCA on barrier function with that of the hydrophilic 7‐β isomer, UDCA, highlighted the importance of structure and stereochemistry of ‐OH groups in BA action. Therefore, UDCA, like LCA, could be used to ameliorate the deleterious effects of other dihydroxy BAs and serve as a target therapeutic drug for inflammatory and diarrheal diseases. Support or Funding Information APS‐STRIDE National Heart, Lung and Blood Institute (Grant #1 R25 HL 115473‐01) to SK and UD, APS‐UGSRF to MH, NSSRP Benedictine Funds to FD, IS, SK, MH, UD, MP, JS, DMR, NSF‐MRI: DB‐1427937 to JS
The FASEB Journal · 2020-04-01
articleLung cancer is one of the leading causes of cancer death. Most current treatments have debilitating side effects with poor selectivity and pharmacodynamic properties. To develop more effective and safer anticancer drugs, we synthesized trioxane (DMR) and dioxazinane (HSM), both novel Artemisinin (ART) analogs. These analogs induced apoptosis in cancer but not normal lung cells and was reactive oxygen species (ROS) dependent. We also showed that cancer cells have higher transferrin receptor (TfR) expression compared to normal cells. We hypothesize high levels of TfR expression and [iron] i are responsible for the cancer specific effects of analogs. To study this, we confirmed iron’s role in ART analog‐induced apoptosis. We also knocked out TfR in cancer cells and overexpressed TfR in normal cells. Confluent normal (BEAS2B) and cancer (A549) human lung cells were treated (18 H) with 10μM of DMR, HSM ±Deferoxamine (DFO, iron chelator; 10 μM). [Iron] i was assessed in cell lysates using a colorimetric assay (Biovision, CA). Cell death was assessed by i) staining with FITC‐Annexin V (AV, apoptosis), propidium iodide (PI, cell death), followed by imaging, and quantification using flow cytometry and/or microscopy (Image J) and ii) measuring Lactate dehydrogenase (LDH) release. Cells were transfected with CRISPR/Cas9 overexpression (OE) or knockout (KO) plasmid (Santa Cruz, TX) containing Green Fluorescent Protein (GFP). Co‐transfection with HDR plasmid allowed for puromycin selection. Transfection efficiency was assessed using RT‐PCR, Western blot and GFP expression. A549 cells had 7‐fold more [iron] i than BEAS2B cells. This was essential for the apoptotic effects, as chelating iron with DFO prevented ART analog‐induced cell death (% AV + A549 cells, 18 H: HSM: 54±4; HSM+DFO: 1±0.5; DMR: 32±3; DMR+DFO: 0.3±0.1, n≥3). KO of TfR in A549 cells yielded a low transfection efficiency (10%, Image J). Western blot of cell lysates did not show a significant reduction in TfR protein expression. Co‐transfection with HDR plasmid followed by puromycin selection increased transfection efficiency. However, there was increased cell death in TfR KO cells in culture (72 H, PI + cells; mean pixel intensity (mpi), control: 15±0.2; GFP: 19±2, TfR KO: 49±42; n=3). Overexpression of TfR in BEAS2B cells yielded a higher transfection efficiency (~25%; Image J and RT‐PCR). Similar to TfR KO in A549 cells, after 72 H, there was a marked increase in cell death in TfR OE BEAS2B (PI + cells (mpi), control: 18±2; GFP: 13±4, TfR OE: 83±20; n=3). TfR overexpression in normal lung cells possibly resulted in iron overload and ferroptosis. Our findings demonstrate that abnormal TfR expression and the associated changes in iron uptake induces death in normal and cancer cells, highlighting its importance in cell survival and proliferation. Understanding the role of TfR and iron in carcinogenesis will help develop potent therapeutic drugs to treat cancer, a disease that accounts for ~ 9 million deaths annually. Further, synthesizing novel analogs such as DMR‐tagged transferrin will provide specific and efficient drug delivery to cancer cells. Support or Funding Information APS‐STRIDE (Grant #1 R25 HL 115473‐01); NSSRP BenU Funds
Navigating the Human Gut Microbiome: Pathway to Success from Lessons Learned
Gastroenterology · 2020 · 19 citations
- Sociology
- Biology
- Computational biology
Physiology of Electrolyte Transport in the Gut: Implications for Disease
Comprehensive physiology · 2019-06-12 · 46 citations
review1st authorCorrespondingABSTRACT We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR‐CAS technology, stem cell‐derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na + /K + ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl − channels and the basolateral Na + ‐K + ‐2Cl − cotransporter, NKCC1 and K + channels. Absorption chiefly involves apical membrane Na + /H + exchangers and Cl − /HCO 3 − exchangers in the small intestine and proximal colon and Na + channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947‐1023, 2019.
Recent grants
NIH · $107k · 1988
NIH · $165k · 1988
NIH · $1.3M · 2008
NIH · $692k · 2002
Frequent coauthors
- 58 shared
Eugene B. Chang
University of Chicago
- 40 shared
Crescence Bookstein
- 36 shared
Jayashree Sarathy
Benedictine University
- 35 shared
Mei Ao
University of Illinois Chicago
- 22 shared
Chaivat Toskulkao
Ministry of Science and Technology Thailand
- 21 shared
Manoocher Soleimani
New Mexico VA Health Care System
- 20 shared
Mark W. Musch
University of Chicago
- 19 shared
Jayashree Venkatasubramanian
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