Background: Despite the availability of various classes of antihypertensive medications, a large proportion of hypertensive individuals remain resistant to treatments. The reason for what contributes to low efficacy of antihypertensive medications in these individuals is elusive. The knowledge that gut microbiota is involved in pathophysiology of hypertension and drug metabolism led us to hypothesize that gut microbiota catabolize antihypertensive medications and compromised their blood pressure (BP)-lowering effects. Methods and Results: To test this hypothesis, we examined the BP responses to a representative ACE (angiotensin-converting enzyme) inhibitor quinapril in spontaneously hypertensive rats (SHR) with or without antibiotics. BP-lowering effect of quinapril was more pronounced in the SHR+antibiotics, indicating that gut microbiota of SHR lowered the antihypertensive effect of quinapril. Depletion of gut microbiota in the SHR+antibiotics was associated with decreased gut microbial catabolism of quinapril as well as significant reduction in the bacterial genus Coprococcus . C. comes , an anaerobic species of Coprococcus , harbored esterase activity and catabolized the ester quinapril in vitro. Co-administration of quinapril with C. comes reduced the antihypertensive effect of quinapril in the SHR. Importantly, C. comes selectively reduced the antihypertensive effects of ester ramipril but not nonester lisinopril. Conclusions: Our study revealed a previously unrecognized mechanism by which human commensal C. comes catabolizes ester ACE inhibitors in the gut and lowers its antihypertensive effect.

Introduction Drug resistant HTN (rHTN) affects around 15% to 20% of hypertensive (HTN) patients. The underlying mechanisms of resistance to treatment remain poorly understood. The majority of angiotensin‐converting enzyme inhibitors (ACEi) are esters, whereby we hypothesized that select gut microbiota hydrolyze ACEi rendering lower efficacy (Figure 1A). To test this hypothesis, we investigated if and which gut microbe modulates the effectiveness of ACEi. Methods Vancomycin, Meropenem and Omeprazole (VMO) were given to 16‐week‐old male Spontaneously Hypertensive Rats (SHR) at 50 mg/kg/day for five days. A single dose of 8mg/kg Quinapril was orally administered to both SHR and SHR+VMO, and blood pressure (BP) was recorded via radio‐telemetry. Liquid chromatography–mass spectrometry was used to measure the catabolism of quinapril. The hydrolysis of p‐nitro‐phenylbutyrate was used to measure the activity of bacterial esterase. 16S rRNA sequencing was used to study the microbial composition. At last, ester ACEi ramipril and non‐ester lisinopril were co‐administered with Coprococcus comes, respectively, to generalize the effect of C. comes on ACEi's effectiveness. Results Compared to the SHR, depletion of gut microbiota in the SHR+VMO group preserved the BP lowering effect of Quinapril, an ester ACEi (Figure 1B). The SHR+VMO group showed (1) reduced Coprococcus (Figure 1C); (2) lower esterase activity per gram of cecal microbiota to hydrolyze quinapril (Figure 1D); (3) a 50% lower reduction in quinapril quantity (nmol) after incubation with 1mg of cecal lysate for 3 hr (Figure 1E). C. comes,a species in Coprococcusgenus, catabolized quinapril in vitro and reduced its BP‐lowering effects in the SHR (Figure 2A‐B). Importantly, C. comes also reduced the BP‐lowering effects of ramipril (ester), but not lisinopril (non‐ester) in the SHR (Figure 2C‐D). Conclusion These observations constitute the first report of an unrecognized role of a select gut microbe, C. comes, in reducing the effectiveness of ester ACEi. As such, this mechanistic study serves as the foundation for expanding clinical management of antihypertensive drug resistance via manipulation of gut microbiota.

The worldwide burden of cancers is increasing at a very high rate, including the aggressive and resistant forms of cancers. Certain levels of breakthrough have been achieved with the conventional treatment methods being used to treat different forms of cancers, but with some limitations. These limitations include hazardous side effects, destruction of non-tumor healthy cells that are rapidly dividing and developing, tumor resistance to anti-cancer drugs, damage to tissues and organs, and so on. However, oncolytic viruses have emerged as a worthwhile immunotherapeutic option for the treatment of different types of cancers. In this treatment approach, oncolytic viruses are being modeled to target cancer cells with optimum cytotoxicity and spare normal cells with optimal safety, without the oncolytic viruses themselves being killed by the host immune defense system. Oncolytic viral infection of the cancer cells are also being genetically manipulated (either by removal or addition of certain genes into the oncolytic virus genome) to make the tumor more visible and available for attack by the host immune cells. Hence, different variants of these viruses are being developed to optimize their antitumor effects. In this review, we examined how grave the burden of cancer is on a global level, particularly in sub-Saharan Africa, major conventional therapeutic approaches to the treatment of cancer and their individual drawbacks. We discussed the mechanisms of action employed by these oncolytic viruses and different viruses that have found their relevance in the fight against various forms of cancers. Some pre-clinical and clinical trials that involve oncolytic viruses in cancer management were reported. This review also examined the toxicity and safety concerns surrounding the adoption of oncolytic viro-immunotherapy for the treatment of cancers and the likely future directions for researchers and general audience who wants updated information.