Cigarette Smoking and Human Gut Microbiota: History
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Subjects: Microbiology
Contributor:
Francesca Gallè
,
Maria Sofia Cattaruzza

The intestinal microbiota is a crucial regulator of human health and disease because of its interactions with the immune system. Tobacco smoke also influences the human ecosystem with implications for disease development. This entry aims to analyze the available evidence, until June 2021, on the relationship between traditional and/or electronic cigarette smoking and intestinal microbiota in healthy human adults.

  • gut microbiota
  • cigarette smoking
  • dysbiosis
  • healthy adults

1. Introduction

The pivotal role of the gut microbiota is now an unquestionable scientific assumption [1][2][3]. Several studies have demonstrated that it significantly contributes to maintaining the physiological equilibrium of the mucosal microenvironment, and it also interacts intimately with the intestinal immune system [1][2][3][4][5][6][7][8]. In particular, the microbiome is considered the “new” biomarker of human health because of its fundamental role in maintaining normal body physiology while developing and educating the immune system [1].
Indeed, the intestinal microbiota maintains the mucosal integrity, regulates the absorption of ingested food, and exerts a competitive inhibition by preventing invasion or colonization by any other potential pathogenic microorganism [2]. Microbial products, such as short chain fatty acids (SCFAs) and polysaccharide A, modulate immune homeostasis and local immune response towards pro-inflammatory or anti-inflammatory status [3].
The clinical importance of the microbiota in maintaining the homeostasis in the human body is clear, particularly considering its involvement in a wide spectrum of human diseases ranging from autoimmune [4] to metabolic and neurological disorders [5]. Recent discoveries confirm that it is even able to affect the pharmacological response to drugs [6]. Moreover, the microbial components can interact with local immune cells leading to functional changes also outside the gastrointestinal tract: it can cause alterations in the release of circulating cytokines, and it can influence immune cells in other body sites, such as the brain. In particular, the gut microbiota is reported to regulate the microglia in its development and functioning [3].
Nowadays, thanks to the availability of new molecular identification techniques based on 16S ribosomal RNA sequencing, it is known that about 30 different bacterial phyla and more than a thousand species coexist in the intestinal microenvironment [7]. Among the various phyla, Firmicutes and Bacteroidetes are undoubtedly predominant. Firmicutes, mostly consisting of Gram-positive bacteria of the genera Bacilli and Clostridia, is the most common phylum in the gastrointestinal tract, accounting for 11% to 43% of the microbial population. Bacteroidetes are Gram-negative, obligate anaerobic bacteria, with fermenting and non-fermenting properties [8].
Clinical and microbiological studies focused on the importance of species diversity for improving microbial community resilience, even considering that each individual tends to develop a specific microbial profile [9]. These profiles tend to be stable over time, even if they may be altered at any time by drugs, such as antibiotics [10] or lifestyle choices, including diet, physical activity, and smoking [11][12][13].
Cigarette smoking is a well-known risk factor for almost every disease; in particular, tobacco is an important part of the inflammation pathway in many diseases (e.g., asthma, Chronic Obstructive Pulmonary Disease (COPD, cancer). However, only recently have scientists started assessing its possible effects. not only as a pathogenetic player in multifactorial diseases, but also as a crucial element that can influence the human ecosystem.
The interest of the scientific community initially focused on the study of the upper airway’s microbiota, being the first mucosal contact of the body with smoke during inhalation [14].
In 2012, Garmendia et al. demonstrated that continuous exposure to tobacco smoke is associated with the presence of opportunistic pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes in the nasopharyngeal microbiota of smokers, whereas Beta-hemolitic Streptococci, Peptostreptococcus spp., and Prevotella spp. [15] were mainly found in non-smokers. Garmendia et al. also reported that cigarette smoke promotes pathogen colonization, whereas smoking cessation is associated with a reversion to the microflora detected in never smokers [15]. Subsequent research focused on the analysis of the relation between intestinal microbiota and smoke, hypothesizing a role of cigarette smoking in mediating the weight gain that commonly follows smoking cessation, connecting it with the development of diseases, such as inflammatory bowel disease (IBD) [16][17].
In murine models exposed to tobacco smoke, the intestinal microbiota is mostly composed by Firmicutes and Actinobacteria, less by Bacteroides and Proteobacteria; this profile was associated with weight gain during the observational period, even without changes in the murine diet [18].
Similar results were detected in obese humans, who express microbial profiles that are more efficient in the extraction of calories from ingested food [2].
Since this first piece evidence, further studies have tried to address the effects of cigarette smoking on gut microbiota composition. In 2018, Savin et al. [19] reviewed this, considering the intestinal and non-intestinal microbiome in humans and animals, both in physiological and pathological conditions. Through their findings they tried to give possible explanations for smoking-induced dysbiosis: “smoking reduces inflammatory pathways by decreasing phosphorylation of NFkB-P65, a key mediator in the NFkB inflammatory pathway [20] and was shown to alter levels of cytokines, such as CXCL2, IL-6, INF-γ, and TGF-β [18][21]. Smoking also generates reactive oxygen species (ROS) in the blood stream, resulting in oxidative stress [22][23]. Nevertheless, their findings suggested the necessity to carefully examine the interaction between smoking and microbiota on the development of intestinal and systemic diseases.
In 2021, Gui et al. reported that tobacco smoking has been associated with significant changes in gut bacterial taxa [24]. Indeed, smoking implies the assumption of more than 7000 toxic substances that could play a role in gut microbiota composition, however research to identify the specific influence of these toxic substances on gut microbiota is still ongoing.
Even electronic cigarette (e-cigarette) users are exposed to toxic substances, which can modify the inflammatory human response. In particular, the in vitro study by Lee et al. found that “exposure of endothelial cells to e-liquid, conditioned media induced macrophage polarization into a pro-inflammatory state, eliciting the production of interleukin-1β (IL-1β) and IL-6, leading to increased ROS” [25].
This systemic pro-inflammatory status might also have an impact on the gut microbiota composition, as suggested by available studies on the impact of e-cigarette use on animals’ gut microbiota and on oral microbiota composition in humans [26][27].
To date, the effects of smoking on gut microbiota have not been systematically evaluated, especially in humans.

2. Researches and Findings

The underlying mechanism linking cigarette smoking with intestinal microbiota dysbiosis is largely unknown. Several compounds and mechanisms have been proposed that may regulate this interaction [24].
Cigarette smoke contains many toxic substances, including polycyclic aromatic hydrocarbons (PAHs), aldehydes, nitrosamines, and heavy metals, which are inhaled into the lungs. These substances may reach the gastrointestinal tract and induce microbiota dysbiosis via different mechanisms, such as antimicrobial activity or regulation of the intestinal microenvironment [24][28].
Exposure to smoke components can benefit some bacteria populations by elevating the intestinal pH or decreasing the production of organic acids, enabling some species to thrive, and cause intestinal microbiota dysbiosis [29][30].
Changes in the concentration of bacteroides, which normally constitute about 25% of all gut microbiota and provide amino acids and vitamins from dietary proteins, seem to modulate gut production of amino acids (serotonin, catecholamines, glutamate), with a possible role in the alteration of vagal nerve transmissions to the brain [31]. Polycyclic aromatic hydrocarbons, which result mainly from the thermal cracking of organic resources and incomplete burning of organic material at low temperatures, may cause various diseases due to their toxicity, mutagenicity, and carcinogenicity. Intestinal microbiota can transform these compounds into non-hazardous or less toxic substances through fermentation [32]. However, evidence suggests that excessive ingestion of these substances may significantly alter the diversity and abundance of the intestinal microbiota, causing moderate inflammation and increasing the penetrability of intestinal mucosa [33].
Cigarette smoke contains high levels of toxic volatile organic compounds (VOCs), such as benzene. Some studies have shown that benzene may alter the overall structure of intestinal microbiome [34].
Acetaldehyde, a low-molecular-weight aldehyde, is a highly reactive substance that may cause different diseases, such as liver injury and gastrointestinal cancers. Many intestinal bacteria can convert acetaldehyde into ethanol through fermentation, which can lead to the overgrowth of relevant bacteria species [35]. Furthermore, acetaldehyde increases the permeability of the intestinal tract, allowing microorganisms and endotoxin to cross the intestinal mucosal barrier. Acetaldehyde also induces endotoxemia, with subsequent injuries to liver and other organs, intestinal inflammation, and rectal carcinogenesis [36]. In addition, acetaldehyde and reactive oxygen species induce neutrophil infiltration and consequent release of tissue-damaging compounds, which cause translocation of intestinal microbiota [37].
The main toxic gases contained in tobacco smoke enter into blood through alveolar exchange, which affects O2 transport, decreases blood pH, and induces systemic inflammation and diseases. Exposure to carbon monoxide in particular alters the intestinal microbiome by favoring bacterial species that express molecules involved in iron acquisition [38].
Moreover, cigarette smoke contains heavy metals (such as cadmium, arsenic, chromium, iron, mercury, nickel) which may be ingested and cause intestinal microbiota dysbiosis affecting the transport, oxidative, and inflammatory status of gut epithelium [39][40].
The human gut microbiome has a pivotal role in regulating inflammatory pathways taking part in the so-called gut-brain and gut-lung axes and there is evidence that pulmonary disorders may be implicated in the development of intestinal diseases. Patients with chronic lung diseases, whose pathogenesis is strictly related to cigarette smoking, have a higher prevalence of intestinal diseases, such as Intestinal Bowel Disease and Intestinal Bowel Syndrome [41][42]. Nicotine, or its metabolites, reduces gut microbial diversity and it worsens the symptoms in patients with Crohn’s disease [43]. There is much evidence that gut-residing microorganisms interact with the immune system, linking gut dysbacteriosis with inflammation progression and tobacco-related illnesses (e.g. asthma, COPD). Furthermore, tobacco is a well-known factor related to the release of inflammatory cytokines, which are a milestone for the development of diseases, such as cancer [1][3][44]. Similarly, the vapor of e-cigarettes seems to contribute to exposure to toxic aldehydes (e.g., formaldehyde and acrolein) released by thermal decomposition of the major vehicle components of e-cigarette e-liquids (propylene glycol and glycerol) and flavorings [45].
Dysbiosis of intestinal microbiota is also closely associated with skin diseases, such as acne, psoriasis, and atopic dermatitis. Cigarette smoking may lead to intestinal microbiota dysbiosis through the skin-gut axis. Skin inflammation might contribute to intestinal disorders through immunologic regulations and shifts in the microbiota composition [46].
For all these reasons, research on humans is needed to better clarify these mechanisms and to provide possible methods to counteract their effects after smoking cessation.
There were some limitations. First, selected studies show important differences in sociodemographic characteristics (two studies enrolled only males) and smoke exposure of participants (mainly self-reported), which limited the comparison and may affect the consistency of results.
Furthermore, the studies differed in quality, and the main quality item involved was related to the lack of strategies to take account of the confounding factors, which weakened the strength of the findings. In particular, only a few studies considered the possible interference of diet on smoking-related effects on gut microbiota composition.
However, the first attempt to characterize, systematically, the effects of tobacco smoking on gut microbiota composition in healthy humans and it opens new perspectives for future research about strategies of smoking cessation and the possible role of probiotics to counteract smoke-related dysbiosis.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10020510

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