Hydroxychloroquine and Microbiota

Jean-Christophe Sergère, PhD - 2020/04/15

 No need to introduce COVID-19 and its associated virus SARS-Cov-2. At the time of writing this article, more than 4.000 scientific articles have been registered in Pubmed database (https://www.ncbi.nlm.nih.gov/pubmed/?term=(%22covid-19%22+OR+%22sars-cov-2%22).

As an ecologist of the Human body, I wondered about a possible interaction between one of the potential treatments against SARS-Cov-2 named hydroxy-chloroquine (HCQ), and human microbiota (1). HCQ is used for decades as an antimalarian drug, more specifically to prevent and treat acute attacks of the malaria including in infants and children. It is also used to treat discoid or systematic lupus erythematosus, and rheumatoid arthritis. This drug has been given to billions of people worldwide. Most common side effects include headache, dizziness, loss of appetite, nausea, diarrhea, stomach pain, vomiting or skin rash.

The subject of this article is to simply bring a state of the art on published scientific articles, and explore some perspectives.

What we know

An exhaustive research in Pubmed database using the combination “hydroxychloroquine AND (microbiota OR microbiome)” only lists 5 scientific articles (2-6)!!! As you will read, these papers do not bring lots of elements about HCQ and microbiota interactions.

The first article (4) is an artifact, since both keywords appear in the text, but there is no microbial study of HCQ impact on the microbiome/microbiota.

Primary Sj?gren syndrome is one of the most prevalent autoimmune diseases. It is characterized by dry eye and dry mouth symptoms. Two out of the five articles focus on the Sj?gren syndrome (SS). The first one from Fudan University (Shanghai; China) describes oral microbiome changes in SS (5). SS patients might have carry less diverse oral microorganisms compared with healthy subjects. Moreover, the oral microbiome might be influenced by a treatment associating prednisone acetas to HCQ. There was no relevant data about HCQ alone.

The third article (2) investigated gut dysbiosis in patients with SS or dry eye syndrome (DES) compared to normal subjects and evaluated the association of dysbiosis with dry eye severity. The authors observed that SS patients showed significant gut dysbiosis compared to controls and environmental DES, while DES patients showed compositional changes of gut microbiome somewhere in between Sj?gren's syndrome and controls. Dysbiosis of the gut microbiota was partly correlated to dry eye severity. In this article, HCQ was mentioned because 5 out of 10 SS patients had been taking oral HCQ. Not particular information could be exploited from this subpopulation analysis.

The forth article focused on a mouse model of rheumatoid arthritis that develops atherosclerosis (3). Again, HCQ was not tested alone, but present or absent of a high fat diet (HFD). Interestingly, HCQ partially reverted serum markers altered by a HFD. Moreover, based on community alpha diversity, the authors concluded that HFD lead to abnormal intestinal flora with a decreased diversity, while HCQ altered this effect (one could conclude to a partial restoration or a limitation in dysbiosis). As the authors wrote, “at the phylum level, the five major intestinal microbiomes were Firmicutes, Bacteroidetes, Verrucomicrobia, Proteobacteria and Actinobacteria”. The authors concluded that HCQ treatment of this mouse model of RA alleviated the HFD-induced dyslipidemia and atherosclerosis, and altered the composition of intestinal flora. HCQ might thus exert a protective effect on intestinal microbiota in this model.

A last article from Raoult’s team published in 2014 investigated the impact of long-term treatment with doxycycline and HCQ in Q fever endocardis patients compared to healthy patients (6). Unfortunately, HCQ was systematically associated to doxycycline. Thus and again, it was impossible to investigate the possible interaction between HCQ and fecal microbiota.

In fact, almost nothing

An exhaustive (sic) analysis of the scientific literature did not provide any strong data about a link between hydroxychloroquine and microbiota.

This is a surprise since 1/ this drug is used for more than 40 years 2/ billions people received this treatment 3/ microbiome/microbiota studies are emerging since the beginning of the century and a huge number of scientists look for any change of a microbiota in almost anything 4/ some side effects might be explained at least partially by a drug/microbiota interaction (see at the top of the article) 5/ a treatment associating HCQ associated to antibiotics such as azithromycin are currently used to treat COVID-19, and synergies/antagonisms and side effects should be taken into account (and also some start to hypothesize that a microorganism might also be implicated in addition to the SARS-CoV-2 virus).

What to do?

Anyone interested in microbiota and drugs will note that even if a drug is used for decades, there is a usually a lack of work concerning its potential link with microbiota. This case is a clear example of the lack of data on this kind of drug.

There is an increasing amount of data showing that a drug can impact on a specific microbiota. A research article published in 2018 extensively studied the impact of non-antibiotic drugs on human gut bacteria (7). The authors screened more than 1,000 marketed drugs against 40 representative gut bacterial strains, and they found that 24% of the drugs with human targets, including members of all therapeutic classes, inhibited the growth of at least one strain in vitro.

At the opposite, a microbiota can metabolize a drug, either in a positive way (pro-dug to drug conversion) or a negative way (drug catabolism). A recent study also showed that about two thirds of 271 assayed drugs were metabolized by at least one strain present in the human gut (8).

In the light of this lack of data, here are some suggestions. Several investigations should be performed, depending on the researchers tropism, their skills, facilities, access to models etc, several parameters would be:

-         Model: animal / human, ideally with an initial point without treatment then with a follow up of the microbiota/microbiome during quite a long treatment. Alternatively, for clinical studies, 2 (healthy) arms might be compared. In this second approach, several additional parameters should be integrated to obtain statistically significant data and get rid of the heterogeneity (as usual)

-         Place - look at several microbiota: gut, lung, skin etc. Note that in the case of animal models, it might be interesting to investigate several parts of the digestive tract (including attached microbes aka biofilms), since 1/ there is an microbiota heterogeneity along the tract and 2/ HCQ is not homogenously distributed along the tract.

-         Tools: metagenomics coupled to metaproteomic approaches might be preferred, since these technologies are complementary

These are very common studies, quite easy to perform, that might bring lots of information about HCQ.

In an ideal world…

In an ideal world, I would love all the drugs and drug candidates to be tested this way. Basic knowledge, tools, and even some proofs are now available. This might allow to better understand why and how a drug acts (or not), what are the side effects, how it could be repositioned in other pathologies etc.

One day maybe…

 Thanks a lot for reading this note.

All the best,

Chris.

 References

1.       Concepts and differences beween microbiota and microbiome have been discussed elsewhere: https://www.dhirubhai.net/pulse/differences-beween-microbiome-microbiota-what-you-should-sergere/
2.       Moon J, Choi SH, Yoon CH, Kim MK. Gut dysbiosis is prevailing in Sj?gren's syndrome and is related to dry eye severity. PLoS One. 2020 Feb 14;15(2):e0229029. doi: 10.1371/journal.pone.0229029. eCollection 2020. PubMed PMID: 32059038; PubMed Central PMCID: PMC7021297.
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0229029&type=printable
3.       Shi N, Zhang S, Silverman G, Li M, Cai J, Niu H. Protective effect of hydroxychloroquine on rheumatoid arthritis-associated therosclerosis. Animal Model Exp Med. 2019 Apr 19;2(2):98-106. doi: 1002/ame2.12065. eCollection 2019 Jun. Review. PubMed PMID: 31392302; PubMed Central PMCID: PMC6600633.
https://onlinelibrary.wiley.com/doi/epdf/10.1002/ame2.12065
4.       Rodrigues JC, Bargman JM. Antimalarial Drugs for the Prevention of Chronic Kidney Disease in Patients with Rheumatoid Arthritis: The Importance of Controlling Chronic Inflammation? Clin J Am Soc Nephrol. 2018 May 7;13(5):679-680. doi: 10.2215/CJN.03300318. Epub 2018 Apr 16. PubMed PMID: 29661771; PubMed Central PMCID: PMC5969469.
https://cjasn.asnjournals.org/content/clinjasn/13/5/679.full.pdf
5.       Li M, Zou Y, Jiang Q, Jiang L, Yu Q, Ding X, Yu Y. A preliminary study of the oral microbiota in Chinese patients with Sj?gren's syndrome. Arch Oral Biol. 2016 Oct;70:143-148. doi: 10.1016/j.archoralbio.2016.06.016. Epub 2016 Jun 16. PubMed PMID: 27351333.
https://www.sciencedirect.com/science/article/pii/S0003996916301571?via%3Dihub
6.       Angelakis E, Million M, Kankoe S, Lagier JC, Armougom F, Giorgi R, Raoult D. Abnormal weight gain and gut microbiota modifications are side effects of long-term doxycycline and hydroxychloroquine treatment. Antimicrob Agents Chemother. 2014 Jun;58(6):3342-7. doi: 10.1128/AAC.02437-14. Epub 2014 Mar 31. PubMed PMID: 24687497; PubMed Central PMCID: PMC4068504.
https://aac.asm.org/content/aac/58/6/3342.full.pdf
7.       Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, Brochado AR, Fernandez KC, Dose H, Mori H, Patil KR, Bork P, Typas A. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018 Mar 29;555(7698):623-628. doi: 10.1038/nature25979. Epub 2018 Mar 19. PubMed PMID: 29555994; PubMed Central PMCID: PMC6108420.
https://www.nature.com/articles/nature25979
8.       Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019 Jun;570(7762):462-467. doi: 10.1038/s41586-019-1291-3. Epub 2019 Jun 3. PubMed PMID: 31158845; PubMed Central PMCID: PMC6597290.
https://www.nature.com/articles/s41586-019-1291-3