French researchers have discovered that influenza disrupts the balance of intestinal flora, thereby weakening pulmonary immune defenses and increasing the likelihood of bacterial superinfections.
Each winter, millions of French people catch the flu. Despite vaccination campaigns and treatment, the most vulnerable can develop complications which at times prove fatal. These severe forms are generally linked to pneumonia caused by bacterial superinfections. A recent study published in a prestigious journal suggests that the gut microbiota is involved.
Imbalance of intestinal flora
It is now accepted that the intestinal flora plays a key role in the proper functioning of the immune system. In this study, flu-infected mice showed a transitory imbalance in the composition and activity of their gut microbiota ( (sidenote:
Dysbiosis
Generally defined as an alteration in the composition and function of the microbiota caused by a combination of environmental and individual-specific factors.
Levy M, Kolodziejczyk AA, Thaiss CA, et al. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219-232.)). In addition, the production of short-chain fatty acids ( (sidenote:
SCFAs
Short Chain Fatty Acids are a source of energy (fuel) for the cells of the individual. They interact with the immune system and are involved in the communication between the intestine and the brain.
Sources:
Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020;11:25.
)) was greatly reduced. SCFAs, and especially acetate, have the ability to act at a distance from the intestines on certain immune cells in the lungs (macrophages) by stimulating their antibacterial activity. In short, a dysbiosis of intestinal microbiota associated with flu is thought to reduce acetate production, compromising the lungs’ immune defenses against bacteria.
The role of diet
This intestinal imbalance is not caused directly by the virus itself, but instead seems to be the result of a reduction in food intake due to loss of appetite, a frequent flu symptom. Accordingly, in order to preserve the integrity of intestinal microbiota and strengthen immune defenses, it is recommended to consume foods that are rich in dietary fiber (e.g. vegetables, fruits and pulses). Similarly, reducing calorie intake or fasting are strongly advised against during flu outbreaks.
New therapeutic strategies
It has been shown in mice that this susceptibility to bacterial superinfection can be corrected by acetate treatment. Based on these findings, a treatment based on acetate or similar compounds is a potentially valuable therapeutic approach. Furthermore, therapeutic strategies based on the use of prebiotics and probiotics should be assessed.
Sources:
Sencio V, Barthelemy A, Tavares LP, et al. Gut Dysbiosis during Influenza Contributes to Pulmonary Pneumococcal Superinfection through Altered Short-Chain Fatty Acid Production. Cell Rep. 2020;30(9):2934–2947.e6.
In blood cancer patients undergoing a hematopoietic stem cell transplantation (HSCT), a more diverse intestinal microbiota is associated with reduced mortality.
(sidenote:
The patient receives stem cells from a histocompatible donor
). However, the risks involved are significant, foremost among them the potentially lethal (sidenote:
Graft-versus-host disease
Immune response directed against host cells initiated by cells transplanted from the donor
).It remains difficult to foresee when such complications will arise in a given patient. The intestinal microbiota, which plays a role in immunity and whose balance is disturbed in patients undergoing HSCT, could prove useful in this regard.
A multicenter study spanning three continents
A team sought to characterize the potential links between microbial composition and post-transplant prognosis, at the same time testing whether its findings were dependent on the patient’s place of care. Although alterations in the intestinal microbiota had already been linked to HSCT and its prognosis, it remained unclear whether these links were consistent in nature. A study was therefore carried out on 1,362 allograft patients (average age of 53 years) from four medical centers (New York and Durham, USA; Regensburg, Germany; Sapporo, Japan), allowing for between-center comparisons.
Survival linked to post-op diversity of microbiota
The study showed that greater diversity in the gut microbiota (α diversity), measured 7 21 days after the transplant (neutrophil development period), was associated with a lower risk of death (approximately 30%-50% lower, depending on the center and model) within 24 months from the procedure. In some patient subgroups, greater diversity was also associated with a reduction in transplant-related mortality and GvHD-related mortality.
Certain taxa are over-represented in the postoperative setting
The loss of diversity in the microbiota has also been associated with the over-representation of certain taxa of Enterococcus, Klebsiella, Escherichia, Staphylococcus and Streptococcus genera. This predominance of a specific taxon in the microbiota of transplant patients had already been reported in a previous study. Although not found in all patients, it was observed in all four centers. In short, allografts are frequently associated with an alteration of the microbiota and characteristic microbial profiles.
Pre-operative microbiota: a predictive tool?
The researchers also looked at the microbial profile of patients prior to transplant. By comparing patients to healthy control subjects, the researchers showed that their microbiota already presented a dysbiosis pre-transplant. Moreover, in the New York center, greater pre-operative diversity predicted successful outcomes. Ultimately, these results may lead to the development of clinical strategies to improve post-transplant prognosis by regulating the microbiota at two key moments, either before the transplant or during the neutrophil development period.
Release molecules directly in the heart of the tumor to assist the immune response and facilitate regression: this is the challenge taken up by probiotic bacteria specially designed to reach their target, multiply and release their cellular content.
While immune checkpoint inhibitors (ICIs)–monoclonal antibodies directed against immune system checkpoints–have revolutionized cancer treatment, they only work in a small number of patients and can produce a multitude of unwanted side effects (e.g. fatigue, skin rashes, endocrine disorders and hepatotoxicity). In addition, although combinations of several inhibitors can prove more effective, they may have higher toxicity, hence the reluctance to use them. In order to provide a more localized, more durable, and less invasive therapeutic option, it is therefore crucial to improve their method of administration. Due to their colonization method and preferential growth within tumors, bacteria may prove to be an ideal solution to deliver these cancer treatments locally.
A single dose for a prolonged effect
With this in mind, a team designed probiotic bacteria capable of releasing blockade nanobodies locally. These target two membrane receptors–the lymphocyte receptor CTLA-4 and the tumor receptor PD-L1–involved in the defense mechanisms activated by the tumor to prevent T cells from attacking it. Specifically, a single intravenous or intra-tumoral injection transports these probiotic bacteria to the heart of the tumor, where they multiply to a critical density and destroy the tumor cells by effectively and continuously releasing therapeutic nanobodies into the tumor’s microenvironment.
Effective on even the most aggressive tumors
The research team subsequently injected the probiotic into murine models for lymphoma and colorectal cancer. For lymphomas, a single intra-tumoral or intravenous injection of the probiotic bacteria “carrying” the treatment proved more effective than standard immunotherapy, leading to a complete regression of the tumor and the prevention of metastasis in both early and advanced models. But what about cancers known to be more resistant to immunotherapy, such as colorectal cancer? A single intra-tumoral dose of a combination of nanobodies and a growth factor (GM-CSF, used to improve anti-tumor response) was enough to shrink the tumor without any side effects.
Bacteria: the ideal vehicle for the future?
This research should help advance immunotherapy by providing a “carrier”, i.e. bacteria, with many advantages: possibility of combination therapies; continuous production of therapeutic substances; minimized toxicity; localized treatment distribution close to control points; and of course, use among a larger number of cancer patients.
A team has recently proved how certain genotoxic strains of Escherichia coli damage DNA, leading to an increased risk of colorectal cancer. In the future, will it be possible to curb this process?
While various species of the gut microbiota are linked to colorectal cancer (CRC), a direct role of bacteria in the onset of carcinogenic mutations has not been demonstrated yet. For example, certain bacteria, including genotoxic strains of E. coli, are more commonly found in the feces of CRC patients than in those of healthy subjects (60% vs 20%). These bacteria carry a DNA unit called pks (polyketide-nonribosomal peptide synthase operon) that encodes enzymes for synthesis of colibactin, a toxin capable of damaging DNA.
An ex vivo signature...
Through repeated luminal injections over five months, a group of researchers exposed human intestinal (sidenote:
Organoids
Organoids are new ex vivo models of organs, halfway between in vivo models and in vitro cell cultures. The stem cells or partially differentiated cells from which they are obtained spontaneously self-organize into functional tissue in an adapted three-dimensional environment
) to genotoxic E. coli (pks+E. coli). Sequencing of the organoid genome before and after this exposure showed that colibactin induces a mutation (recombination between the two DNA strands) at a very specific location in the genome. This mutation was then “corrected” (i.e. resolution) by the cells of the organoid via single base substitution (SBS) or insertion/deletion (ID), based on recognizable patterns. These two types of resolution, called SBS-pks and ID-pks, are not observed in organoids exposed either to non-genotoxic E. coli strains or to a simple dye. Therefore, they represent the signature of an exposure to pks+E. coli.
...confirmed in humans
It remained to be seen whether SBS-pks and ID-pks signatures were present in human tumors. Based on data from more than 5,000 tumors covering dozens of different types of cancer, both signatures are much more commonly found in CRC-derived metastases than in any other cancer type. Moreover, an analysis of seven cohorts of CRC patients showed that 2.4% of the mutations that most frequently lead to CRC were colibactin-induced. Many of these mutations affected the APC gene, which prevents uncontrolled cell proliferation.
A way to prevent CRC?
Another team had previously found these signatures in the colonic crypts of healthy individuals. This suggests that mutagenesis takes place in the healthy colon of individuals who harbor genotoxic strains of pks+ E. coli, increasing the risk of CRC. This cohort also included a few cases of urogenital cancer and head and neck cancer displaying pks signature, which suggests that pks+ E. coli may also act outside the colon. Accordingly, the detection and suppression of pks+ E. coli, as well as the reevaluation of pks-carrying probiotic strains, may reduce the risk of cancer in a large number of individuals.
Ageing is associated with the deterioration of numerous body functions and generalized inflammation, which contribute to (sidenote:
Frailty syndrome
Frailty syndrome is diagnosed based on three of the following five criteria: sedentary lifestyle; recent weight loss; exhaustion or fatigue; decreased muscle strength; and slow walking pace. It involves a risk of functional decline, institutionalization, and death, French National Academy of Medicine, 2013.
) among the elderly. It seems highly likely that diet plays a role in this process, since lack of variety leads to alterations in the gut microbiotathought to increase the risk of frailty. Conversely, it is possible that a balanced diet contributes towards maintaining or restoring the bacterial flora and helps fight frailty. A group of researchers sought to find out whether this is the case, focusing specifically on the (sidenote:
Mediterranean diet
Rich in fruit, vegetables, cereals, oilseeds (nuts) and fish, and low in red meat, saturated fats and dairy products.
Lăcătușu CM, Grigorescu ED, Floria M, et al. The Mediterranean Diet: From an Environment-Driven Food Culture to an Emerging Medical Prescription. Int J Environ Res Public Health. 2019 Mar 15;16(6):942.).
“Good” bacteria associated with “good” ageing
The Mediterranean diet is the “ultimate” healthy diet, and offers many benefits, including reduced inflammation, lower risk of disease and lower mortality. According to numerous studies, it is also associated with changes in the gut microbiota. The researchers therefore analyzed the gut microbiota of approximately 600 individuals aged between 65 and 79 years who showed few or no signs of frailty. This was done before and after the subjects had followed a normal diet or a Mediterranean diet for one year. With the Mediterranean diet, the gut microbiota remained diverse (associated with good health) and the number of “good” bacteria (associated with decreased frailty, improved brain function and reduced inflammation) increased. The researchers also observed improved memory, increased walking speed and increased strength in participants’ hands.
Bacteria to protect against frailty?
These results confirm the benefits of Mediterranean diet for the elderly, and reveal that part of these benefits is directly linked to changes in the gut microbiota. The results therefore open up new avenues for the prevention of frailty among people at risk, based on direct administration of the “good” bacteria identified in the study.
Recommended by our community
"Absolutely, aging gracefully often starts from within! A balanced diet rich in nutrients, especially those supporting gut health, can play a pivotal role in overall well-being as we age. It's never too late to embrace healthy eating habits for a vibrant and active life. Cheers to health and longevity!" -Aware Health Rewards App (From My health, my microbiota)
Ghosh TS, Rampelli S, Jeffery IB, et al. Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut 2020;0:1–11.
With COVID-19 continuing to spread, we all hope to have the necessary equipment to fight it. From birth onwards, the immune system accomplishes its defense mission in close cooperation with the gut microbiota.
Whether it is the coronavirus or not, any microbe (bacterium, virus or fungus) that enters our body is potentially dangerous. When this occurs, defense mechanisms carefully orchestrated by immune cells and the intestinal flora are put into action to eliminate it. This protective barrier, erected by the intestine, prevents foreign bodies from entering the bloodstream.
Intestinal barrier
The purpose of this immune system-gut alliance is to promote and maintain intestinal balance throughout our lifetime. The gut microbiota forms a microbial lining which prevents bad bacteria from colonizing the gut and multiplying. A balance between intestinal cells and flora creates an environment conducive to the development of good bacteria. On the contrary, any change in this ecosystem alters the interactions involved: a vicious circle sets in whereby inflammation promotes colonization by harmful microorganisms, which in turn exacerbate inflammation. Intestinal cells, for their part, form a natural physical barrier lined with thick mucus which ensures that bacteria, viruses and fungi are confined to the center of the gastrointestinal tract.
Intestinal defense cells
Some immune cells, such as (sidenote:
Macrophages and lymphocytes
Macrophages and lymphocytes are white blood cells that act as immune cells. They defend the body by eliminating intruders
), promote innate immunity, which is quick-acting but (sidenote:
Non-specific action is general and not targeted against a particular molecule or microbe.
): “I see you, I catch you, I kill you”. The rest, including (sidenote:
Macrophages and lymphocytes
Macrophages and lymphocytes are white blood cells that act as immune cells. They defend the body by eliminating intruders
), are part of the adaptive immune system, which mobilizes more slowly, is (sidenote:
Specific action is targeted against a particular molecule or microbe.
) and remembers previous infections: “I recognize you, I catch you, I kill you”. Among other functions, cells of the adaptive immune system produce antibodies. Precise control of the immune system prevents excessive inflammation in response to good bacteria and avoids food allergies by allowing tolerance of (sidenote:
Nutrients
Nutrients are small molecules released during the digestion of food.
)
Highly synchronized cooperation
Bacteria are in constant dialogue with the intestine, either directly or through the transmission of signals. The messages received enable the immune cells to be on constant alert and to strengthen the intestinal barrier where necessary. They also facilitate activation of the innate and adaptive immune responses. According to studies carried out on animals, these exchanges have an impact on other organs too: a diet rich in fiber enables the microbiota to produce small molecules that have a beneficial effect on pulmonary allergic responses. Indeed, the microbiota can slow excessive inflammation even at a distance from the intestine (infection, stress, seasonal allergy or (sidenote:
Food intolerance occurs when the immune system incorrectly identifies food molecules as harmful substances.
)).
Boosting our microbiome
Even if these mechanisms are still to be confirmed in humans, and although studies on a possible link between COVID-19, microbiota and the immune system are incomplete, a healthy lifestyle which takes care of the microbiota (with a balanced dietfor example) seems to be the best way of maintaining our intestinal barrier.
Sources
Gaboriau-Routhiau, Cerf-Bensussan. Microbiote intestinal et développement du système immunitaire 2016. Med Sci (Paris). 32(11): 961–967.
Caminero A, Meisel M, Jabri B, et al. Mechanisms by which gut microorganisms influence food sensitivities. Nat Rev Gastroenterol Hepatol. 2019;16(1):7‐18.
Although at present there is nothing to confirm a link between infection and gut microbiota, several signs nonetheless point towards an association with the digestive system. Certain precautionary measures are therefore justified.
Fever, cough and respiratory distress are three symptoms of COVID-19, but they are not the only ones. A first studya has reported that half of patients testing positive for coronavirus also complain of digestive symptoms such as loss of appetite, diarrhea and, to a lesser extent, vomiting or abdominal pain.
Digestive symptoms
Excluding loss of appetite, which is not specific to intestinal disorders, about one in five patients involved this study had strictly digestive symptoms which worsened with the aggravation of COVID 19.a The incidence of diarrhea varied widely between studies (2%-34%)a,b but the genetic material of the virus –or even active virus (i.e. able to spread)– was found in patients’ fecesc-e, suggesting that it may multiply in our digestive system. Another study showed an imbalance of the intestinal flora (dysbiosis) in two patients aged 65 and 78 years who subsequently died from COVID 19f; however, the link between intestinal dysbiosis and COVID-19 seems of little relevance here since it is well known that elderly people typically display gut flora imbalances.g Lastly, a debateh has recently kicked off about the potential role played by Prevotella bacteria in the infection, but to date no scientific evidence has confirmed any such role.
At-risk patients
Admittedly, these initial findings are open to criticism, since the studies were carried out in a limited number of patientsf, and some of them were not subject to peer review prior to publication.f Despite this, the findings warrant caution. For example, on March 16, 2020, the (sidenote:
ANSM
French Agency for the Safety of Medicines and Health Products
) enhanced precautionary measures in the case of fecal microbiota transplants in order to prevent intestinal infections due to the transmission of other pathogens through Clostridium difficile treatment. Enhanced precautions will also apply to patients suffering from inflammatory bowel disease, particularly to those treated with immunosuppressants, who are more susceptible to viral infections, even if specific datab are still lacking. While they are not advised to discontinue immunosuppressive treatment (the risk of flare-up far exceeds other), they must carefully comply with prevention measures.b
Although at present there is nothing to confirm a link between infection and gut microbiota, several signs nonetheless point towards an association with the digestive system. Certain precautionary measures are therefore justified.
Fever, cough and respiratory distress are three symptoms of COVID-19, but they are not the only ones. A first study1 has reported that half of patients testing positive for coronavirus also complain of digestive symptoms such as loss of appetite, diarrhea and, to a lesser extent, vomiting or abdominal pain.
Digestive symptoms
Excluding loss of appetite, which is not specific to intestinal disorders, about one in five patients involved this study had strictly digestive symptoms which worsened with the aggravation of COVID 191. The incidence of diarrhea varied widely between studies (2%-34%)1,2 but the genetic material of the virus –or even active virus (i.e. able to spread)– was found in patients’ feces3,4, suggesting that it may multiply in our digestive system. Another study showed an imbalance of the intestinal flora (dysbiosis) in two patients aged 65 and 78 years who subsequently died from COVID 195; however, the link between intestinal dysbiosis and COVID-19 seems of little relevance here since it is well known that elderly people typically display gut flora imbalances6. Lastly, a debate7 has recently kicked off about the potential role played by Prevotella bacteria in the infection, but to date no scientific evidence has confirmed any such role.
At-risk patients
Admittedly, these initial findings are open to criticism, since the studies were carried out in a limited number of patients6, and some of them were not subject to peer review prior to publication6. Despite this, the findings warrant caution. For example, on March 16, 2020, the ANSM (French Agency for the Safety of Medecines and Health Products) enhanced precautionary measures in the case of fecal microbiota transplants in order to prevent intestinal infections due to the transmission of other pathogens through Clostridium difficile treatment. Enhanced precautions will also apply to patients suffering from inflammatory bowel disease, particularly to those treated with immunosuppressants, who are more susceptible to viral infections, even if specific data2 are still lacking. While they are not advised to discontinue immunosuppressive treatment (the risk of flare-up far exceeds other), they must carefully comply with prevention measures2
Sources
1. Lei Pan, Mi Mu, Pengcheng Yang et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study.Preproof version. https://journals.lww.com/ajg/Documents/COVID_Digestive_Symptoms_AJG_Preproof.pdf [last consult: 14 april 2020]
2. Ungaro RC, Sullivan T, Colombel JF et al. What Should Gastroenterologists and Patients Know About COVID-19? Clin Gastroenterol Hepatol. 2020 Mar 17. doi: 10.1016/j.cgh.2020.03.020.
3. Gu J, Han B, Wang J. COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission [published online ahead of print, 2020 Mar 3]. Gastroenterology. 2020;. doi:10.1053/j.gastro.2020.02.054
4. Holshue ML, DeBolt C, Lindquist S, et al.; Washington State 2019-nCoV Case Investigation Team. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020 Mar 5;382(10):929-936. doi: 10.1056/NEJMoa2001191.
5. Fei Xiao, Meiwen Tang, Xiaobin Zheng et al. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020 Mar 3 doi: 10.1053/j.gastro.2020.02.055
6. Lilei Yu, Yongqing Tong, Gaigai Shen et al. Immunodepletion with Hypoxemia: A Potential High Risk Subtype of Coronavirus Disease 2019. Unreviewed prepint published on medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.03.20030650v1 [last consult: 14 april 2020]
7. O'Toole PW, Jeffery IB. Gut microbiota and aging. Science. 2015;350(6265):1214–1215. doi:10.1126/science.aac8469
Does vaping promotes mouth infections by causing an imbalance in the oral microbiota? A study has attempted to prove this theory while casting doubt on the safety of electronic cigarettes.
E-cigarettes are extremely popular among young Americans since they are used by more than 20% of high- school students and almost 5% of junior high students in the United States. Portrayed until now as a healthy alternative to tobacco, they no longer seem so harmless. The latest generation of e cigarettes have nicotine and toxicity levels comparable to those of tobacco and are thought to be responsible for a cascade of inflammatory reactions through their effect on the oral microbiota. However, a study published in 2018 had cleared e-cigarettes of having any adverse effects on the gut, mouth or saliva microbiotas.
Oral microbiota imbalance among vapers
To measure the impact of vaping on the oral microbiota, a team divided around a hundred volunteers into three groups: smokers (half a pack per day on average), vapers (half an e-cigarette per day) and non-smokers. Their first finding was that the severity index of tooth, gum and mouth diseases among vapers (42.5%) was significantly lower than among smokers (72.5%), but markedly higher than among non-smokers (28.2%). The second finding was that vapers showed an imbalance (dysbiosis) of the oral microbiota comparable to that of smokers. Their saliva was generally richer in bacteria than that of non-smokers, and displayed proliferation of various species harmful to oral health. In addition, human cells exposed to e-cigarette aerosols show increased sensitivity to bacterial infections compared to cells exposed to air.
Understanding long-term effects
According to the authors, the results of this study–carried out both on human subjects (in vivo) and on cells (in vitro)–confirm that vaping leads to an imbalance of the oral microbiota and increases susceptibility to infections (cavities, (sidenote:
periodontitis
Inflammation of the membrane surrounding the teeth
)). However, this link remains to be proven, and more in-depth studies on the overall effects of vaping on oral, respiratory and cardiovascular health, particularly over the long term, seem necessary.
Pushalkar S., Paul B., Li Q., et al. Electronic Cigarette Aerosol Modulates the Oral Microbiome and Increases Risk of Infection. iScience. 2020 Mar 27;23(3):100884.
Many diseases can affect our lungs. Respiratory infections are the subject of many studies, particularly during this pandemic period. The involvement of the intestinal microbiota in certain respiratory diseases opens the door for new therapeutic options. But we still need to understand the underlying mechanisms.
Researchers recently rediscovered the critical role the intestinal microbiota plays in our defense mechanisms against infections. Changes in the composition of the intestinal microbiota (called dysbiosis) can affect our immune response and, as a result, can be involved in the onset of certain respiratory diseases like asthma, chronic obstructive pulmonary disease (COPD), and respiratory infections. Australian researchers have shed light on the connection between the microbiota and the “gut-lung” axis.
Focus on asthma and COPD
In the case of asthma, beyond revealing intestinal dysbiosis, a reduction of certain bacterial components in the stool (lipopolysaccharides) seems to be associated with a risk of developing symptoms. In COPD, it appears to be difficult to specify whether changes in the intestinal microbiota or the respiratory microbiota are the cause or the consequence of the disease. Nevertheless an undeniable "intestine-lung" link exists.
The protective effect of the intestinal microbiota
Lastly, for respiratory infections, the intestinal microbiota’s protective effect has largely been recognized: several studies have shown a link between imbalance in the microbiota, disruptions in immune defense mechanisms, and the development of bacterial or viral respiratory infections. Certain probiotic strains (particularly certain lactobacilli and certain bifidobacteria) have shown clinical usefulness in these circumstances. According to the authors, although additional studies are necessary to further understand the relationship between the intestinal microbiota and respiratory diseases, this result indicates the potential for the emergence of new therapeutic options.
