The bidirectional communication axis between the gut and lungs, called the “gut–lung axis” influences the immune status of both organs.

Lung and gut microbiota influence each other and may have an impact on respiratory diseases.⁴

The microbiota plays critical roles in the development and education of the host’s innate and adaptive immune system components, while the immune system orchestrates the maintenance of key features of host-microbe symbiosis. Maintaining homeostasis between the gut microbiota and the immune system is essential, determinants interfering with neonatal gut establishment (antibiotics...) may potentially lead to negative health outcomes.¹

What factors cause flare-ups ? 

Inflammatory outbreaks can be triggered by multiple factors, including stress, pollution, cold, humidity, certain allergens (pollen), certain medications, woolen clothing, and certain cosmetics containing plants or essential oils.

What do we know about the links between atopic dermatitis, the microbiota and immunity?

On a pathophysiological level, AD is characterized by an alteration of the skin barrier, a skin and gut dysbiosis, and immune dysregulation with the activation of Th2 lymphocytes. This immune dysregulation leads to a major cytokine surge, which in turn causes the inflammatory reactions.²

An alteration of the skin barrier is the starting point for a dysbiosis of the skin microbiota characterized by a reduction in bacterial diversity and the proliferation of Staphylococcus aureus. Allergen penetration leads to the activation of keratinocytes and the production of interleukin (IL-33, IL-25, TSLP), resulting in the differentiation of Th2 lymphocytes. These in turn secrete pro-inflammatory cytokines (IL-4, IL-5 and IL-13) characteristic of Type 2 inflammation (Fig 9). These cytokines directly activate the sensory nerves, provoking pruritus.

With chronic lesions, the skin barrier repairs itself poorly and becomes thicker, since it is subject to chronic inflammation. There is also a progressive increase in cytokines and Th cells (Th1, Th2, Th22) which secrete cytokines that contribute to the destruction of keratinocytes. Lastly, a gut dysbiosis may play a role in the disease’s pathophysiological mechanism.³

FIGURE 9: Pathogenesis, main mechanisms and pathophysiology of atopic dermatitis.

Adapted from Sugita K et al, 2020⁴

What have recent discoveries about the microbiota taught you? Has your practice changed?

Recent discoveries about the microbiota have led me to better understand the importance of maintaining and repairing the skin barrier to control inflammation. As a systemic treatment, I advise my patients to use a cleansing gel that preserves the skin’s pH (pH ~5, avoid products with a basic pH), as well as a moisturizer and tailored cosmetic products. The findings also help us to better understand the skin’s immunological system and how to respect the skin’s microbiota.

What are your thoughts on the use of probiotics to treat AD or prevent relapse?

There are many ways to rebalance the skin microbiota in case of AD (probiotics, prebiotics, symbiotics, etc.)⁵ but the postbiotic approach seems to me the most interesting. Postbiotics are preparations of inanimate microorganisms and/or their components that confers a health benefit on the host.⁶ They can restore the skin barrier via an anti-inflammatory action that allows bacteria to recolonize, therefore having a long-term impact on the microbiota. Oral probiotics or prebiotics are another interesting approach to regulating the intestinal system, which itself plays a general immunomodulatory role in the immune system.⁷

Since the COVID-19 pandemic started, the need for a robust and long-lasting immunity induced by vaccines has never been more apparent.²⁰ However, vaccine- induced immune responses are highly variable between individuals and many factors have been suggested that may alter vaccine immunogenicity and efficacy (Fig 8).²¹Therefore, gaining a better understanding of the factors driving variations in vaccine efficacy is critically important.

One factor known to control vaccine efficacy is the gut microbiota.²¹ Interestingly, certain gut microbiota profiles (i.e. higher abundance of Actinobacteria, Clostridium cluster XI and Proteobacteria) are associated with greater vaccine responses against other viral infections such as HIV and rotavirus.^22-26 Additionally, a recent study reported that antibiotic-induced intestinal microbiota dysbiosis led to impaired vaccine responses against influenza, such as a reduced antibody-based neutralization of the virus, as well as lower concentrations of antibodies produced in responses to vaccination.²⁷ This and other similar studies provide evidence of the important role that the gut microbiota plays in vaccine efficacy.^23,28

FIGURE 8: Factors suggested to alter vaccine immunogenicity and/or efficacy, including intrinsic host factors, behavioural, environmental, nutritional and perinatal factors.

Most of these factors have also been shown to influence the composition of the gut microbiota and baseline immunity. Vaccine immunogenicity is also dependent on vaccine intrinsic factors.

Adapted for Lynn DJ et al, 2021²⁰

To date no studies have investigated what impact the gut microbiota may have on SARS-CoV-2 vaccine efficacy, but it seems likely that individuals with gut microbiota dysbiosis may be at increased risk of developing relatively poor vaccine responses. Thus, future research which examines whether specific gut microbiota signatures affect SARS-CoV-2 vaccine efficacy will be critically important.

COVID-19, a highly contagious respiratory disease caused by the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) primarily affects the respiratory tract but gastrointestinal symptoms (i.e. diarrhea, constipation, nausea) have also been reported in some patients.¹⁴

Preliminary studies have found that the gut microbiota is altered in patients with COVID-19 and that its composition correlates with infection severity, suggesting crosstalk between the gut microbiota and lung in response to SARS-CoV-2 infection.¹⁵

It should be noted that the changes in lifestyle adopted to curb the COVID-19 pandemic could also have a negative impact on the gut microbiome of uninfected individuals.¹⁶

These changes in hygiene, and a corresponding increased incidence of several autoimmune and allergic diseases,^18,19 have given rise to the hypothesis that they are causally linked (hygiene hypothesis). Notably, practices implemented to prevent the spread of COVID-19, such as physical distancing, frequent hand washing and sanitizer use, reduced travel and face mask wearing, will likely lead to further loss of key gut microbes.¹⁶

Taken together, the preventative health practices that have been implemented due to COVID-19 may exert collateral damage on the gut microbiome as well as long term health outcomes, particularly in children born just prior to or during the pandemic.¹⁶ Utilizing approaches known to enhance microbial diversity and support a healthy microbiota balance may prevent the negative health impacts associated with the enhanced hygiene practices implemented to prevent the spread of COVID-19.

Interestingly, microbiota at both tissue sites appear to be perturbed during respiratory infections, reinforcing the theory that all mucosal sites are interconnected and that the gut-lung axis is bidirectional.¹

Gut bacteria, their fragments, as well as SCFAs may translocate across the intestinal barrier and travel along the mesenteric lymphatic system to reach the systemic circulation and modulate immune cells in the lung.¹¹ During Influenza respiratory infections, lung microbiota and immune functions are altered, and a gut microbiota dysbiosis is also observed which may explain the commonly associated gastroenteritis-like symptoms (Fig 7A).¹⁰

FIGURE 7: Gut-lung axis during viral respiratory infection (A) and model of microbiota modulation using probiotics (B).

Adapted from Dumas A et al, 2018²

Probiotics may be helpful to recover a healthy status (microbiota homeostasis, infection control, modulation of immune responses) via gut microbiota metabolites (SCFAs…) or host-derived products.

There are likely several causes of this gut dysbiosis including loss of appetite (leading to reduced food and calorie intake), as well as inflammatory cytokine release. This may have local consequences: intestinal inflammation, disruption of gut barrier, decreased production of antimicrobial peptides (AMPs), a drop in SCFAs, potentially leading to secondary enteric infections.¹⁰

Gut barrier alteration promotes bacterial translocation as well as endotoxin release into the blood, leading to systemic inflammation, lung damage aggravation and increased risk of secondary bacterial infections.¹⁰ The reduced SCFA production by the gut microbiota also contributes to the reduced antibacterial immunity seen in the lungs.¹⁰ This highlights the vital role that the gut microbiota plays in the lung’s defenses against respiratory infections.

Modulation of the gut microbiota using strategies such as probiotics may help reduce susceptibility to respiratory infections via the gut-lung axis, or they may be helpful in recovering from infection and reaching a healthy status (Fig 7B). Several studies in mice have shown that specific probiotics administered prior to influenza infection led to the reduced accumulation of immune cells in the infected lungs. These probiotics also enhanced viral clearance, improved overall health and reduced alterations in the gut microbiota.^12,13

Recommended by our community

In comparison to the gut microbiota, studies on the lung microbiota are still in their infancy.⁵ The lung was originally thought to be sterile but recently, researchers have discovered that the lung harbours its own microbiota, with a composition distinct from the gut microbiota.⁶

Studies have shown that gut microbiota may be involved in providing protection against viral respiratory infections (such as influenza and respiratory syncytial virus),² via numerous mechanisms. For example, gut microbial metabolites such as SCFAs (obtained from dietary fiber fermentation by commensal bacteria) and desaminotyrosine (a degradation product of plant flavonoids produced by human gut bacteria)⁷ influence the lung production of Type I interferon (IFNs) which elicit anti-viral protection. ^8,9 Along with microbial metabolites, microbial components (such as LPS) help arm the lungs against viral respiratory infections (Fig 6). The gut microbiota also plays a role in viral (influenza) clearance by stimulating CD8+ T-cell effector function.¹⁰

FIGURE 6: The role of the gut microbiota in viral respiratory infections.

Adapted from Sencio V et al, 2020¹⁰

Any factors inducing gut microbiota dysbiosis (aging, antibiotics, diseases such as obesity, diabetes…) can also alter the normally beneficial gut-lung cross-talk, increasing susceptibility to respiratory infections.¹⁰

There are many ways to influence gut microbiota composition and modulate the immune response (prebiotics, probiotics…).³¹ One of the options is dietary interventions that have the potential to alter the activity of the local immune system, thereby dampening the increased inflammatory tone observed with these conditions - this is termed immunonutrition.³² The most widely studied immunonutrients include omega-3 polyunsaturated fatty acids (n-3 PUFA), vitamin D, arginine, nucleotides and glutamine.³²

Vitamin D and its effects on intestinal immune responses 

While the best characterized function of vitamin D is its role in controlling calcium levels and thereby maintain bone health, it is also known to have a significant effect on GI immune responses. Vitamin D regulates several genes that regulate gut barrier function as well as genes that encode antimicrobial peptides, thus helping to maintain intestinal balance (Fig 5).³³ It exerts an immunomodulatory effect, including immune cell differentiation, migration and anti-inflammatory functions,³⁴ and can act directly on Paneth cells to promote defensin-2 secretion.³⁵ Vitamin D also promotes the compositional diversity of the gut microbiota, leading to increased production of butyrate. Butyrate can exert anti-inflammatory effects, increase gut barrier function, and promote Paneth cells to secrete defensins (Fig 5). Interestingly, some probiotic bacteria (e.g. Lactobacillus strains) have been shown to increase vitamin D levels in the blood.³⁶

FIGURE 5: Effects of vitamin D on intestinal cells, gut microbiota and gut barrier.

Adapted from Chen J et al, 2021.³⁷

In a previous study² it was shown that fecal microbiota transplantation (FMT) is effective after 3 months in improving abdominal symptoms, fatigue and quality of life in patients suffering from irritable bowel syndrome (IBS). In this new study, the researchers wanted to extend the follow-up of their cohort to one year in order to evaluate long-term effects.

Benefits persist at 1 year 

77 of the 91 IBS patients who had responded to FMT in the previous study (≥ 50-point decrease in IBS symptom severity score) were the subject of a follow-up for 1 year after FMT. Of these patients, 31 had received a 30g stool graft and 40 a 60g stool graft from a single “superdonor".

A total of 86.5% in the 30g group and 87.5% in the 60g group had maintained their response to FMT one year after treatment. In addition, at 1 year, abdominal symptoms and fatigue were significantly less severe and quality of life significantly better than at 3 months. Furthermore, 32.4% of patients in the 30g group and 45% in the 60g group had achieved complete remission at 1 year, compared to 21.6% and 27.5%, respectively, at 3 months (p = 0.1 and p = 0.4, respectively). All relapsed patients (n = 10) regularly used medication. There was no difference in response rate or symptom improvement between men and women, or between the various IBS subtypes.

Improved gut bacterial diversity

In the previous study, the dysbiosis index (DI) had not improved at 1 month after FMT, whereas it had improved at 1 year in this study, indicating an increase in bacterial diversity. In both the 30g group and the 60g group, the levels of several bacteria were significantly higher at 1 year after FMT. The presence of Bacteroides stercoris, Alistipes spp. and Bacteroides spp. & Prevotella spp. was inversely correlated with IBS severity and patient fatigue for both groups, while the same inverse correlation was seen for Parabacteroides spp. in the 60g group. No bacterial markers were significantly changed in the group of patients who had clinically relapsed at 1 year after FMT. In addition, fecal levels of certain short-chain fatty acids were also altered (increase in isobutyric and isovaleric acids, decrease in acetic acid) in both complete remission and responder patients, suggesting that their microbial metabolism had shifted from a saccharolytic to a proteolytic fermentation pattern at 1 year after FMT. 

Apart from mild intermittent abdominal pain, diarrhea and constipation during the first two days after FMT, no adverse events were reported during the follow-up period. As in the first study, FMT again confirms its potential. It holds great promise for the long-term treatment of IBS symptoms and for the restoration of the gut microbiota.

Neurodevelopmental disorders (NDD) such as autism or attention deficit hyperactivity disorder (ADHD) may be caused by disturbances in the first months of life when the central nervous system (brain, nerves, spinal cord, etc.) is under development. Their origin is still poorly understood, but many genetic and environmental factors are thought to be involved. Might antibiotics be among them? 

Gut-brain axis suspected

According to a team of scientists in the US, a number of indications suggest this may be the case. The incidence of NDD has been rising sharply over the last few decades, with exposure to antibiotics only widespread since 1945. In the US, an average child receives nearly 3 courses of antibiotics before the age of 2, a critical period for neurodevelopment.

We also know that the gut acts as our “second brain” thanks to a biochemical “axis” of communication between the two organs. Recent research suggests that antibiotics taken during childhood disrupt the developing gut microbiota.² At the same time, a link has been found between dysbiosis and various diseases, including neurological and psychiatric disorders.²

The researchers therefore administered very low doses of penicillin to newborn mice for three weeks. By comparing their microbiota to that of untreated mice, they found an alteration in their gut flora, notably a decrease in “good” bacteria, lactobacilli. Furthermore, they identified different activity between the two groups in 74 frontal cortex genes and 23 amygdala genes. These two parts of the brain are highly involved in emotional and cognitive functions and are also vulnerable to early disturbances. The researchers were also able to discover a link between certain microorganisms in the microbiota and genetic expressions in these brain areas.

Role and impact of antibiotics on childhood neurodevelopment not yet explored 

Therefore, in mice, antibiotics taken very early in life may, even at low doses, affect the activity of certain genes in brain areas (frontal cortex and amygdala) that are involved in NDD in humans. But the scientists remain cautious: they have not determined with certainty whether these changes in gene expression are directly caused by the antibiotics or by their effects on the microbiota. It also remains to be shown that these changes are significant for neurodevelopment. Moreover, results obtained in mice are not necessarily translatable to humans. They rather open new paths of research.