A controversial subject for sure....as I am slightly reactive to eggs (both yolk and white) I tend to eat them once or twice a week and try to stay away from too many baked goods, containing eggs, therefore I cannot comment on this from personal experience...

I do, however wish to point out that research is subjective and many of the variants are not covered here, like were the people eating organic or conventional eggs....there is a difference between what free range chickens and conventional chickens eat and are fed. The linoleic acid content in conventional eggs will be way higher etc. (more inflammatory)

I always recommend eating eggs from free range chickens that have not been consuming GMO corn and I also like to know where my organic eggs are coming from.

Having said that....

You decide how this fits or feels for you.

A Beloved Food That Surprisingly Has Been Found to Contribute to Diabetes

Ronald Grisanti D.C., D.A.B.C.O., DACBN, MS, CFMP

Over the last few years I started seeing an unanticipated trend that totally took me by surprise. The trend was totally fit individuals who were eating three to six eggs a day were developing Type 2 Diabetes (T2D) confirmed with an elevated Hemoglobin A1c levels ranging from 5.8 to 6.2.!

 

Ha1c Readings from Two Very Fit Patients Eating 3-6 Eggs Per Day

The A1C test—also known as the hemoglobin A1C or HbA1c test—is a simple blood test that measures your average blood sugar levels over the past 3 months. It's one of the commonly used tests to diagnose prediabetes and diabetes, and is also the main test to help you and your health care team manage your diabetes.

My Research And Discovery on The Relationship Between Increased Egg Consumption and the Trend Toward Diabetes

According to a study published 2021 in the British Journal of Nutrition, consuming one or more eggs per day may increase the risk of diabetes by 60%!.

Researchers compared egg consumption with blood glucose levels in more than 8,000 participants from the China Health and Nutrition Survey. Those who habitually consumed the most eggs increased their risk for diabetes when compared to those who ate the fewest eggs. 

A study published in Nutrition found an increased risk for diabetes and high cholesterol among Chinese women, while research published in Circulation found a link between higher egg consumption and prevalence of diabetes mellitus and hypertension.

Although an older study, the medical journal, Circulation from a meta-analysis and data from the Physicians' Health Study and Women's Health Study showed an increased risk for diabetes of up to 77% with seven or more eggs consumed per week.

Higher egg consumption was associated with higher blood glucose in subjects with T2D.

What the Medical Literature is Leaning Toward as it Relates to Diabetes and Eggs

Many studies, including meta-analyses, systematic reviews, case-control studies, and large-scale epidemiological studies, all point in the same direction. 

Eating eggs increases your risk for the development of type 2 diabetes, heart disease, diabetes complications, and all-cause mortality. 

Whether you are currently living with diabetes, consuming an increased number of eggs per week can significantly elevate your risk for developing diabetes and its health related complications such as cardiovascular disease and kidney disease.

Dr. Grisanti's Comments:

My analysis of the research was an eye-opener and to be quite honest if it wasn't for the fact that I was seeing what appeared to be perfectly fit patients exhibiting elevated Ha1c with a possible correlation of increased egg consumption, I would have been doubtful on the conclusions of these studies.

I suggest limiting egg consumption to three eggs per week

I found the following short video from Michael Greger M.D. FACLM (author of How Not to Die and his most recent book, How Not to Age) a good summary on this important topic.

https://nutritionfacts.org/video/eggs-and-diabetes/

** As a side note, I realize that there will be egg proponents that will debate me and show me other peer reviewed studies negating the contents of my article. My response will be the fact that I see the true evidence with real patients and not simply some conflicting studies. I prefer to err on the side of being cautious and do no harm. 

This is a controversial topic with two opposing sides and I have done my due diligence and weighed out the evidence and I believe over abundance of egg consumption should be carefully curtailed as to be 100% certain you are doing no metabolic damage to yourself and your patients.

If you are staunch advocate of increased egg consumption, I simply say, do the benefits out weigh the risk.

Again what I have observed in clinical practice with real patients, the lab tests do not lie and with no evidence of other reasons for compromised glucose metabolism (diabetes), I report that eggs may indeed be the culprit.

I will continue to report on my findings as I continue to monitor my patients.

References:

https://pubmed.ncbi.nlm.nih.gov/33028452/
https://pubmed.ncbi.nlm.nih.gov/20471806/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861752/
https://europepmc.org/article/med/33028452
https://pubmed.ncbi.nlm.nih.gov/26739035/
https://pubmed.ncbi.nlm.nih.gov/19017774/
https://link.springer.com/article/10.1007/s00394-017-1566-0
//www.functionalmedicineuniversity.com/Harvard-egg-diabetes.pdf

** Always consult with a physician or healthcare practitioner with significant integrative or functional medicine training before starting any of the above recommendations.

You can find a qualified and certified functional medicine practitioner by going to: www.FunctionalMedicineDoctors.com

The information on this website is not intended to replace a one-on-one relationship with a qualified health care professional and is not intended as medical advice. It is intended as a sharing of knowledge and information from the research and experience of Dr. Grisanti and his functional medicine community. Dr. Grisanti encourages you to make your own health care decisions based upon your research and in partnership with a qualified health care professional. Visit www.FunctionalMedicineUniversity.com for more information on our training in functional medicine. Look for practitioners who have successfully completed the Functional Medicine University's Certification Program (CFMP) www.functionalmedicinedoctors.com. This content may be copied in full, with copyright, contact, creation and information intact, without specific permission, when used only in a not-for-profit format. If any other use is desired, permission in writing from Dr. Grisanti is required

Sleep Dysfunction and the Microbiome

 

Sleep Dysfunction & the Microbiome: Emerging Treatments

Sleep is a dynamic process that affects every system of the body, and the interplay of different environmental and lifestyle factors influences sleep quality and architecture.1 

Recent research suggests that some of these factors may influence sleep via the microbiota-gut-brain axis, both directly and indirectly.1-3 What is the connection between lower sleep quality and quantity and a dysbiotic gut microbiome? What emerging interventions targeting the microbiota-gut-brain axis may be beneficial for the treatment of impaired sleep patterns?

From a young age, microbial communities within the body interact with the sleep-wake cycle in a complex manner.1The gut microbiome, which produces a variety of metabolites and compounds with neuroactive and immunomodulatory properties, including short-chain fatty acids, secondary bile acids, and neurotransmitters, may affect brain function and behavior through the microbiota-gut-brain axis.4 These microbial products are also involved in sleep physiology.3 While the mechanisms underlying the microbiota-gut-brain axis are not fully understood, some evidence has suggested that neuroendocrine, immune, and metabolic pathways may regulate interactions.3

Growing evidence reports a positive correlation between sleep efficiency and the diversity of the gut microbiota from childhood through adulthood.3 For example, a recent study of 143 largely Caucasian children ages 3-4 found that children with a high total nighttime sleep duration (average 9.48 hours), greater sleep efficiency, and less time awake at night showed a higher relative abundance of Bifidobacterium and Bacteroides.5 Both bacteria have been linked to sleep-related neurochemicals in previous studies, such as serotonin and its precursors tryptophan and gamma-aminobutyric acid. In the 2022 study by Wang et al, five taxa showed greater abundance in children who had shorter night-time sleep duration, less sleep efficiency, and longer waking time, including Blautia, Coprococcus, and other Lachnospiraceae.5

Evaluating individuals with healthy sleep quality, a 2020 pilot study of 28 young adults by Grosicki et al found higher proportions of the abundance of Blautia and Ruminococcus (belonging to Firmicutes), lower proportion of Prevotella(belonging to Bacteroidetes), and higher ?-diversity of the gut microbiota among individuals reporting superior sleep quality.6 Researchers hypothesize that sleep quality may be positively correlated with the ratio of Firmicutes/Bacteroidetes and microbial diversity.3,6

A 2021 cross-sectional pilot study found that adult short sleepers have different microbial composition, such as an increased abundance of the bacteria Pseudomonas (0.14% vs. 0.08%) in feces and a lower abundance of Sutterella(0.38% vs. 1.25%) compared to normal length sleepers.1,7 Interestingly, Sutterella has been associated with lower relative abundance in patients with depression and may play a role in the microbiota-gut-brain axis.7 Several other studies indicate that a lower sleep quantity and quality are associated with a dysbiotic gut microbiome characterized by a lower microbial diversity, an increase of pathogenic microbiota, or the loss of beneficial microbes.4,8-9

Sleep-Related Disorders & the Microbiome

 OBSTRUCTIVE SLEEP APNEA (OSA)

OSA leads to fragmented night sleeping and daytime sleepiness due to episodes of obstruction of the upper airway; it is accompanied by repeated sleep fragmentation and forced awakening from sleep due to airway collapse.1,3Studies suggest that those suffering from OSA may have a prolonged N1 stage and a shortened REM sleep stage.3

Evidence suggests that intermittent hypoxia may result in changes to the gut microbiota, including increased Firmicutes richness and decreased Bacteroidetes richness, as well as decline in ?-diversity.3,10 A 2020 pilot study in children with OSA showed a significant decrease in gut microbial diversity compared to healthy children and an increase of inflammation and gut barrier disruptor–related strains.1,3,11 In 2019, Ko et al found gut microbial dysbiosis, in varying degrees, in adults with OSA-hypopnea syndrome.1,12 Specifically, short-chain fatty acid–producing bacteria was decreased and the level of interleukin-6 was increased compared to controls.1,12

More recently, a 2023 prospective case control study of 48 Chinese adults age 18-65 found that the severity of OSA was related to differences in the structure and composition of the fecal microbiome.13 Enriched Fusobacterium, Megamonas, and Lachnospiraceae_UCG_006 and reduced Anaerostipes was found in patients with severe OSA. Enriched Ruminococcus_2, Lachnoclostridium, Lachnospiraceae_UCG_006, and Alloprevotella was found in patients with high intestinal barrier biomarkers. Lachnoclostridium and Lachnospiraceae_UCG_006 were the common dominant bacteria of OSA and intestinal barrier damage. Fusobacterium and Peptoclostridium were independently associated with apnea-hypopnea index. The dominant genera of severe OSA were also associated with glucose, lipids, neutrophils, monocytes, and BMI.13

INSOMNIA

A range of psychiatric and inflammatory disorders as well as metabolic syndromes are comorbid with insomnia.2,14Marked changes in gut microbiota diversity and composition was found by Liu et al in 2019 among 10 chronic insomnia patients compared to 10 healthy controls.1,15 A later study by Li et al observed a decrease in microbiome diversity in acute and chronic insomnia patients, with greater effects on bacterial diversity found in patients with disordered sleep.1,13 These individuals also show an increase in the inflammatory cytokine interleukin-1?.13 Both of these studies noted that an increase of Bacteroidetes phylum could be a biomarker to identify insomnia.1

A 2022 multiomics analysis reveals that the composition and structure of gut microbiota and metabolism in insomnia patients differs from healthy controls.14 Compared to healthy controls, the relative abundances of Lactobacillus, Streptococcus, and Lactobacillus crispatus were significantly increased in people with insomnia. (Lactobacilli possess several health-ameliorating attributes, including alleviation of chronic diseases, immune system stimulation, pathogen protection, and nutritional physiology.)14 Five metabolic pathways in patients with insomnia differed between the two groups as well, including glycerophospholipid metabolism; glutathione metabolism; nitrogen metabolism; alanine, aspartate, and glutamate metabolism; and aminoacyl-tRNA biosynthesis.15Researchers also found that IL-1? levels were significantly higher in insomnia patients while TNF-? was significantly reduced; the changes in the level of IL-1? and TNF-? were associated with some specific bacteria and metabolites, such as Prevotella amnii, Prevotella buccalis, Prevotella timonensis, and Prevotella colorans.15

Clinical Applications: Microecological Therapy

A novel treatment strategy referred to as microecological therapy has emerged, featuring several potential interventions targeting the gut microbiota to improve sleep quality and quantity.3 The targets of this therapy include regulating the abundance of specific bacterial groups, microbial metabolites, intestinal barrier function, and host immune response. Evidence suggests that microbiota manipulations like dietary interventions and the use of probiotics may be beneficial for the treatment of impaired sleep.3

PROBIOTICS

Although probiotics are transient visitors, they play a role in shifting the overall balance of the microbiome, modulating the immune system, and decreasing inflammation.18 Consuming probiotics in foods or supplements may encourage colonization of commensal organisms over time.18 Studies suggest that probiotics may improve sleep latency, sleep quality and duration, sleepiness upon wakening, and recovery from fatigue.19-21

A 2023 systematic review and meta-analysis of six studies showed significant improvement in sleep quality of 343 healthy adults with mild to moderate stress as an effect of daily consumption of L. gasseri compared to controls (-0.77, 95% CI -1.37 to-0.16, P=0.01).21 In addition to the cumulative beneficial effect shown using the PSQI global score, four of six studies reported a statistically significant positive effect of L. gasseri on sleep quality as indicated by at least one of the Pittsburgh Sleep Quality Index component scores (sleep latency, duration of sleep, sleep disturbance, and daytime dysfunction due to sleepiness).21

In a group of 94 healthy medical students from Japan studying for national exams, researchers found that sleep latency prolongation was less in the intervention group that received Lacticaseibacillus casei strain Shirota.4,19 EEG measurements also showed that, as the examination approached, the time spent in NREM stage 3 sleep was reduced in the placebo group but maintained in the intervention group. In this double-blind, randomized, placebo-controlled trial, researchers also found a reduction of the mean Pittsburgh Sleep Quality Index (PSQI) score, indicating improved sleep quality among the intervention group compared to the placebo group.4,19 

In a 2018 randomized crossover study, 40 adults aged 20-64 consumed either Lactobacillus helveticus or placebo for four weeks.4,20 Sleep efficiency was measured as the total time spent in REM and NREM sleep divided by the total time from sleep onset to awakening. The researchers found that sleep efficiency significantly improved in the intervention group compared with placebo, including improved sleepiness on awakening, onset and maintenance of sleep, dreaming, and recovery from fatigue. It is important to note that the intervention group also received theanine, which has stress-reducing effects, while the placebo group did not.4,20

MEDITERRANEAN DIET

Nutritional imbalances are potential contributors or causes of several chronic conditions, and nutrition-based interventions are fundamental components of many therapeutic strategies used to combat chronic illness and restore optimal health. These personalized treatments may include therapeutic food plans like the Mediterranean diet, a plant-based, antioxidant-rich, unsaturated fat dietary pattern that has been consistently associated with lower rates of disease and total mortality.22 Studies indicate that greater adherence to the Mediterranean diet may be associated with adequate sleep duration and with several indicators of better sleep quality. For example:

• In 2018, Castro-Diehl et al found that a Mediterranean-style diet was associated with adequate sleep duration and fewer insomnia symptoms.23,24 This cross-sectional, multi-ethnic study of 2,068 adults with atherosclerosis found that compared with individuals who currently reported a low aMed score, those with a moderate-high aMed score were more likely to sleep 6-7 vs. <6 hr/night (p <0.01) and less likely to report insomnia symptoms occurring with short sleep (vs. no insomnia or short sleep alone; p <0.05). An increase in aMed score over the preceding 10 years was not associated with sleep duration or insomnia symptoms. However, compared with those with decreasing aMed score, individuals with an unchanging score reported fewer insomnia symptoms (p ?0.01).23,24

• In a 2019 cross-sectional study of 1,314 Southern Italian adults, a higher adherence to the Mediterranean diet was associated with a higher likelihood of adequate overall sleep quality (highest vs. lowest quartile, OR=1.82, 95% CI: 1.32, 2.52).25 Interestingly, in a sub-analysis of this study, researchers found the benefit of the Mediterranean diet on sleep latency was observed in normal and overweight individuals (highest vs. lowest quartile of adherence score, OR=2.30, 95% CI: 1.49, 3.54) but was not evident in the obese (highest vs. lowest quartile of adherence score, OR=1.12, 95% CI: 0.33, 3.79).22,25

• In a 2021 cross-sectional study of 2,169 Costa Rican adults (1,600 men and 569 women), the association between sleep duration and adherence to the Mediterranean diet differed between men and women. In women only, a lower adherence to the Mediterranean diet was associated with shorter sleep duration, a finding that researchers say was primarily driven by lower consumption of fruits, vegetables, and legumes.26 However, the literature is inconsistent regarding whether associations between sleep and diet are gender based. For example, a 2020 study conducted among young adults 21 to 30 years old found that men with lower fruit and vegetable intake had a higher risk of insomnia as compared to women.26,27

Functional Medicine Considerations

Taken together, these studies illustrate the important connection between the gut microbiome and sleep patterns. Screening patients for sleep disorders is encouraged as a regular practice in functional medicine, and there are a range of effective lifestyle interventions for patients suffering from poor sleep. A close working relationship between clinician and patient can help identify sleep troubles early on so that they may be targeted with behavioral and lifestyle therapies to prevent or reverse further damage.

References:

1. 1) Wang Z, Wang Z, Lu T, et al. The microbiota-gut-brain axis in sleep disorders. Sleep Med Rev. 2022;65:101691. doi:1016/j.smrv.2022.101691
2. 2) Sen P, Molinero-Perez A, O’Riordan KJ, et al. Microbiota and sleep: awakening the gut feeling. Trends Mol Med. 2021;27(10):935-945. doi:1016/j.molmed.2021.07.004
3. 3) Han M, Yuan S, Zhang J. The interplay between sleep and gut microbiota. Brain Res Bull. 2022;180:131-146. doi:1016/j.brainresbull.2021.12.016
4. 4) Haarhuis JE, Kardinaal A, Kortman GAM. Probiotics, prebiotics and postbiotics for better sleep quality: a narrative review. Benef Microbes. 2022;13(3):169-182. doi:3920/bm2021.0122
5. 5) Wang Y, van de Wouw M, Drogos L, et al. Sleep and the gut microbiota in preschool-aged children. Sleep. 2022;45(6):zsac020. doi:1093/sleep/zsac020
6. 6) Grosicki GJ, Riemann BL, Flatt AA, Valentino T, Lustgarten MS. Self-reported sleep quality is associated with gut microbiome composition in young, healthy individuals: a pilot study. Sleep Med. 2020;73:76-81. doi:1016/j.sleep.2020.04.013
7. 7) Agrawal R, Ajami NJ, Malhotra S, et al. Habitual sleep duration and the colonic mucosa-associated gut microbiota in humans—a pilot study. Clocks Sleep. 2021;3(3):387-397. doi:3390/clockssleep3030025
8. 8) Matenchuk BA, Mandhane PJ, Kozyrskyj AL. Sleep, circadian rhythm, and gut microbiota. Sleep Med Rev. 2020;53:101340. doi:1016/j.smrv.2020.101340
9. 9) Simkin DR. Microbiome and mental health, specifically as it relates to adolescents. Curr Psychiatry Rep. 2019;21(9):93. doi:1007/s11920-019-1075-3
10. 10)  Zhang X, Wang S, Xu H, et al. Metabolomics and microbiome profiling as biomarkers in obstructive sleep apnoea: a comprehensive review. Eur Respir Rev. 2021;30(160):200220. doi:1183/16000617.0220-2020
11.  11) Valentini F, Evangelisti M, Arpinelli M, et al. Gut microbiota composition in children with obstructive sleep apnoea syndrome: a pilot study. Sleep Med. 2020;76:140-147. doi:1016/j.sleep.2020.10.017
12.  12) Ko CY, Liu QQ, Su HZ, et al. Gut microbiota in obstructive sleep apnea-hypopnea syndrome: disease-related dysbiosis and metabolic comorbidities. Clin Sci (Lond). 2019;133(7):905-917. doi:1042/cs20180891
13.  13) Li Q, Xu T, Shao C, et al. Obstructive sleep apnea is related to alterations in fecal microbiome and impaired intestinal barrier function. Sci Rep. 2023;13(1):778. doi:1038/s41598-023-27784-0
14.  14) Rastogi S, Singh A. Gut microbiome and human health: exploring how the probiotic genus Lactobacillusmodulate immune responses. Front Pharmacol. 2022;13:1042189. doi:3389/fphar.2022.1042189
15.  15) Wang Q, Chen B, Sheng D, et al. Multiomics analysis reveals aberrant metabolism and immunity linked gut microbiota with insomnia. Microbiol Spectr. 2022;10(5):e0099822. doi:1128/spectrum.00998-22
16.  16) Liu B, Lin W, Chen S, et al. Gut Microbiota as an objective measurement for auxiliary diagnosis of insomnia disorder. Front Microbiol. 2019;10:1770. doi:3389/fmicb.2019.01770
17.  17) Li Y, Zhang B, Zhou Y, et al. Gut microbiota changes and their relationship with inflammation in patients with acute and chronic insomnia. Nat Sci Sleep. 2020;12:895-905. doi:2147/nss.s271927
18.  18) Mazziotta C, Tognon M, Martini F, Torreggiani E, Rotondo JC. Probiotics mechanism of action on immune cells and beneficial effects on human health. Cells. 2023;12(1):184. doi:3390/cells12010184
19.  19) Takada M, Nishida K, Gondo Y, et al. Beneficial effects of Lactobacillus casei strain Shirota on academic stress-induced sleep disturbance in healthy adults: a double-blind, randomized, placebo-controlled trial. Benef Microbes. 2017;8(2):153-162. doi:3920/bm2016.0150
20. 20)  Nakagawa M, Yamamoto H, Kawaji M, Miura N, Wakame K, Endo T. Effects of lactic acid bacteria-containing foods on the quality of sleep: a placebo-controlled, double-blinded, randomized crossover study. Funct Foods Health Dis. 2018;8(12):579-596. doi:31989/ffhd.v8i12.572
21.  21) Chu A, Samman S, Galland B, Foster M. Daily consumption of Lactobacillus gasseri CP2305 improves quality of sleep in adults – a systematic literature review and meta-analysis. Clin Nutr. 2023;42(8):1314-1321. doi:1016/j.clnu.2023.06.019
22.  22) Scoditti E, Tumolo MR, Garbarino S. Mediterranean diet on sleep: a health alliance. 2022;14(14):2998. doi:10.3390/nu14142998
23.  23) Qi X, Ye J, Wen Y, et al. Evaluating the effects of diet-gut microbiota interactions on sleep traits using the UK Biobank Cohort. Nutrient 2022;14(6):1134. doi:10.3390/nu14061134
24.  24) Castro-Diehl C, Wood AC, Redline S, et al. Mediterranean diet pattern and sleep duration and insomnia symptoms in the Multi-Ethnic Study of Atherosclerosis. Sleep. 2018;41(11):zsy158. doi:1093/sleep/zsy158
25.  25) Godos J, Ferri R, Caraci F, et al. Adherence to the Mediterranean diet is associated with better sleep quality in Italian adults. 2019;11(5):976. doi:10.3390/nu11050976
26.  26) Gupta K, Jansen EC, Campos H, Baylin A. Associations between sleep duration and Mediterranean diet score in Costa Rican adults. 2022;170:105881. doi:10.1016/j.appet.2021.105881
27.  27) Jansen EC, She R, Rukstalis MM, Alexander GL. Sleep duration and quality in relation to fruit and vegetable intake of US young adults: a secondary analysis. Int J Behav Med. 2021;28(2):177-188. doi:1007/s12529-020-09853-0

Antiviral Lactoferrin Now pitted against COVID-19

Antiviral Lactoferrin Now Pitted Against COVID-19

 by Noelle Patno, PhD

Lactoferrin (LF) has been advocated by researchers1–3 as a potential method to prevent or treat COVID-19. These recent reviews promote a hypothesis that the natural, endogenous compound which has shown antiviral capabilities for other viruses including SARS-CoV may be effective against the SARS-CoV-2 virus as well. With over 70 years since the discovery of this glycoprotein, this iron-scavenging milk protein now deserves greater attention. The current literature demonstrates that LF has many anti-inflammatory, immunomodulatory, and even anticarcinogenic effects; what remains to be discovered is its specific activity against the pandemic virus of our times, SARS-CoV-2. A large body of in vitroevidence suggests that lactoferrin may have efficacy because of its ability to inhibit viruses and bind to viral surface receptors, which are related to SARS-CoV-2 mechanisms. Now is the time to discover more about this glycoprotein and its potential against SARS-CoV-2.

Mechanism of binding to heparan sulfate

A recent paper (published in Cell, November 2020) demonstrated that SARS-CoV-2 infection depends on attachment to cellular heparan sulfate (HS) and ACE2.4 While ACE2’s role was predicted in January5 and subsequently demonstrated in March,6 this revelation in November reveals the importance of HS as an essential factor in the virus’s attachment and entry to infect the cell. Heparan sulfate, a complex carbohydrate on almost every cell’s surface, is useful to the host to determine the cell’s response to stimuli such as metabolic or inflammatory stimuli and critically as part of immune functions.7 However, many viruses hijack HS to bind and depend on it for their infection. In vitro evidence supports this mechanism for other viruses including the Nipah and Hendra viruses;8 entrovirus 71, which is associated with hand foot mouth disease;9 enteroaggregative E. coli, which is a significant cause of diarrhea and foodborne outbreaks;10 rift valley fever virus;11 and human papillomavirus.12 This list overlaps with the list of pathogenic viruses that lactoferrin inhibits in vitro, which includes but is not limited to the following: herpes simplex virus, hepatitis B virus, hepatitis C virus (HCV), avian flu, enterovirus 71, Japanese encephalitis virus, respiratory syncytial virus, influenza A virus, parainfluenza virus, cytomegalovirus, poliovirus, rotavirus, and human immunodeficiency virus (HIV), with clinical evidence for enterovirus 71, HCV, norovirus, and rotavirus.2 With lactoferrin’s previous ability demonstrated to prevent the Japanese encephalitis virus,13 alphavirus,14 Toscana virus,15 dengue virus,16 and the SARS pseudovirus17 from entering cells through HS receptors and infecting the cells, then LF has the possibility of preventing SARS-CoV2 from entering cells as well.

Potential mechanisms by which LF might help against SARS-CoV-2 are therefore the following:1

Prevent attachment to heparan sulfate receptors on the cell and inhibit viral entry4,13
Prevent attachment to ACE2 and inhibit viral entry/infection of the cell18

Prevent attachment to DC-SIGN, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin receptor and thereby prevent infection of the cell3
Prevent attachment and viral entry via other receptors17

Inhibit viral replication15,19
Decrease IL-6,20 which is part of the cytokine storm

Current clinical trials evaluating lactoferrin in COVID-19

The table below lists the current clinical trials on clinicaltrials.gov evaluating lactoferrin in COVID-19.

Three recent publications further suggest that lactoferrin may help against SARS-CoV-2:

1. In vitro, bovine lactoferrin was able to decrease significantly the numbers of SARS-CoV-2-infected bronchial epithelial cell mimetics, the single compound mentioned in the abstract of the preprinted paper, and one of 17 dose-responsive compounds from a 1,425 library in a drug-repurposing high throughput screen19

2. The completed randomized clinical study listed above, in 32 patients with confirmed COVID-19 by RT-PCR, showed an early clearance of the virus, recovery from symptoms, and statistically significant reduction in IL-6 , with additional in vitro and in silico support for lactoferrin’s ability to prevent cells from infection through preincubation as well as simulated binding of lactoferrin to the ACE2 receptor.18

3. A 10-day study evaluating the effect of a liposomal bovine lactoferrin syrup that included vitamin C alone or with zinc (for a total of 256 to 384 mg of lactoferrin per day) and additional nasal and mouth spray or aerosol application for additional symptoms. IgM/IgG antibody rapid test in whole blood was used for confirmed COVID-19 diagnosis in 75 people. Symptoms were scored on a scale of 0 to 3 in severity twice a day for 10 days and then a follow-up after one month. By the fifth day, all patients recovered from respiratory distress and headache symptoms. The percentage of patients without symptoms of coughing, muscular pain, nasal congestion, tiredness, and diarrhea all increased by 48 hours and 5 days after study start.21

There are many limitations to the above three studies. The first two preprinted articles have not been peer-reviewed. The third lacked clear dosing instructions, did not use the more accurate SARS-CoV-2 diagnostic tests; did not follow-up test for the virus after-treatment; used additional interventions for subsets of patients; lacked more rigorous, randomized, and controlled design and more objective and validated methodology; and was not the complete data set for the study, among other limitations. Clinical studies on the effects of lactoferrin supplementation in COVID-19 patients is a promising and interesting research advancement to watch.

Citations

1. Campione E et al. Lactoferrin as protective natural barrier of respiratory and intestinal mucosa against coronavirus infection and inflammation. Int J Mol Sci. 2020;21(14):4903.

2. Chang R et al. Lactoferrin as potential preventative and adjunct treatment for COVID-19. Int J Antimicrob Agents. 2020;56(3):106118.

3. Wang Y et al. Lactoferrin for the treatment of COVID-19 (Review). Exp Ther Med. 2020;20(6).

4. Clausen TM et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell. 2020;183(4):1043-1057.e15.

5. Wan Y et al. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94(7).

6. Hoffmann M et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.e8.

7. Simon Davis DA et al. Heparan sulfate: a ubiquitous glycosaminoglycan with multiple roles in immunity. Front Immunol. 2013;4.

8. Mathieu C et al. Heparan sulfate-dependent enhancement of henipavirus infection. mBio. 2015;6(2).

9. Kobayashi K et al. Heparan sulfate attachment receptor is a major selection factor for attenuated enterovirus 71 mutants during cell culture adaptation. PLOS Pathogens. 2020;16(3):e1008428.

10. Rajan A et al. Enteroaggregative E. coli adherence to human heparan sulfate proteoglycans drives segment and host specific tesponses to infection. PLOS Pathogens. 2020;16(9):e1008851.

11. de Boer SM et al. Heparan sulfate facilitates Rift Valley fever virus entry into the cell. J Virol. 2012;86(24):13767-13771.

12. Selinka H-C et al. Inhibition of transfer to secondary receptors by heparan sulfate-binding drug or antibody induces noninfectious uptake of human papillomavirus. J Virol. 2007;81(20):10970-10980.

13. Chien Y-J et al. Bovine lactoferrin inhibits Japanese encephalitis virus by binding to heparan sulfate and receptor for low density lipoprotein. Virology. 2008;379(1):143-151.

14. Waarts B-L et al. Antiviral activity of human lactoferrin: inhibition of alphavirus interaction with heparan sulfate. Virology. 2005;333(2):284-292.

15. Pietrantoni A et al. Bovine lactoferrin inhibits Toscana virus infection by binding to heparan sulphate. Viruses. 2015;7(2):480-495.

16. Chen J-M et al. Bovine lactoferrin inhibits dengue virus infectivity by interacting with heparan sulfate, low-density lipoprotein receptor, and DC-SIGN. Int J Mol Sci. 2017;18(9).

17. Lang J et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS One. 2011;6(8). doi:10.1371/journal.pone.0023710

18. Campione E et al. Pleiotropic effect of Lactoferrin in the prevention and treatment of COVID-19 infection: randomized clinical trial, in vitro and in silico preliminary evidences. bioRxiv. Published online August 17, 2020:2020.08.11.244996.

19. Mirabelli C et al. Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19. bioRxiv. Published online September 28, 2020.

20. Lepanto MS et al. Efficacy of lactoferrin oral administration in the treatment of anemia and anemia of inflammation in pregnant and non-pregnant women: an interventional study. Front Immunol. 2018;9.

21. Serrano G et al. Liposomal lactoferrin as potential preventative and cure for COVID-19. Int J Res Health Sci. 2020;8(1):8.

Noelle Patno, PhD is the Nutrition Scientist for Digestive Health at Metagenics. Dr. Patno received her PhD in Molecular Metabolism and Nutrition and Masters in Translational Science from the University of Chicago, studying the role of microbial components in intestinal epithelial cell survival related to inflammatory bowel disease. Prior to her graduate studies, Dr. Patno received a chemical engineering degree from Stanford University and worked as an engineer. She has personal experience and interest in preventive nutrition and nutritional therapies for chronic disease, and her current role involves researching and developing probiotics, prebiotics, and other nutritional programs for the promotion of digestive and overall health.