What do we already know about this subject?

Clinical, biological and/or endoscopic scores such as the PUCAI (pediatric ulcerative colitis activity index), are used to classify the severity of pediatric UC. Disease severity can be scored as mild (PUCAI 10-30), moderate to severe (35-60) or severe/fulminant (≥ 65). 5-aminosalycilates may be effective in mild forms, while corticosteroids are used in moderate disease, although some children will become steroid-dependent or refractory and require escalation of therapy to immunomodulators or anti-TNFα.

However, there is no prospective study evaluating the response to standardized therapy in newly diagnosed UC.

What are the main insights from this study? 

Between 2012 and 2015, 467 children aged 4 to 17 years were recruited into this prospective multicenter study conducted in 29 sites in the United States and Canada (Figure 1). The primary outcome was week 52 remission, defined by a PUCAI score < 10, with no therapy other than mesalazine (no corticosteroids and no colectomy). Baseline severity was defined as mild (therapy with mesalazine or oral corticosteroids with PUCAI < 45), or moderate to severe (oral corticosteroids with PUCAI ≥ 45 or intravenous corticosteroids). In addition to the usual clinical and biological parameters, this study also assessed gene expression from rectal biopsies as well as the rectal and fecal microbiota before treatment. 428 children started therapy: mean age was 12.7 years, 50% female, 42% with mild disease (mean PUCAI 31.9 ± 12.1 SD) and 58% with moderate to severe disease (mean PUCAI 62.9 ± 13.2 SD). At week 52, 150 (38%) of 400 evaluable participants achieved corticosteroid-free remission, of whom 80 (49%) had mild disease and 70 (30%) had moderate to severe disease (Table 1).

The clinical, biological, and endoscopic parameters that were associated with corticosteroid- free remission were validated in an independent prospective cohort of 307 children. It should be noted that corticosteroid- free remission was achieved by week 16 for moderate to severe disease (after which it can no longer be achieved) whereas it could be obtained up to week 52 in mild forms. Moreover, even patients with very severe disease were able to achieve week 52 corticosteroid-free remission (41/133 [31%] with PUCAI ≥ 65) and, conversely, some patients with mild disease were receiving anti-TNFα at week 52 (13/90 [14%] with PUCAI < 35). The authors identified 33 genes that were differently expressed between patients with moderate to severe disease who achieved corticosteroid-free remission (n = 51) or not (n = 101). Among these genes, 18 genes associated with cellular transport and ion channels were up-regulated and 15 genes involved in the antimicrobial response were down-regulated (Figure 2). The antimicrobial α-defensin signaling pathway showed the strongest negative correlation with week 52 corticosteroid-free remission. However, all 33 genes were negatively associated with the need for therapeutic escalation to anti-TNFα.

What are the consequences in practice? 

It is important to keep in mind the predictors of corticosteroid-free remission and therapeutic escalation as determined from multivariate analyses.

Predictors of week 52 corticosteroid-free remission were:

• PUCAI < 45, Hb ≥ 10 g/dL;
• remission by 4 weeks;
• low expression of antimicrobial genes;
• increased relative abundance for Ruminococcaceae and decreased for Sutterella.

Predictors of escalation to anti-TNFα therapy were:

• total Mayo score ≥ 11;
• eosinophil count in rectal biopsies < 32 per field at high magnification;
• 25OH vitamin D < 20 ng/mL; - Hb < 10 g/dL;
• no remission by 4 weeks;
• decrease in genes involved in transport and antimicrobial genes;
• decreased relative abundance of Oscillospira.

Historically, the lungs of healthy individuals were considered sterile; the description of the LRT microbiota (Lower Respiratory Tract, from larynx to alveoli of the lungs)¹ is a recent achievement.^2,3 Along with viral and fungal communities, six bacterial phyla dominate a healthy lung microbiota: Firmicutes, Bacteroidetes, Fusobacteria, Proteobacteria, Acidobacteria, and Actinobacteria.^1,2,4

A loss of diversity in the lung microbiota

Microbial dysbiosis is observed in a range of respiratory disorders, including lung infection, asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF).^5,6 But only few studies have explored the direct effects of antibiotics on lung microbiota. Recent investigation has shown that azithromycin treatment decreased bacterial diversity in patients with persistent uncontrolled asthma;¹ however clinical benefits are still controversial.^1,7,8 In COPD patients, azithromycin treatment lowered alpha diversity;¹ in those suffering from CF, antibiotics appear to be the primary drivers of decreased airway microbiota diversity.⁵

The plague of broad-spectrum antibiotics

While the misuse of antibiotics is known to lead to the emergence and selection of resistant bacteria, antibiotic prophylaxis, without a microbial diagnosis, is still widely used to treat lung infections.⁴ Of the 12 antibiotic-resistant ‘priority pathogens’ listed by the WHO, 4 affect lungs: Pseudomonas aeruginosa, Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus aureus.^4,9 There is agreement among the scientific community as a key route to minimize antimicrobial resistance that the disease management of lung infections needs to be improved.^4,10,11

What do we already know about this subject?

Parkinson’s disease is a debilitating neurological condition affecting more than 1% of the global population aged 60 and above. The primary medication used to treat Parkinson’s disease is levodopa (L-dopa). [2] To be effective, L-dopa must enter the brain and be converted to the neurotransmitter dopamine by the human enzyme aromatic amino acid decarboxylase (AADC). However, the gastrointestinal tract is also a major site for L-dopa decarboxylation, and this metabolism is problematic because dopamine generated in the periphery cannot cross the blood-brain barrier and causes unwanted side effects. Thus, L-dopa is co-administered with drugs that block peripheral metabolism, including the AADC inhibitor carbidopa. Even with these drugs, up to 56% of L-dopa fails to reach the brain. Moreover, the efficacy and side effects of L-dopa treatment are extremely heterogeneous across Parkinson’s patients, and this variability cannot be completely explained by differences in host metabolism. Previous studies in humans and animal models have demonstrated that the gut microbiota can metabolize L-dopa.[3] The major proposed pathway involves an initial decarboxylation of L-dopa to dopamine, followed by conversion of dopamine to m-tyramine by a dehydroxylation reaction.

Although these metabolic activities were shown to occur in complex gut microbiota samples, the specific organisms, genes, and enzymes responsible were unknown. The effects of host-targeted inhibitors such as carbidopa on gut microbial L-dopa metabolism were also unclear. As a first step toward understanding the gut microbiota’s effect on Parkinson’s disease therapy, the authors sought to elucidate the molecular basis for gut microbial L-dopa and dopamine metabolism.

What are the main insights from this study? 

The authors hypothesized that L-dopa decarboxylation would require a pyridoxal phosphate (PLP)-dependent enzyme. They searched gut bacterial genomes and identified a conserved tyrosine decarboxylase (TyrDC) in Enterococcus faecalis (Figure 1A). Genetic and biochemical experiments revealed that TyrDC simultaneously decarboxylates both L-dopa and its preferred substrate, tyrosine. Next, they used enrichment culturing to isolate a dopamine- dehydroxylating strain of Eggerthella lenta (Figure 1A). Transcriptomics analysis showed that the enzyme responsible for this activity is a molybdenum cofactor-dependent dopamine dehydroxylase (Dadh). Unexpectedly, the presence of this enzyme in gut bacterial genomes did not correlate with dopamine metabolism. Instead, it is a single-nucleotide polymorphism (SNP) in the dadh gene that predicts activity. L-dopa metabolism through this pathway was variable across subjects (Figure 1B). In gut microbiotas from Parkinson’s patients, the abundance of E. faecalis, TyrDC, and the SNPs of dadh correlated with L-dopa and dopamine metabolism, confirming their relevance. The authors then showed that the human AADC inhibitor carbidopa had only a minimal effect on L-dopa decarboxylation by E. faecalis, and was completely ineffective in complex gut microbiotas from patients, suggesting that this drug likely does not prevent microbial L-dopa metabolism in vivo. Given TyrDC’s preference for tyrosine, the authors examined tyrosine “mimics” and identified (S)-α-fluoromethyltyrosine (AFMT) as a selective inhibitor of gut bacterial L-dopa decarboxylation. Co-administering AFMT with L-dopa and carbidopa to mice colonized with E. faecalis increased the serum concentration of L-dopa.

What are the consequences in practice?

These findings show that the gut microbiota can metabolize L-dopa and thereby influence the effectiveness and side effects of this drug. This study paves the way towards the discovery of predictive biomarkers for L-dopa efficacy and toxicity. Furthermore, since the underlying molecular mechanisms are known, the use of specific inhibitors of gut microbial L-dopa metabolism may be possible in patients whose microbiota contains bacteria with deleterious activities.

What is commonly referred to as the “ears, nose and throat (ENT) microbiota” is in fact comprised not of one but rather of several microbiota. Antibiotics are likely to act individually on these different microbiota, ranging over the oral cavity through to the pharynx, including inside the sinuses and even the middle ear. This chapter is mainly devoted to the effects of antibiotics on the Upper Respiratory Tract (URT) microbiota, which is an excellent textbook case: the URT microbiota appears to be one of the safeguards of auricular health, yet it is threatened by antibiotics prescribed for this purpose, notably in cases of acute otitis media.

The URT microbiota, an ally of aricular health?

The URT microbiota is colonized directly after birth by a variety of commensals (Dolosigranulum Corynebacterium, Staphylococcus, Moraxella, Streptococcus). Mounting evidence suggests that a higher relative abundance of commensal species (Dolosigranulum spp. and Corynebacterium spp.) as well as a greater diversity in the nasopharyngeal microbiota¹ are associated with a lower incidence of URT colonization by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis,^2,3 three otopathogens implicated in acute otitis media (AOM) .

Antibiotic treatment: much risk for little benefit

Exposure to antibiotics impacts the URT microbiota by decreasing the abundance of protective species and by increasing the abundance of Gram-negative bacteria (Burkholderia spp., Enterobacteriaceae, Comamonadaceae, Bradyrhizobiaceae),^4,5 as well as S. pneumoniae, H. influenzae and M. catarrhalis.⁵ As a result of acquiring antimicrobial resistance, these bacteria, which could not otherwise successfully compete in this niche, are given the opportunity to multiply during treatment to an extent that they may become pathogenic.⁶ Furthermore, antibiotics are considered unlikely to confer any benefit in most cases of pediatric AOM (the primary reason for prescribing antibiotics to children⁷) and other URT infections (sore throats or common colds),^7,8 due to the frequently non-bacterial nature of these conditions: from 60% to 90% of children with a AOM recover without antibiotics.^9,10 Finally, antibiotics lead to gut microbiota dysbiosis that can translate into side effects such as antibiotic-associated diarrhea^3,11 (see gut microbiota section).

Long regarded mainly as a source of infection, the human skin microbiota is nowadays commonly accepted as an important driver of health and wellbeing.¹ By promoting immune responses and defense, it plays a key role in tissue repair and barrier functions by inhibiting colonization or infection by opportunistic pathogens.²

To each skin site, its own microbiota

The skin microbiota harbors millions of bacteria, as well as fungi and viruses in lower relative abundances. Corynebacterium, Cutibacterium (formerly known as Propionibacterium), Staphylococcus, Micrococcus, Actinomyces, Streptococcus and Prevotella are the most common genera of bacteria encountered on the human skin.³ However, the relative abundance of bacterial taxa greatly depends on the local microenvironment of the particular piece of skin being considered, and especially on its physiological characteristics, i.e., whether it is sebaceous, moist or dry. Hence lipophilic Cutibacterium species dominate sebaceous sites while Staphylococcus and Corynebacterium species are particularly abundant in moist areas.⁴

From physiology to pathology, the ambivalent role of C. acnes

The aerotolerant anaerobe C. acnes is one of the most abundant bacterial species in the skin microbiota. It has been implicated in acne, a chronic inflammatory disorder of the skin with complex pathogenesis.⁵ In contrast with previous thinking, recent studies indicate that C. acnes hyperproliferation is not the only factor implicated in the development of acne.⁶ In fact, a loss of balance between the different C. acnes strains, together with a dysbiosis of the skin microbiota will trigger acne.⁶ Moreover, interactions between S. epidermidis and C. acnes are of critical importance in the regulation of skin homeostasis: S. epidermidis inhibits C. acnes growth and skin inflammation. In turn, C. acnes, by secreting propionic acid which participates, among other things, in maintaining the pilosebaceous follicle acidic pH, inhibits the development of S. epidermidis. Malassezia, the most abundant skin fungus is also thought to play a role in refractory acne by recruiting immune cells, though its involvement needs to be further explored.⁶

Acne treatment, an important source of antibiotic resistance

Despite being used routinely to treat acne, topical and oral antibiotics have proved to be problematic in several ways. A first concern expressed by experts is the disruption to the skin microbiota, although precise data on the subject remain scarce. In this vein, a recent longitudinal study compared the cheek microbiota of 20 acne patients before and after six weeks of oral doxycycline therapy. Interestingly, antibiotic exposure was associated with an increase in bacterial diversity; according to the authors, this could be due to a diminished colonization by C. acnes, which would liberate space to allow the growth of other bacteria.⁷

However, the most significant concern over the use of antibiotics for acne treatment relates to bacterial resistance. First observed in the 1970s, it has been a major worry in dermatology since the 1980s.⁸ C. acnes resistance is by far the most documented: the latest data point to resistance rates reaching over 50% for erythromycin in some countries, 82-100% for azithromycin and 90% for clindamycin. As for tetracyclines, although still largely effective against the majority of C. acnes strains, their resistance rates are rising, ranging from 2% to 30% in different geographic regions.⁹ And antibiotic resistance is not limited to C. acnes: while topical antibiotics used by acne patients (especially as monotherapy) have been shown to increase the emergence of resistant skin bacteria such as S. epidermidis, oral antibiotics have been associated with the increased emergence of antibiotic-resistant oropharyngeal S. pyogenes.^8,10 In addition, increased rates of upper respiratory tract infection and pharyngitis have been reported as being associated with the antibiotic treatment of acne.^11,12

A call for a limited use of antibiotics in acne

The potential consequences of antibiotic resistance triggered by acne treatment are numerous: failure of the acne treatment itself (see clinical case), infection by opportunistic pathogens (locally or systemically), and the dissemination of resistance among the population.⁸ Despite this, the levels of antibiotic prescriptions for acne remain high and for longer durations than recommended in the guidelines.¹³ Against this background of mounting concerns, experts are calling for a more limited use of antibiotics in the treatment of acne.¹³ In particular, a strategy has been proposed in this regard by the Global Alliance to Improve Outcomes in Acne (see box below).

Obesity, metabolic syndrome and diabetes 

We are witnesses of an obesity epidemic worldwide that no country has yet been able to reverse. The overall obesity prevalence has tripled in the US and many EU countries since the 1980s, becoming one of the greatest public health challenges of the 21st century. In fact, obesity shows high comorbidity rates, constituting a major risk factor for the development of multiple non-communicable diseases. Obesity-induced insulin resistance is considered a key causal factor of MetS, which often progress to pancreatic β cell failure that finally triggers T2DM onset.[1]

Metabolic inflammation: the path from obesity to chronic comorbidities

Currently, it is well-documented that the chronic inflammatory state associated with obesity and causally linked to metabolic complications affects the adipose tissue and other organs, including the brain, muscle, liver, pancreas and gut, which show different particularities.[1, 2] Specifically, the involvement of the intestinal immune system and the microbes that expand under the exposure to unhealthy diets have recently emerged as additional drivers of obesity-associated metabolic inflammation and could also represent therapeutic targets.[2, 3]

How is the intestinal microbiota involved? 

The involvement of the gut microbiota in obesity has been partly inferred from observational studies reporting dysbiosis in obese subjects compared to lean ones in cross-sectional assessments. Evidence of gut microbiota changes during dietary, medicinal or surgery interventions intended for weight loss and for improving metabolic complications allowed establishing similar relationships where obesity was associated with reductions in species diversity and increases in bacterial taxa like Proteobacteria (enterobacteria) and Bilophila wadsworthia. By contrast, healthy metabolic phenotypes were often associated with increases in the phyla Bacteroidetes or Bacteroidetes/ Firmicutes ratio or the genera Bacteroides, Prevotella, Akkermansia, Faecalibacterium or Christensenella.[4, 5] However, findings were not fully consistent across studies partly due to the heterogeneity of the studies and limitations of their designs. Further meta-analyses have indicated that the only biomarker that could be generalized for obesity was reduced bacterial species diversity.[6] It is also likely that all obese subjects cannot be categorized by the same dysbiotic pattern, particularly considering the high interindividual variability of the microbiota and complexity of the metabolic phenotypes (obesity with and without other complications). More recently, the gut microbiota alterations that precede the development of obesity have been identified as causally involved in the aetiology. Of note it is a recent longitudinal study showing that a reduced bacterial species diversity, linked to unhealthy dietary habits, provides a scenario favouring the overgrowth of Proteobacteria (enterobacteria), which precedes the development of overweight during a 4-year follow-up in children.[7]

More definitive proof of a causal role of the microbiota in defining the metabolic phenotype of the subject has been achieved through FMT, where the dysbiotic microbiota from diseased subjects was transferred to new animal recipients. Most of these experiments showed that FMT was sufficient to replicate the metabolic phenotype of the donor (lean or obese).[8]

Microbiota-mediated mechanisms of action 

Gut microbes influence energy metabolism through their capacity to increase the human ability to metabolize nutrients and extract calories from the diet as well as regulating the absorption of sugars and lipids and their deposition in peripheral tissues [8]. Gut microbes and their metabolic products are also involved in the regulation of the enteroendocrine system, for example, via the production of short-chain fatty acids, which induced the synthesis of intestinal hormones (e.g., GLP-1, PYY) that act via endocrine and neural routes regulating appetite, food intake and glucose metabolism [9]. Moreover, the gut microbiota is a major regulator of the gut barrier and the immune system, whose alterations are implicated in obesity-associated low grade inflammation and insulin resistance as detailed below and schematized in (Figure 1).[2,3]

Defective mucosal barrier function in obesity 

Unhealthy diets cause defects in the intestinal mucosal barrier affecting its penetrability and favouring the translocation of bacterial components, such as the bacterial lipopolysaccharide (LPS) and the peptidoglycan or even whole microorganisms, which may activate innate immunity in metabolically active organs. The defective intestinal mucosal barrier has been attributed to local inflammation caused by diets rich in saturated fat and the diet-induced dysbiosis as well as to associated disturbances in the mucus layer [10] and in antimicrobial peptides production by Paneth cells (Reg3γ, lysozyme 1) [11]. For example, increased LPS plasma levels (known as “metabolic endotoxemia”) was shown to cause obesity and metabolic dysfunction in animal models and to be associated with an elevated body mass index, HF feeding, postprandial inflammation and risk of T2DM in humans. This could be favoured by the overgrowth of Gramnegative bacteria like enterobacteria, which are a source of LPS under HF feeding. LPS could activate innate immunity in the gut and beyond and induce the recruitment of inflammatory immune cells in metabolic tissues, like macrophages. Diets rich in saturated fat may also promote the growth of other Gram negative bacteria like Bilophila wadsworthia, which generates hydrogen sulphide, a toxic metabolite for enterocytes leading to a leaky gut, inflammation and metabolic dysfunction.[12] Finally, HF diet (HFD) may also increase circulating peptidoglycans, likely through the diet-induced changes in the expression of the antimicrobial peptide lysozyme 1 that hydrolyse components of the bacterial cell-walls. Depending on the peptidoglycan type, these could act as Nod1 ligands of pro-inflammatory macrophages of the adipose tissue or liver causing insulin resistance, while opposite effects seem to occur in pancreas beta cells, possibly as a counterbalance mechanism.[13]

Dysregulation of intestinal immunocompetent cells in obesity

Similar to other metabolic organs, including the adipose tissue and liver, breakdown of immune homeostasis has been observed in the intestine during obesity. In diet-induced obesity diverse subsets of innate and adaptive immune cells within the gut adopt a pro-inflammatory phenotype, primarily demonstrated by increases in proinflammatory macrophages and cytokines (IFNγ).

In parallel, there are reductions in proportions of Treg cells and type 3 ILCs producing IL-22, which help to maintain mucosal integrity and intestinal homeostasis in lean subjects.[2,3] Some of these alterations are reversed through microbiota depletion (e.g., antibiotic treatment) or the administration of, for example, specific bifidobacteria that also restore diet-induced intestinal dysbiosis in obesity, supporting a causal role of the gut microbiota in metabolic inflammation.[3] Also, intestinal IgA+ immune cells act as mucosal mediators of whole-body glucose regulation in HFD-induced obesity. The HFD reduces the number of IgA+ immune cells and secretory IgA.

The reduction of IgA could add another level of destabilization in the bacterial community to that caused by HFD, linked to increases in gut permeability and adipose tissue inflammation.[14]

How microbiota modulation could impact the disease evolution 

FMT

A clinical trial showed that insulin sensitivity could be improved in humans with MetS 6 weeks after being transplanted with gut microbiota from a lean healthy donor.[5] An increase in microbial diversity and abundance of bacteria producing butyrate was also observed. Another trial conducted in subjects with indexes of MetS receiving the microbiota of responders to bariatric surgery reported changes in the expression of dopamine receptors, which could account for a better control of food intake, but did not confirm effects on insulin resistance. Many other trials to evaluate the effects of FMT on obesity have been registered, but the outcomes have not been published yet.[5] Therefore, scientific evidence supporting the use of this strategy to tackle obesity complications is still very limited.

Dietary fibres

Consumption of diets with fibre intake above current recommendations (25 g/day for adults) improves weight maintenance and reduces the risk of coronary heart disease and T2DM, according to a large body of evidence from humans. Some of the effects of dietary fibre are due to its physicochemical properties (e.g., indigestibility, viscosity, etc.), which contribute to reducing the glycemic responses and the energy intake, and improving the blood lipid profile. Other effects could be mediated by their impact on the subject’s gut microbiota, which ferments fibres generating metabolites such short chain fatty acids (SCFAs: butyrate, propionate, etc.) with an active role in the host’s metabolism. SCFAs induce the production of enteroendocrine peptides (GLP-1, GLP-2, PYY) that strengthen the gut barrier, induce satiety, improve glucose metabolism and exert anti-inflammatory effects in obesity. Fibre intake also increases gut microbiota diversity which is associated with a healthy metabolic phenotype. Also, beneficial effects of fibres depend not only on the type and amount of fibre, but also on the person’s microbiota structure, its diversity and the presence or absence of specific bacterial species involved in their utilization.[15] Altogether this points to the need of progressing towards more personalized dietary recommendations.[15]

Beneficial bacteria

The first and second generation of probiotics: The majority of clinical efficacy trials have been conducted with bacterial strains traditionally used as probiotics for humans, “the first generation of probiotics”, which essentially include Lactobacillus and Bifidobacterium. Table 1 summarizes some examples, although much more can be found in literature, with positive and negative outcomes. A few attempts have also been made to isolate new bacterial species of the human indigenous microbiota, consistently associated with a healthy metabolic phenotype, with a view to create a “second generation of probiotics”. These may help us to enlarge our potential to replenish the gut microbiota with missing microbes. Table 2 summarizes some of the studies conducted in animal models (preclinical trials) and the only one conducted in humans so far.

Historically, until recent scientific work, urine was regarded as sterile. Compared to other microbiota, this ecosystem has low biomass.¹ While a consensus regarding the precise composition has yet to be reached, around 100 species have been identified from 4 principal phyla (Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes).² And though the role of the urinary microbiota is currently a matter of debate, it is well understood that diminished diversity seems to be a risk factor for urinary tract infections.

Yet, the vaginal microbiota gains on the other hand from having low diversity and being largely dominated by lactobacilli.³ Despite considerable variability among women, 5 community state types (CST) have been described in the vaginal flora: 4 dominated by one or several species of the Lactobacillus genus (L. crispatus, L. gasseri, L. iners or L. jensenii) and one polymicrobial.⁴ In both cases, dysbiosis following antibiotic treatment may increase the risk of infection.⁵

A spectrum of fungus at each antibiotic treatment 

This is what many women being treated with antibiotics dread: developing post-antibiotic vulvovaginal candidiasis. This anxiety is more than justified: antibacterial therapy, whether systemic or applied locally to the vagina, is thought to be one of the main factors leading to vulvovaginal candidiasis.⁵ This infection may be associated with vaginal microbiota disruption together with Candida yeast proliferation (C. albicans in the majority of cases ; Figure 3). The most common clinical signs of this infection are vulvar pruritus, a burning sensation accompanied by vaginal pain or irritation that may lead to dyspareunia or dysuria.⁶

FIGURE 3. Yeast proliferation induced by antibiotics exposure

The vicious circle of bacterial vaginosis

Though the etiology of bacterial vaginosis (BV), the main form of vaginal infection, remains unclear, it is believed that antibiotic-induced dysbiosis could be partly responsible for its development: dominant lactobacilli are supplanted by polymicrobial flora derived from numerous bacterial genera (Gardnerella, Atopobium, Prevotella, etc.). A vicious circle could be initiated: though antibiotics can be used to treat BV, they are also, alongside sexual history, vaginal douching, contraceptive use, age, stage in the menstrual cycle, tobacco use, etc., among the numerous risk factors associated with this type of infection.⁷

Urinary microbiota: a textbook case of antibiotic resistance 

Urinary tract infections (UTI) affect millions of men (a 3% annual incidence rate in the US) and women (10%) every year.⁸ Recurrent UTIs contribute greatly to this incidence: notwithstanding their receiving appropriate antibiotic therapy, more than 30% of women will experience a subsequent infection within the following 12 months.⁸ UTIs are becoming increasingly difficult to treat because of the rapid spread of drug resistance among Gram-Negative organisms, notably UPEC (uropathogenic Escherichia coli) which cause approximately 80% of UTIs.⁸

Paradoxically, broadspectrum antibiotics used to treat both community acquired and hospital-associated UTIs have become a risk factor for their occurrence.⁸ Mechanisms involving both gut and vaginal microbiota are suspected: in the gut, the ultimate reservoir for UPEC, antibiotic exposure increases inflammation and promotes the proliferation of E. coli; in the vagina, they diminish colonization by Lactobacillus species that suppress vaginal UPEC invasion and subsequent bacterial ascension from the vagina into the urinary tract. This is the reason why, experts nowadays recommend that they should be used with caution and that microbiota-sparing treatments should be developed.⁸

Antibiotics are a powerful tool in the fight against bacterial infections. However, research has also documented detrimental effects on the trillions of commensal bacteria that live in the intestinal tract. This resultant dysbiosis renders the gut microbiota less able to fulfil its protective functions. In the short term, dysbiosis leaves the door open for opportunistic pathogens and the selection of multi-resistant bacteria. In the long term, the gut microbiota, despite having a certain degree of resilience, can sometimes fail to fully restore itself;^1,2 this is understood to pave the wave to a range of diseases. Recent research has shown that antibiotics may alter the bacterial diversity and abundance of the normal microbiome and that this impact may be prolonged (typically 8-12 weeks after antibiotics have been discontinued).^3,4

Diarrhea, the most common adverse effect of antibiotics

As the main short-term consequence, some patients treated with antibiotics experience a change in their intestinal transit, most often resulting in diarrhea. The incidence of antibiotic-associated diarrhea (AAD) depends on several factors (age, setting, type of antibiotic, etc.) and may range between 5 and 35% of patients taking antibiotics.^3,5,6

Among children this percentage can reach up to 80%.³ Most of the time, the diarrhea is purely functional, caused by the antibioticinduced dysbiosis. It is usually of mild intensity and is self-limiting, lasting 1-5 days. Antibiotics displaying a broader spectrum of antimicrobial activity like clindamycin, cephalosporins, and ampicillin/amoxicillin are associated with higher rates of diarrhea.⁶

The particular case of C. difficile 

In 10 to 20% of cases, diarrhea results from infection with Clostridioides difficile (formerly known as Clostridium difficile) colonizing the microbiota.⁶ This bacterium, which persists in the environment via spores, is a gram-positive, spore-forming, obligate anaerobe. Infection occurs via spores ingestion. Under specific circumstances (e.g., antibiotic-induced dysbiosis), the spores may germinate and vegetative bacterial cells of this opportunistic pathogen may colonize the intestines. In the infective phase, C. difficile produces 2 toxins that damage the colonocytes and trigger an inflammatory response with a variety of clinical outlooks, ranging from moderate diarrhea to pseudomembranous colitis, toxic megacolon and/or death.

FIGURE 2. Downstream effects of antibiotic-induced gut dysbiosis. (source : adapted from Queen et al., 2020¹⁰)

Most recognized common risk factors for C. difficile infection (CDI) include age > 65 years, use of proton pump inhibitors, comorbidities and of course antibiotic use. The latest is the most relevant modifiable risk factor for CDI. The association of antibiotics with CDI has been established in hospitals and more recently in community settings,⁷ where the risk of infection varies from intermediate for people exposed to penicillins, high for these exposed to fluoroquinolones and highest for those receiving clindamycin. As for tetracyclines, they trigger no increased risk.⁸ In a hospital setting, the highest risk of developing CDI was observed for cephalosporins (from 2nd to 4th generations), clindamycin, carbapenems, trimethoprim sulfonamide, fluoroquinolones and penicillin combinations.⁹

When the gut microbiota becomes a reservoir of antibiotic resistance 

When exposed to antibiotics, microbial communities respond in the short term not only by changing their composition, but also by evolving, optimizing and disseminating antibiotic resistant genes. The human gut microbiota overly exposed to antibiotics is now considered a significant reservoir of resistance genes, in adults as well as in children.² By contributing to the growing difficulty to combat bacterial infections, antibiotic resistance has become a major public health concern.

Gut microbiome fermentation determines the efficacy of exercise for diabetes prevention

^{Liu Y, Wang Y, Ni Y, et al. Gut microbiome fermentation determines the efficacy of exercise for diabetes prevention. Cell Metabolism. 2020 Jan 7;31(1):77-91.e5.} 

The impact of exercise on gut microbiota was examined in prediabetic men. Exercise responders had a decrease in fasting insulin and insulin resistance (HOMA-IR), whereas in non-responders they remained unchanged or even deteriorated. Exercise caused increased abundance of Firmicutes, Bacteroides, and Proteobacteria. Alterations of the gut microbiota correlated with the reduction of HOMA-IR. DNA synthesis, amino acid (AA) metabolism, and short chain fatty acid (SCFA) synthesis enhanced in responders. In non-responders, AA fermentation was shifted to production of colonic gases and detrimental compounds, which associate with increased insulin resistance. Increased serum short chain fatty acids, but decreased branched chain amino (BCAA) and aromatic amino acids were detected only in responders. SCFAs have a beneficial role in energy and glucose metabolism, whereas increased BCAAs associate with insulin resistance.

In conclusion, exercise responders’ gut microbiome had enhanced capacity to produce short chain fatty acids but increased breakdown of BCAAs, whereas the microbiome of non-responders produced metabolically detrimental compounds.

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

^{Duan Y, Llorente C, Lang S, et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature. 2019 Nov;575(7783):505-511.}

Alcoholic hepatitis (AH) patients have increased fecal Enterococcus faecalis (EF), 80% of AH patients are positive for EF. Germ-free mice on ethanol diet were colonized with cytolysin-positive (CL) EF feces of AH patients. Those infected with CL + feces developed a more severe ethanol-induced liver damage. Mice having overgrowth of intestinal enterococci and on ethanol diet were given bacteriophages lysing CL + EF. They developed less severe liver damage. Thus phage therapy may attenuate ethanol-related liver disease caused by CL + EF and improve prognosis in severe AH

Microbe-host interplay in atopic dermatitis and psoriasis

^{Fyhrqvist N, Muihead G, Prat-Nielsen S, et al. Microbe-host interplay in atopic dermatitis and psoriasis. Nat Commun. 2019 Oct 16;10(1):4703.} 

The authors compared atopic dermatitis (AD) and psoriasis (PSO) microbiota with that of healthy volunteers. The authors detected 26 and 24 microbes typical for AD and PSO, respectively. The most discriminative taxa for AD were genus Staphylococcus, and most discriminating microbes for PSO were Corynebacterium simulans, Neisseriaceae g. spp., C. kroppenstedtii, Lactobacillus spp. and L. iners.

AD is characterized by S. aureus abundance. In PSO, many different bacteria such as Corynebacterium may be involved. The depletion of Lactobacillus is typical for both diseases. In AD, loss of strictly anaerobic bacteria is typical with diminished production of lactic and short chain fatty acids leading to increased skin pH. Microbe-host interactions are important both in skin homeostasis and disease pathogenesis.

Staphylococcus epidermidis: a potential new player in the physiopathology of acne?

^{Claudel JP, Affret N, Leccia MT, et al. Staphylococcus epidermidis: a potential new player in the physiopathology of acne? Dermatology; 2019;235(4):287-294.} 

The interplay between skin and cutaneous microbiota is essential to differentiate between commensal and pathogenic bacteria. During puberty, over-colonization of skin pilosebaceous units (PU) by Cutibacterium acnes (CUA) may cause acne. Some strains of S. epidermidis modulate host innate immune reactions, and some isolates have antimicrobial activity against CUA. Conversely, some CUA strains have antimicrobial activity against S. epidermidis which may also control CUA via succinic acid. The use of topical antibiotics may result in the development of antibiotic-resistant strains of CUA and S. epidermidis. Eliminating only CUA may lead to proliferation of S. aureus and S. epidermidis increasing the risk of infections. Lactobacillus may be efficient in acne and other inflammatory skin diseases. The authors suggest that regular oral or topical supplementation of skin microbiota could be treatment option in acne.