What doesn’t kill you makes you stronger. The immune system applies this saying to the letter. Its adaptive responses to pathogens allow for a swifter and more robust defense against subsequent infections. What if the same were true of the gut microbiota? Could initial infections allow it to develop an optimal antimicrobial function, thus increasing resistance to host colonization? So suggest the researchers in this study.

Metaorganism memory

The experiments in question involved the bacterium Klebsiella pneumoniae (Kpn). In orally infected mice, the bacterium is detected transiently in the lumen of the colon and then disappears from the feces. The only exception is when the mice have received a broad-spectrum antibiotic (streptomycin) beforehand, in which case their fecal Kpn load remains high. Colonization of the host by this pathogen thus seems to be regulated by the microbiota. With this point confirmed, a long series of experiments allowed the researchers to progressively elucidate the mechanisms by which a transient infection leads to what they call a long-term “metaorganism memory”. The latter is based on the interdependent and combined functions of the host and its microbiota.

Bile acids involved

Following infection, the host’s liver sees increased production of bile acids. Microbial groups in the gut microbiota that are capable of using these acids (particularly taurine) via anaerobic respiration multiply as a result. They convert taurine into sulfide, an inhibitor of aerobic cell respiration. Many pathogens depend on aerobic respiration to survive. Without it, they die, limiting host colonization. On the other hand, sequestering sulfide favors invasion by pathogens. Interestingly, the intake of exogenous taurine has the same effects as an infection: multiplication of bacteria capable of metabolizing it, reinforcement of resistance to colonization, etc.

Resistance to colonization: questions and hopes

However, many questions remain. For example, what signals trigger increased bile acid synthesis following infection? Does the host immune system work alongside the microbiota to promote resistance to colonization following infection? In any case, with antibiotic resistance worryingly on the increase, using bacterial metabolites to fight infection–rather than bacteria themselves–provides a reassuring alternative. Moreover, this strategy has another clear advantage: therapies based on bacteria (such as fecal transplant) face the problem of inter-individual heterogeneity, whereas more “universal” microbial metabolites should respond to much broader targets.

Loss of smell (anosmia) and taste (ageusia): Covid-19 disturbs our senses. Almost half of symptomatic patients present such disorders¹, with strong variations according to ethnicity (e.g. the incidence in Caucasian populations is three times that of Asians)². Sensory changes are severe in those affected. In a multilingual survey of 4,039 Covid-19 cases worldwide, patients reported an average loss of 80% of their sense of smell and 70% of their sense of taste³.

Daily practice to recover sense of smell

Unfortunately, anosmia is not limited to the often transient cases related to Covid-19. Head trauma, nasal inflammation, allergies and even old age can lead to a loss of smell. The cause? A deterioration in the sensory cells that line the nasal cavities and are responsible for detecting odors. To counteract anosmia, Austrian researchers train their patients to smell and visualize various odors (lemon, rose, etc.) twice a day. The results are positive, with patients regaining their sense of smell after six months of training. Furthermore, MRI imaging shows that the brain areas dedicated to smell are partially restored.

Focus on the nasal microbiota

In addition to this training, the researchers also sought to determine the influence of the microorganisms living in the nasal cavity. They were on the right scent, since they observed a higher diversity of bacteria in the noses of patients with a reduced sense of smell. One bacterium in particular is suspected of altering olfactory performance. Encouraged by these results, the team is taking a close look at whether patient training also modifies the balance of the nasal microbiota. The results are not yet known, but the study raises significant hopes of finding key microbes that are capable of restoring patients’ sense of smell and directing them towards the most appropriate treatment for the disorder.

Long considered a source of infection, today microorganisms are often classified as either “good” or “bad”. Is this black or white view appropriate?

Microbes are neither “good” nor “bad”; nor are they our “friends” or “enemies”. We can’t apply this humanized classification to them. Even the most harmless microbe can cause death if the immune system is weakened. However, it is well known that many microorganisms can benefit their host under certain circumstances, whereas others are generally pathogenic.

For example, Staphylococci are very abundant on human skin. Staphylococcus aureus has quite a bad reputation: it is often associated with wound infections and several skin disorders, it carries many virulence genes, and its multidrug-resistant form (methicillin-resistant S. aureus, or MRSA) is a major cause for concern in hospital environments. At the same time, numerous recent studies have shown that Staphylococcus epidermidis can stimulate the immune system and the skin’s defenses and even destroy S. aureus biofilms. On the other hand, S. epidermidis is a major cause of implant-related infections and can also become resistant to multiple antibiotics, whereas many people are colonized by S. aureus without experiencing any problems. Therefore, it’s not always a good idea to try to improve skin health by simply lowering the ratio of S. aureus to S. epidermidis on the skin. A good balance between the two should be sought.

Which microorganisms are involved in atopic dermatitis?

While microorganisms are probably not the main cause of the disease, they make a significant contribution to its pathology. Affected skin areas can be characterized by a microbial dysbiosis: an increased abundance of S. aureus and a reduced presence of typical skin bacteria such as Cutibacterium and Corynebacterium. S. aureus may benefit from a weakening of the skin barrier, possibly the result of altered antimicrobial peptide production in the skin and/or mutations in filaggrin genes¹, leading to dryness and cracking of the skin. Inflamed skin is usually treated with antibiotics, which risks causing severe damage to the beneficial part of the skin’s microbiota, as well as antibiotic resistance. Probiotic strategies which aim to increase/restore the abundance of coagulase-negative staphylococci (CoNS) are considered optional and/or complementary.

Can topical and/or oral probiotics prevent or cure skin diseases? What part can they play in therapeutic strategies, now and in the future?

The addition of live microorganisms (probiotics) can certainly benefit the host’s health, for example, by reducing the abundance of pathogens or stimulating the host’s defenses and immune system. Due to the existence of a gut-skin axis, oral probiotics can also have a positive impact on the skin.

However, for most (if not all) major skin diseases,the role of the skin microbiota remains unclear. Although such diseases see marked changes in the structure (community composition) and function (physiological properties) of the skin microbiota, it’s not usually clear whether these changes are the cause or effect of the underlying disease. This is the classic chicken and egg conundrum.

Therefore, in my opinion, it’s a little too early to hope that a simple probiotic cream or capsule can make a significant therapeutic contribution to the prevention or cure of serious skin diseases. Furthermore, research in the gut has shown that, compared to conventional chemical therapies, the effects of probiotics are rather mild and influenced by so many factors that it’s difficult to extrapolate them from highly standardized animal models to humans. Only robust clinical trials could show the effectiveness of probiotics. However, although it’s too early to give a definite opinion for the most serious diseases, to me probiotics seem to be an additional therapeutic option for managing less serious skin disorders and a valuable strategy for improving skincare products. Since it now seems clear that a balanced and diversified microbiota is a characteristic of healthy skin, it makes full sense to preserve and protect such a state, including with probiotic approaches, for example in the case of blemished, sensitive or irritable skin, etc.

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In numerous murine models, a Lactobacillus-enriched diet reduces skin sensitivity, rash, inflammation, dermatitis, etc., and improves skin phenotype (increased dermal thickness, enhanced folliculogenesis and increased sebocyte production).²³ These beneficial probiotic effects have been confirmed by several interventional studies in humans involving lactobacilli and/or bifidobacteria.²³ Managing skin diseases by modulating the gut microbiota will most likely involve probiotics (beneficial live bacteria), prebiotics (bacterial substrates) and symbiotics (combinations of pro- and prebiotics).²³

A lack of adverse effects makes oral probiotics of even greater interest for the management of skin diseases.¹⁴

For example, in atopic dermatitis, daily consumption of probiotics (Bifidobacterium) and prebiotics (galacto-oligosaccharides) improves skin hydration in healthy adult women.¹⁴ To take another example, oral Lactobacillus supplementation reduces skin sensitivity and strengthens the skin’s barrier function in adults²⁹ and children³⁰. Several clinical trials have shown probiotics to have a positive effect when taken alone or in a cocktail (lactobacilli, bifidobacteria and/or S. thermophilus), with a reduction in lesions and severity in the case of acne.^12,23 The positive effects of oral probiotics may be due to their ability to reduce systemic oxidative stress, regulate cytokines and reduce inflammatory markers.⁹ In the case of psoriasis, there are still few clinical data, but two studies in humans show beneficial effects: a reduction in inflammation markers with B. infantis; a reduction in the severity and appearance of lesions with B. longum, B. lactis and L. rhamnosus alongside a topical corticosteroid treatment.¹³ There were similar results for seborrheic dermatitis, with inflammation and symptoms relieved by oral L. paracasei.¹² Some probiotics may even protect against skin cancer.¹⁶ However, clinical trials are still required to identify the most effective formulation of probiotic strains, the optimal duration of supplementation and the patients most likely to benefit.¹⁴

The first clinical trials seem to support the use of topical applications to rebalance the skin microbiota. However, further trials are needed to confirm these results.

In general, there have been few clinical trials evaluating the topical application of probiotics in skin diseases.¹² For acne, creams containing S. epidermidis or bacteriophages of C. acnes that preferentially target pathogenic strains have shown positive results.¹² The application of R. mucosa in patients with atopic dermatitis may reduce lesion severity, the need to use topical steroids and the presence of S. aureus.^28,29 The limited availability of microbial candidates on the skin has forced researchers to also use other sources of microorganisms. Derived from thermal spring water, Vitreoscilla filiformis may be beneficial in seborrheic dermatitis: one study reported a reduction in erythema, desquamation and pruritus by soothing the inflammation.¹² 

In acne, Nitrosomonas eutropha decreases lesion severity¹², while the topical use of bacterial products (E. faecalis enterocins) reduces lesions by 60% compared to controls.¹² An alternative strategy corrects the dysbiosis by using sucrose to promote the growth of S. epidermidis over C. acnes.⁹ Scientific data are scant for skin cancer and non-existent for rosacea. In murine models of UV-related cancers, a molecule produced by S. epidermidis was shown to inhibit tumor proliferation.^12,16

As early as 1930, dermatologists John Stokes and Donald Pillsbury^25,26, suggested that emotional states such as anxiety or depression can alter the gut microbiota and induce local or systemic inflammation²⁷. They recommended the use of fermented milk to reintroduce beneficial microorganisms.

More precisely, stress leads to the secretion of neurotransmitters (serotonin, norepinephrine and acetylcholine). These neurotransmitters increase gut permeability, leading to local inflammation. At the same time, they also provoke systemic inflammation via the bloodstream.^11,23

For example, stress hormone cortisol is thought to alter the composition of the gut microbiota and blood levels of neuroendocrine molecules (tryptamine, trimethylamine and serotonin), ultimately affecting the skin barrier and skin inflammation.²⁵

Acne and atopic dermatitis 

This gut-brain-skin axis is implicated in certain skin diseases. For example, upregulation and strong expression of substance P (a neurotransmitter and neuromodulator of the central and peripheral nervous systems) are observed in both acne and gut dysbiosis. Substance P is known to trigger the expression of many pro-inflammatory mediators implicated in the development of acne (IL-1, IL-6, TNF-α, PPAR-γ).^22,23

The gut-brain-skin axis is also thought to be involved in atopic dermatitis.²⁵ An altered gut microbiota may modify the production of various neurotransmitters and neuromodulators, affecting the functioning of the skin barrier and immune system, two key parameters of the pathophysiology of atopic dermatitis.²⁵

Tryptophan produced by the gut microbiota is thought to cause skin itching, while lactobacilli and bifidobacteria may inhibit these sensations.²⁵ Moreover, some researchers ask whether the gut-brain-skin axis is a two-way axis: can the skin in turn act on the gut via the nervous system?²²

Skin ulcers or psoriasis in patients with inflammatory bowel disease (IBD), dermatitis and psoriasis in celiac patients, a gut dysbiosis and H. pylori infection in people with rosacea... There are many examples of associations between digestive and skin conditions.²²

Although the gut-skin axis is not fully understood, several explanations have been put forward.

The gut microbiota may influence the composition of the skin microbiota.²³ Short-chain fatty acids (SCFAs, e.g. acetate, propionate) produced by the gut microbiota via fiber fermentation in the gut may modify the predominance of certain microorganisms or microbial profiles in the skin. For example, gut bacterium Propionibacterium (see table) mainly produces acetate and propionate. Propionic acid has an antimicrobial effect against certain skin pathogens, particularly methicillin-resistant Staphylococcus aureus.²³ In contrast, commensal skin bacteria S. epidermidis and Cutibacterium acnes have been shown to tolerate wider shifts in SCFAs.²³

Children with atopic dermatitis also seem to suffer from a gut dysbiosis. A damaged gut barrier sees increased penetration by food antigens, bacterial toxins and pathogens.¹⁴ For example, gut bacteria, especially Clostridiales difficile, can produce free phenol and p-cresol, which can disturb the skin barrier and reduce keratin production.^14,22,23

A low level of vitamin D has been associated with atopic dermatitis and psoriasis. Vitamin D may be regulated by the gut microbiota and may participate in a signaling mechanism between microbiota and host.¹⁴

In the case of acne, microbial metabolites may regulate various skin functions (cell proliferation, lipid metabolism, etc.) via other metabolic pathways.¹⁴

A high glycemic load, typical of adolescent meals in developed countries, influences insulin metabolism, ultimately triggering sebaceous gland hyperproliferation, lipogenesis and hyperplasia of keratinocytes, thereby contributing to the development of acne.^14,23 This appears to be a two-way process, with the metabolic pathway in turn affecting the composition of the gut microbiota via the gut barrier. This may result in a vicious circle via a positive feedback cycle of inflammation.²³

The mechanisms by which the gut microbiota acts on the skin microbiota may also involve the modulating effect of gut microorganisms on systemic immunity.²² Some gut microbes and metabolites facilitate anti-inflammatory responses²⁴. For example, SCFAs are thought to exert local and remote anti-inflammatory effects, particularly on the skin.²² Conversely, other metabolites may participate in the inflammatory loop and the appearance of skin diseases. For example, filamentous bacteria may promote the accumulation of pro-inflammatory Th17 and Th1 cells.²³

In the case of rosacea, some authors suggest a link with Helicobacter pylori. This bacterium may exert pro-inflammatory effects via peptides.^11,22

Other mechanisms have been mentioned in psoriasis, involving a decrease in beneficial species such as Faecalibacterium prausnitzii¹³ or Akkermansia muciniphila, with the latter thought to strengthen the integrity of the gut epithelium and protect against inflammatory diseases.¹ Psoriasis patients whose blood contains bacterial DNA, have significantly higher levels of systemic inflammatory response markers, including IL-1β, IL-6, IL-12, tumor necrosis factor, and interferon γ.¹¹

Discomfort, irritation, diaper rash

Sensitive skin “tightens”, tingles or burns in response to stimuli that would not normally cause such sensations. It is seen both in people with normal skin and in those with a disruption of the skin barrier.¹⁹ A hyperreactive cutaneous nervous system, the skin barrier and the skin microbiota are thought to be involved.¹⁹ An alteration of the stratum corneum in sensitive subjects may contribute to penetration by chemical, environmental and microbial agents associated with increased skin sensitivity.¹⁹

Diaper rash only affects skin exposed to diaper friction, excessive hydration and a variable pH, and in constant contact with urine and feces. Candida albicans and Staphylococcus aureus are potentially involved.²⁰

Wound healing 

As a result of the physical tear of skin tissue, the wound healing process begins with inflammation that results from close cooperation between immune cells and bacteria involved in the process.²¹ Commensal bacteria such as Staphylococcus, Streptococcus, Pseudomonas and Corynebacterium have both positive and negative effects on wound healing. They stimulate the host immune system and reduce invasion by other pathogenic microorganisms, but this loss of microbial diversity is often accompanied by prolonged inflammation, which may slow wound healing.²¹

This close relationship between host and skin microbiota in wound healing processes could open the door to novel therapies, such as creams rich in antimicrobial peptides, biofilm-destroying probiotics or anti-inflammatory bacteria.^12,21

Body odor

Human body odors result from the metabolization by bacteria of sweat components (amino acids, fatty acids and glycerols), leading to the production of malodorous molecules, e.g. the “sulfurous” or “sour” odor of acetic acid produced by Staphylococcus spp. in children and adolescents, or the “sour” odor of thiols produced by Corynebacterium and Staphylococcus spp. in adults.⁷ The repeated use of deodorants and antiperspirants alters bacterial diversity in the armpit, favoring staphylococci over Corynebacterium, which may have counterproductive effects in adolescents.⁷

Although it remains difficult to define, a “healthy” skin microbiota is generally considered synonymous with a diversified flora and the presence of commensal bacteria.² This balanced microbiota is thought to help protect against infection, limiting colonization by pathogens. For example, C. acnes, which lives in the sebaceous glands, releases fatty acids from sebum, contributing to the acidity of the skin, which in turn inhibits the proliferation of pathogens.⁸

Other bacteria secrete bacteriocins and other antimicrobial factors. For example, S. epidermidis releases a protease that destroys S. aureus biofilms, while nasal bacterium, Staphylococcus lugdunensis, produces an antibiotic peptide that acts against many pathogens, including S. aureus, Enterococcus faecalis, Listeria monocytogenes, Streptococcus pneumoniae, and Pseudomonas aeruginosa.²

Lastly, Corynebacterium striatum modifies the transcriptional program of S. aureus, repressing virulence-related genes and stimulating those associated with commensalism. ^6,8 The skin microbiota thus maintains its balance not only by competitive exclusion but also via subtle interactions between microorganisms.⁶

The skin microbiota also plays a key role in the development and regulation of the innate and acquired immune systems.² It modulates the expression of innate immune factors (interleukin IL-1α, antimicrobial peptides, etc.) produced by keratinocytes and sebocytes⁶, and even produces some of these factors itself.

For example, S. epidermidis can, in different situations, either stimulate or reduce inflammation: it inhibits the release of inflammatory cytokines by keratinocytes and the immune responses of injured skin cells; it reinforces the skin’s defense mechanisms against infection by increasing the expression of genes that encode for antimicrobial peptides; and it modulates the expression of skin T cells.² S. epidermidis promotes tolerance towards the commensal microbiota, while adjusting immune responses to pathogens or those triggered during wound healing.⁸ Roseomonas mucosa, Malassezia spp. or Corynebacterium accolens can also modulate host and keratinocyte immune responses.⁸

Lastly, the genetic profile of bacteria also plays a role. Cutibacterium acnes strains from acne-prone skin have genes that encode for virulence factors, which could explain the higher pro-inflammatory activity observed. Conversely, strains from healthy skin, which do not have these factors, are thought to promote the production of anti-inflammatory cytokines.⁸