FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, May 22, 2023

Health News in Review: A New C. difficile Treatment, New AMA Medical Education, and New Insights into Ribosome Oxidation and the Free Radical Theory of Aging

by Michael Passwater

OMNS (May 22, 2023) On April 26, 2023, the FDA approved Vowst for the prevention of recurrence of Clostridioides (formerly known as Clostridium) difficile infection (CDI). [1] There are approximately 500,000 cases of CDI each year in the United States, leading to 10,000 - 15,000 deaths per year. It is the most common hospital acquired infection. [2] C. diff is considered an opportunistic infection since it tends to only cause disease in people with weakened immune systems such as HIV/AIDS patients and transplant patients taking immunosuppressive medications, or people who have had their normal intestinal bacteria ("gut microbiome") killed by antibiotics. Clindamycin, Fluoroquinolones, and Cephalosporins are the classes of antibiotics most commonly associated with C. diff and other forms of antibiotic associated diarrhea (AAD). The lack of host immune challenge or competition from healthy bacteria allows the invading C diff. bacteria to proliferate and cause illness. Interestingly, standard treatment for CDI is to administer additional antibiotics. Given their weakened, microbiome depleted state, it may not be surprising that people who have had CDI are more likely to suffer from the illness again.

The FDA granted the Vowst drug application "Priority," "Breakthrough Therapy," and "Orphan" status. The only alternative treatment recognized by the FDA for recurrent CDI is Rebyota, which the FDA approved Nov 30, 2022. [3] Both Rebyota and Vowst are fecal microbiota products, meaning they come from screened human donors of fecal matter (stool). Reboyta is administered rectally in a single dose. Vowst is administered orally as 4 pills per day for 3 days. Clinical trials with Reboyta showed a 71% success rate compared to a 58% success rate for a placebo, and Vowst showed an 87% success rate compared to a 60% success rate with a placebo. From both treatments, there is an unquantified risk of infectious disease transmission and food allergies due to the possibility of food particles and other fecal materials from the donor persisting in the finished product. One industry expert predicted the cost of a course of treatment with Vowst might be nearly $20,000. [4]

The concept of fortifying or replacing healthy bacteria in the intestines is not novel. Anecdotal, observational, and prospective clinical trials have suggested effectiveness and safety of a variety of probiotics and fermented foods for the prevention and treatment of AAD, including CDI. [5-23] In 2017, a Cochrane analysis of 31 clinical trials concluded there was moderate evidence of effectiveness and safety for probiotics. The analysis noted that more adverse events were seen in patients receiving placebos than patients receiving probiotics. These reviewers acknowledged the need for further studies, but felt the existing evidence was adequate to recommend advising hospitalized patients of the benefits and risks of probiotics. [24] In 2018, the Journal of the American Medical Association (JAMA) published a review of probiotic use with similar conclusions of efficacy and safety as the Cochrane analysis. [25] Maintaining adequate intestinal flora, especially during and after antibiotic treatment, is important for health. Healthy intestinal bacteria crowd out disease causing bacteria, produce vitamins, fatty acids, and other nutrients essential for a healthy body, and modulate the immune system.

Medical Education

The American Medical Association Education Hub (AMA Ed Hub) now offers a "Nutrition and Health" program with 48.5 continuing medical education units. Promotional material for the program states:

"Traditional medical models have discounted the importance of nutrition in health and in the prevention and management of a variety of health conditions, including cardiovascular disease, cancer, diabetes, and obesity. Recent overwhelming evidence has led to increased attention to nutrition as a core element of health, health equity and health care." (AMA Ed Hub)

Overwhelming evidence, indeed! Although the program is not perfect, and has a distinct anti-supplement bias, it is a step in a healthy direction for American medicine. https://edhub.ama-assn.org/course/303

Those further along in their understanding of nutrition may prefer these educational resources:

International Society of Orthomolecular Medicine online learning: https://isom.ca/online-learning

The Riordon Clinic video library: https://riordanclinic.org/video-gallery

Free Radicals

In 1956, Denham Harman, MD, PhD, published the free radical theory of aging. [26] He suggested that highly reactive oxygen and nitrogen biomolecules generated by cellular respiration and stress caused many of the diseases of aging through destructive actions on cells and tissues. The term "free radical", now more commonly called reactive oxygen and nitrogen species (RONS), refers to the unpaired electron in an oxygen or nitrogen molecule - an energy state that is not sustainable. [27] The molecule will steal an electron from the first thing it encounters, whether that is a nucleic acid, a protein, or a lipid, and cause a molecular chain reaction through the cell. "Antioxidants" are able to absorb or buffer the free radical by donating an electron to prevent or stop the chain reaction.

Dr. Harman suggested a low calorie, nutrient dense diet and supplementation with one or more inhibitors of oxidation could extend human life by 5 years or more. [28] His theory was met with ridicule and largely dismissed. Oxidative stress and, correspondingly, antioxidants, were not considered important to human health in that era. Even as supportive evidence steadily grew over the decades, criticism persisted. However, RONS have been generally accepted as important factors in many human biological processes. While not a complete explanation of all causes of aging and disease, Dr. Harman's theory has helped advance our understanding of biochemistry. The evidence associating strong antioxidant capacity with wellness and longevity, and the number of diseases associated with oxidative stress continues to grow [29-35]. Dr. Harman never received a Nobel Prize, but he was nominated 6 times for the award.

Adding additional support to Dr. Harman's concepts and the involvement of RONS and their neutralization in fundamental mechanisms preventing cellular damage, scientists at UF Scripps recently published insights into the mechanisms used by intracellular ribosomes to absorb free radical damage in a controlled fashion and replace the damaged proteins to restore the function of the ribosome. [36] Ribosomes are the factories that build all proteins. Ribosomes constitute roughly half of the mass of each cell in the human body. The ability of small segments of these critical organelles to "take a hit" to protect the rest of the ribosome is similar to the function of a bumper on an automobile. It is easier to repeatedly replace two proteins (Rps26, Rpl10) than to risk loss of an entire ribosome. Of note, the "bumper proteins" absorbing the free radical hits are rich in the sulfur containing amino acid cysteine, and zinc ions are critical for the bumper protein replacement process. The UF Scripps press release notes that the work could have implications for "cancer, the aging process, and growth and development." If the damage control mechanism is overwhelmed by an excess of free radicals or if the cell lacks adequate repair materials, widespread ribosomal damage results, and therefore absent or altered protein production ensues which may lead to disease.

Summary

It is good to have choices. As the cost of health care in the United States continues to rise, while outcome measures such as lifespan continue to decline, a critical review of all available options to restore health and remain well is warranted. Informed choice allows wise selection of foods, vitamin and mineral supplements, activities, or prescriptions to address health concerns.

It is also encouraging to see the AMA recognize the key role of nutrition in human health - including serious diseases such as cardiovascular disease and cancer, and to provide increased access to nutrition education for physicians. Hopefully the new AMA "Nutrition and Health" program and similar ones will increase interest in the value of nutrition among healthcare providers and patients. As Hippocrates advised, "Let food be thy medicine and medicine be thy food."

Continued careful research into the wondrous intricacies of human genetics and biochemistry increases our understanding of the connections between nutrients that serve as substrates, enzymes, and cofactors and the optimization of wellness. These mechanistic insights further inform choice.

"The doctor of the future will give no medication but will interest his patients in the care of the human frame, diet, and in the cause and prevention of disease" -Thomas A. Edison

References

1. FDA (2023) FDA Approves First Orally Administered Fecal Microbiota Product for the Recurrence of Clostridioides difficile Infection. https://www.fda.gov/news-events/press-announcements/fda-approves-first-orally-administered-fecal-microbiota-product-prevention-recurrence-clostridioides

2. CDC (2010) Clostridioides difficile Infection. https://www.cdc.gov/HAI/organisms/cdiff/Cdiff_infect.html

3. FDA (2022) FDA Approves First Fecal Microbiota Product. Nov 30, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-fecal-microbiota-product

4. Reuters (2023) US FDA approves Seres Therapeutics' pill for deadly C. difficile infections. April 26, 2023. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-approves-seres-therapeutics-pill-deadly-c-difficile-infections-2023-04-26

5. Kalakuntla AS, Nalakonda G, Nalakonda K, et al. (2019) Probiotics and Clostridium Difficile: A Review of Dysbiosis and the Rehabilitation of Gut Microbiota. Cureus. 11:e5063. https://pubmed.ncbi.nlm.nih.gov/31516774

6. Strohl M and Dyer D (2019) Diet and C. Difficile. Oncology Nutrition. https://www.oncologynutrition.org/erfc/eating-well-when-unwell/surgery/diet-and-c-difficile

7. Valdovinos MA, Montijo E, Abreu AT, et al. (2017) The Mexican consensus on probiotics in gastroenterology. Rev Gastoenterol Mex. 82:156-178. https://pubmed.ncbi.nlm.nih.gov/28104319

8. Cameron D, Hock QS, Kadim M, et al (2017) Probiotics for gastrointestinal disorders: proposed recommendations for children of the Asia-Pacific region. World J Gastroenterol. 23:7952-7964. https://pubmed.ncbi.nlm.nih.gov/29259371

9. Shen NT, Maw A, Tmanova LL, et al.(2017) Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a systematic review with meta-regression analysis. Gastroenterology. 152:1889-1900. https://pubmed.ncbi.nlm.nih.gov/28192108

10. Sebastián Domingo JJ (2017) Review of the role of probiotics in gastrointestinal diseases in adults. Gastroenterol Hepatol. 40:417-429. https://pubmed.ncbi.nlm.nih.gov/28185664

11. Lewis PO, Lundberg TS, Tharp JL, Runnels CW. (2017) Implementation of global strategies to prevent hospital-onset Clostridium difficile infection: targeting proton pump inhibitors and probiotics. Ann Pharmacother. 51:848-854. https://pubmed.ncbi.nlm.nih.gov/28821215

12. Issa I, Moucari R. (2014) Probiotics for antibiotic-associated diarrhea: do we have a verdict? World J Gastroenterol. 20:17788-17795. https://pubmed.ncbi.nlm.nih.gov/25548477

13. Szajewska H, Canani RB, Guarino A, et al. (2016) Probiotics for the prevention of antibiotic-associated diarrhea in children. J Pediatr Gastroenterol Nutr. 62:495-506. https://pubmed.ncbi.nlm.nih.gov/26756877

14. Pace F, Pace M, Quartarone G. (2015) Probiotics in digestive diseases: focus on Lactobacillus GG. Minerva Gastroenterol Dietol. 61:273-292. https://pubmed.ncbi.nlm.nih.gov/26657927

15. Barker AK, Duster M, Valentine S, et al. (2017) A randomized controlled trial of probiotics for Clostridium difficile infection in adults (PICO). J Antimicrob Chemother. 72:3177-3180. https://pubmed.ncbi.nlm.nih.gov/28961980

16. Goldenberg JZ, Lytvyn L, Steurich J, et al. (2015) Probiotics For The Prevention Of Pediatric Antibiotic-Associated Diarrhea. Cochrane Database Syst Rev. 2015 Dec 22;(12):CD004827. https://pubmed.ncbi.nlm.nih.gov/26695080

17. McFarland LV (2007) Meta-Analysis Of Probiotics For The Prevention Of Traveler's Diarrhea. Travel Med Infect Dis. 5:97-105. https://pubmed.ncbi.nlm.nih.gov/17298915

18. Basu S, Paul DK, Ganguly S, et al. (2009) Efficacy Of High-Dose Lactobacillus Rhamnosus GG In Controlling Acute Watery Diarrhea In Indian Children. J Clin Gastroenterol. 43:208-213. https://pubmed.ncbi.nlm.nih.gov/18813028

19. Guarino A, Guandalini S, Vecchio AL (2015) Probiotics For Prevention And Treatment Of Diarrhea. J Clin Gastroenterol. 49:S37-S45. https://pubmed.ncbi.nlm.nih.gov/26447963

20. Mu Q, Tavella VJ, Luo XM. (2018) Role Of Lactobacillus Reuteri In Human Health And Diseases. Front Microbiol. 9:757. https://pubmed.ncbi.nlm.nih.gov/29725324

21. Falagas ME, Betsi GI, Tokas T, Athanasiou S. (2006) Probiotics For Prevention Of Recurrent Urinary Tract Infections In Women. Drugs 66:1253-1261. https://pubmed.ncbi.nlm.nih.gov/16827601

22. Muresan AIP, Pop LL, Dumitrascu DL (2019) Lactobacillus Reuteri Versus Triple Therapy For The Eradication Of Helicobacter Pylori In Functional Dyspepsia. Med Pharm Rep. 92:352-355. https://pubmed.ncbi.nlm.nih.gov/31750434

23. Remes-Troche JM, Coss-Adame E, Valdovinos-Día MA, et al. (2020) Lactobacillus Acidophilus LB: A Useful Pharmabiotic For The Treatment Of Digestive Disorders. Therap Adv Gastroenterol. 13:1756284820971201. https://pubmed.ncbi.nlm.nih.gov/33281937

24. Goldenberg JZ, Yap C, Lytvyn L, et al. (2017) Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 12:CD006095. https://pubmed.ncbi.nlm.nih.gov/29257353

25. Goldenberg JZ, Mertz D, Johnston BC. (2018) Probiotics to Prevent Clostridium difficile Infection in Patients Receiving Antibiotics. JAMA. 320:499-500. https://pubmed.ncbi.nlm.nih.gov/30027207

26. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol. 11:298-300. https://doi.org/10.1093/geronj/11.3.298. https://pubmed.ncbi.nlm.nih.gov/13332224

27. Weidinger A, Kozlov AV (2015) Biological Activities of Reactive Oxygen and Nitrogen Species: Oxidative Stress versus Signal Transduction. Biomolecules 5:472-484. https://pubmed.ncbi.nlm.nih.gov/25884116

28. Harman D (1992) Free radical theory of aging: history. EXS. 62:1-10. https://pubmed.ncbi.nlm.nih.gov/1450577

29. Andersen HR, Jeune B, Nybo H, et al. (1998) Low Activity of Superoxide Dismutase and High Activity of Glutathione Reductase in Erythrocytes from Centenarians. Age Ageing 27:643-648. https://pubmed.ncbi.nlm.nih.gov/12675104

30. C.A. Lang, Mills BJ, Lang HL, et al. (2002) High Blood Glutathione Levels Accompany Excellent Physical and Mental Health in Women Ages 60 to 103 Years. J. Lab. Clin. Med. 140:380-381. https://pubmed.ncbi.nlm.nih.gov/12486409

31. Aykac K, Ozsurekci Y, Yayla BCC, et al. (2021) Oxidant and antioxidant balance in patients with COVID-19. Pediatr Pulmonol. 56:2803-2810. https://pubmed.ncbi.nlm.nih.gov/34265172

32. Nar R, Çalış AG. (2018) Assessment of dynamic thiol/disulfide homeostasis in patients with asthma. J Lab Med. 42:99-104. https://www.degruyter.com/document/doi/10.1515/labmed-2017-0144/html

33. Erenler AK, Yardan T. (2017) Clinical utility of thiol/disulfide homeostasis. Clin Lab. 63:867-870. https://pubmed.ncbi.nlm.nih.gov/28627824

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35. Taylor, E.W. (2009) The oxidative stress-induced niacin sink (OSINS) model for HIV pathogenesis. Toxicology 278: 124-130. https://pubmed.ncbi.nlm.nih.gov/19857540

36. Yang Y-M, Jung Y, Abegg D, et al. (2023) Chaperone-directed ribosome repair after oxidative Damage. Mol Cell 83:1-11. https://pubmed.ncbi.nlm.nih.gov/37086725

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