What's already known about this topic:-Microbes are integral components of the human ecosystem.-The cutaneous microbiota plays an important role in the regulation of skin homeostasis.-The composition of skin microbiota is influenced by many factors. What does this study add?-The dominance of P. acnes in the postadolescent sebum-rich skin regions and its role in acne pathogenesis may be explained by the disappearing microbiota hypothesis. Conflict of interest:The authors declare no conflict of interest. 2 AbstractFrom our birth, we are constantly exposed to bacteria, fungi and viruses, some of which are capable of transiently or permanently inhabiting our different body parts as our microbiota.The majority of our microbial interactions occur during and after birth, and several different factors, including age, sex, genetic constitution, environmental conditions and life style, have been suggested to shape the composition of this microbial community. Propionibacterium acnes (P. acnes) is one of the most dominant lipophilic microbes of the postadolescent, sebum-rich human skin regions. Currently, the role of this bacterium in the pathogenesis of the most common inflammatory skin disease acne vulgaris is a topic of intense scientific debate. Recent results suggest that Westernization strongly increases the dominance of the Propionibacterium genus in human skin compared to natural populations living more traditional lifestyles. According to the disappearing microbiota hypothesis proposed by Martin Blaser a few years ago, such alterations in the composition of our microbiota are the possible consequences of socioeconomic and lifestyle changes occurring after the industrial revolution.Evanescence of species that were important elements of the human ecosystem might lead to the overgrowth and subsequent dominance of others because of the lack of ecological competition. Such changes can disturb the fine-tuned balance of the human body and, accordingly, our microbes developed through a long co-evolutionary process. These processes might lead to the transformation of a seemingly harmless species into an opportunistic pathogen through bacterial dysbiosis. This might have happen in the case of P. acnes in acne pathogenesis.3

Human skin cells recognize the presence of the skin microbiome through pathogen recognition receptors. Epidermal keratinocytes are known to activate toll-like receptors (TLRs) 2 and 4 in response to the commensal Cutibacterium acnes (C. acnes, formerly known as Propionibacterium acnes) bacterium and subsequently to induce innate immune and inflammatory events. These events may lead to the appearance of macroscopic inflammatory acne lesions in puberty: comedos, papules and, pustules. Healthy skin does not exhibit inflammation or skin lesions, even in the continuous presence of the same microbes. As the molecular mechanism for this duality is still unclear, we aimed to identify factors and mechanisms that control the innate immune response to C. acnes in keratinocytes using a human immortalized keratinocyte cell line, HPV-KER, normal human keratinocytes (NHEK) and an organotypic skin model (OSM). TNIP1, a negative regulator of the NF-κB signaling pathway, was found to be expressed in HPV-KER cells, and its expression was rapidly induced in response to C. acnes treatment, which was confirmed in NHEK cells and OSMs. Expression changes were not dependent on the C. acnes strain. However, we found that the extent of expression was dependent on C. acnes dose. Bacterial-induced changes in TNIP1 expression were regulated by signaling pathways involving NF-κB, p38, MAPKK and JNK. Experimental modification of TNIP1 levels affected constitutive and C. acnes-induced NF-κB promoter activities and subsequent inflammatory cytokine and chemokine mRNA and protein levels. These results suggest an important role for this negative regulator in the control of bacterially induced TLR signaling pathways in keratinocytes. We showed that all-trans retinoic acid (ATRA) induced elevated TNIP1 expression in HPV-KER cells and also in OSMs, where TNIP1 levels increased throughout the epidermis. ATRA also reduced constitutive and bacterium-induced levels of TNFα, CCL5 and TLR2, while simultaneously increasing CXCL8 and TLR4 expression. Based on these findings, we propose that ATRA may exhibit dual effects in acne therapy by both affecting the expression of the negative regulator TNIP1 and attenuating TLR2-induced inflammation. Overall, TNIP1, as a possible regulator of C. acnes-induced innate immune and inflammatory events in keratinocytes, may play important roles in the maintenance of epidermal homeostasis.

Propionibacterium acnes is a dominant member of the cutaneous microbiota. Herein, we evaluate the effects of different P. acnes strains and propionic acid on autophagy in keratinocytes. Our results showed that P. acnes strain 889 altered the architecture of the mitochondrial network; elevated the levels of microtubule-associated protein 1 light chain 3B-II, Beclin-1, and phospho-5'-adenosine-monophosphate-activated protein kinase α; stimulated autophagic flux; facilitated intracellular redistribution of microtubule-associated protein 1 light chain 3B; increased average number of autophagosomes per cell; and enhanced development of acidic vesicular organelles in the HPV-KER cell line. Propionic acid increased the level of phospho-5'-adenosine-monophosphate-activated protein kinase α, enhanced lipidation of microtubule-associated protein 1 light chain 3B, stimulated autophagic flux, and facilitated translocation of microtubule-associated protein 1 light chain 3B into autophagosomes in HPV-KER cells. P. acnes strains 889 and 6609 and heat-killed strain 889 also stimulated autophagosome formation in primary keratinocytes to varying degrees. These results indicate that cell wall components and secreted propionic acid metabolite of P. acnes evoke mitochondrial damage successively, thereby triggering 5'-adenosine-monophosphate-activated protein kinase-associated activation of autophagy, which in turn facilitates the removal of dysfunctional mitochondria and promotes survival of keratinocytes. Thus, we suggest that low-level colonization of hair follicles with noninvasive P. acnes strains, by triggering a local increase in autophagic activity, might exert a profound effect on several physiological processes responsible for the maintenance of skin tissue homeostasis.

our skin provides a physical barrier to separate the internal part of our body from the environment. Maintenance of complex barrier functions is achieved through anatomical structures in the skin, the stratified squamous epithelium specialized junctional organelles, called tight junctions (TJs). Several members of our microbial communities are known to affect the differentiation state and function of the colonized organ. Whether and how interactions between skin cells and cutaneous microbes, including Cutibacterium acnes (C. acnes), modify the structure and/or function of our skin is currently only partly understood. Thus, in our studies, we investigated whether C. acnes may affect the epidermal barrier using in vitro model systems. Real-time cellular analysis showed that depending on the keratinocyte differentiation state, the applied C. acnes strains and their dose, the measured impedance values change, together with the expression of selected TJ proteins. These may reflect barrier alterations, which can be partially restored upon antibiotic-antimycotic treatment. Our findings suggest that C. acnes can actively modify the barrier properties of cultured keratinocytes, possibly through alteration of tight cell-to-cell contacts. Similar events may play important roles in our skin, in the maintenance of cutaneous homeostasis. One of the most important properties of our skin is the complex barrier it provides to separate the internal part of our body from the environment, limiting contact with harmful chemicals, microbes, allergens and radiation 1-3. The major building blocks of the skin barrier are the keratinocytes, which are capable of recognizing the everchanging environmental conditions and mounting appropriate responses to maintain the integrity of the human body 4,5. Maintenance of complex barrier functions is achieved through anatomical structures in the skin. The stratified squamous epithelium is the uppermost skin layer that contains live keratinocytes and contains specialized junctional organelles, called tight junctions (TJs), which are localized between the cells of the second and third layer of the stratum granulosum 6. TJs provide intimate links between adjacent cells and play major roles in establishing the epidermal barrier, as well as act as important determinants of transepidermal transport 7-9. The complex, multi-protein structure of TJs includes more than 40 proteins 10,11. Claudin (CLDN) protein family members are some of the most important TJ components, as they are critical for the regulation of barrier functions, including permselectivity, which determines the size, ionic charge and electric resistance of molecules that may be transported through the barrier 12,13. Keratinocytes are also in constant contact with various members of the cutaneous microbiota. One of the most well-known members of this community is the Cutibacterium acnes (C. acnes) bacterium, which, beginning with puberty, is a dominant species and preferentially inhabits sebum-rich skin regions 14,15. Current research is eluci...

Összefoglaló. Bevezetés: Magyarországon a csecsemőhalandóság 2014 óta folyamatosan javult, azonban 2019-ben az előző évi adathoz képest 11%-kal magasabb érték mutatkozott. Célkitűzés: A vizsgálat célja a 2019. évi kedvezőtlenebb csecsemőhalálozási mutató lehetséges összetevőinek feltárása. Módszer: A 2018. és 2019. évi csecsemőhalálozási adatokat hasonlítottuk össze a csecsemő kora, a halál oka és a gyógyintézeti, illetve nem gyógyintézeti elhalálozás szerint. A vizsgálathoz a Központi Statisztikai Hivatal adatait használtuk. A trendvizsgálatnál 2010-től elemeztük az adatokat. A nem gyógyintézeti haláleseteket 10 évre összevonva járásonként térképesen ábrázoltuk. Eredmények: 2018-ban 304, 2019-ben 335 csecsemő halt meg Magyarországon, a csecsemőhalálozási arányszám 3,4 ezrelékről 3,8 ezrelékre emelkedett. A 2019. évi érték az előző évtizedek trendjére illesztett görbe alapján megfelelt a várható értéknek. 2019-ben a 0–27 napos csecsemőhalálozás alig változott a 2018. évihez képest, a 28–364 napos korban bekövetkezett halálesetek száma viszont növekedett. A vizsgált évben 59%-kal emelkedett a nem gyógyintézeti csecsemőhalálozás. A 2019. évi csecsemőhalálozás növekedéséért 74%-ban a nem gyógyintézeti esetek voltak felelősek. A nem gyógyintézeti halálozás döntő többsége késői csecsemőkorban következett be. A járásonkénti, 10 évre összevont, nem intézményben elhunyt csecsemők számában és 1000 élve születésre vonatkozó arányában ötszörös területi különbségek mutatkoztak. A halálokok közül a perinatalis szakban keletkező bizonyos állapotok miatt meghalt csecsemők száma emelkedett a leginkább, a nem gyógyintézeti halálozás esetében pedig a hirtelen csecsemőhalál szindrómában meghaltaké. Következtetés: 2019-ben kiugróan magas volt a nem gyógyintézeti, késői csecsemőhalálozás száma és részaránya, ezen esetek feltűnő regionális halmozódást mutattak. A csecsemőhalandóság csökkentésének hatásos eszköze lehetne a jövőben minden egyes csecsemőhalál részletes szakmai értékelése. Orv Hetil. 2021; 162(1): 830–838. Summary. Introduction: In Hungary, infant mortality has been steadily declining since 2014, but in 2019 it increased by 11% compared to 2018.Objective: The aim of our study is to explore the possible components of the above increase. Method: Ten-year trends of infant mortality were analized and compared by age, cause, place of deaths (hospital or non-hospital environment) and location, using Central Statistical Office data. Results: There were 304 infant deaths in Hungary in 2018 and 335 in 2019. Infant mortality rate rose from 3.4‰ to 3.8‰, however, it was in line with the expected value based on the curve fitted to the trend of previous decades. In 2019, 0–27-day infant mortality basically did not change compared to 2018, while the number of deaths at 28–364 days of age increased. Non-hospital infant mortality increased by 59% in 2019 and these cases accounted for 74% of the total increase in infant mortality; the vast majority of these deaths occurred in late infancy. There were fivefold regional differences in the number of non-hospital infant deaths. Among the causes of death, the conditions related to the perinatal period and sudden infant death syndrome increased the most. Conclusion: In Hungary, the number and proportion of non-hospital infant mortality was remarkably high in 2019 compared to previous years. These cases showed a striking regional accumulation. An effective tool for reducing infant mortality could be an appropriate professional assessment of each infant death in the future. Orv Hetil. 2021; 162(21): 830–838.