SnapShot: Microbiota effects

on host physiology
Jennifer H. Hill and June L. Round
Department of Pathology, Division of Microbiology and Immunology,
University of Utah School of Medicine, Salt Lake City, UT 84112, USA

Common mechanisms Colonization resistance Developmental Microbes promote increase in Beneficial interaction
of microbiota Detrimental interaction
modulation of host Local immunomodulatory Intestinal barrier Microbes promote decrease in Either, depending on host

Endocrine Nervous Skin

Both direct and indirect effects of a variety Beneficial microbes indirectly stimulate Both skin and gut microbiota modulate inflammation,
of microbes drive developmental and neurodevelopment and reduce behavioral to directly and indirectly influence disease.
metabolic host phenotypes. disorders and neuroinflammation.
Diseases Major mechanisms
Diseases Major mechanisms Diseases Major mechanisms Acne Inflammation
Diabetes (type 1 & 2) β cell Anxiety and Neurogenesis,
Psoriasis, eczema, Pathogen
proliferation depression synaptogenesis,
and dermatitis resistance
Metabolic syndrome/ and myelination
obesity Insulin production Autism
Melanoma
and glucose Microglia number
regulation Parkinson’s Chronic wound
Fatty liver and PSC
Inflammation infection
Inflammation Multiple sclerosis
Sociability
Fat and cholesterol Serotonin
storage Cardiovascular
Lipase and bile Systemic dissemination of gut & oral microbes
acid production directly inflame vascular tissues, exacerbated by
indirect effects of microbes that promote
fat/cholesterol storage.
Diseases Major mechanisms
Immune Blood cancers Heart size
Microbes play a major role in both local (direct) Trimethylamine
Atherosclerosis
and systemic (indirect) immune cell development
and function. Inflammation
Heart attack
Diseases Major mechanisms and stroke Fat and cholesterol
Lupus Inflammation
Toxic metabolites
Graft vs. host Tolerance

Sepsis Pathogen resistance

Upper GI
Overabundance of detrimental microbes with
direct effects on host tissues tend to drive
disease.
Diseases Major mechanisms
Respiratory Oral, esophageal, Carcinogenic
Both lung and gut microbiota modulate and stomach metabolites
inflammation, to directly and indirectly cancers
influence disease. Inflammation
Tryptophan Periodontitis
Diseases Major mechanisms metabolites and gastritis Epithelial proliferation
Allergy/asthma Novel 2º bile
Mucus production products acids Ulcers
Injection of toxins
COPD and Inflammation
cystic fibrosis
O 2 consumption PGN,
LPS PSA
Pneumonia and Lower GI
tuberculosis
Close proximity to host epithelia results in a
Flagellin SCFAs multitude of direct effects on host physiology.
Lung cancer
Other TLR
ligands Diseases Major mechanisms
IBD/colitis Epithelial proliferation

Celiac disease Mucus production

and peristalsis
Colon, pancreatic, Immune cell
and liver cancers recruitment and
Hirschsprung's development
Carcinogenic
metabolites
Skeletomuscular
Injection of toxins
Gut microbes have multiple indirect influences
on muscle and bone development and local
immune modulation.
Diseases Major mechanisms Urinary/reproductive
Rheumatoid and Inflammation Vaginal Lactobacillus spp. play important roles
osteo-arthritis in female reproductive health, and gut microbes
Muscle and indirectly influence local inflammation.
Muscle atrophy bone mass
Diseases Major mechanisms
Osteoporosis Insulin growth factor Reduced fertility Pathogen resistance
Serotonin Fetal development Sperm count
Osteoblast function Infection Inflammation

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2796 Cell 184, May 13, 2021 © 2021 Elsevier Inc. DOI https://doi.org/10.1016/j.cell.2021.04.026 legends and references
SnapShot: Microbiota effects
on host physiology
Jennifer H. Hill and June L. Round
Department of Pathology, Division of Microbiology and Immunology,
University of Utah School of Medicine, Salt Lake City, UT 84112, USA
The microbiota resides on all environmentally exposed surfaces of the body including the skin, mouth, lung, and reproductive and urinary tracts; however, the greatest
density and diversity of microbes is found within the gastrointestinal tract. Despite its containment to surfaces, it is now appreciated that the microbiota influences the
development and function of all systems of the mammalian body, having both local and systemic effects. Our commensal microbes play important roles in homeostatic
development of many systems including the brain (Cryan et al., 2019), intestine (Zheng et al., 2020), and pancreas (Thomas and Jobin, 2020) where it can regulate the
development of tissue-specific cells such as the microglia, intestinal epithelial cells, or β cells, respectively. Disruptions to the microbiota perturb these homeostatic
processes and can lead to organ specific diseases. Only recently have specific microbes and their mechanisms of action on the mammalian host been identified, high-
lighting common molecules that can have pleotropic effects on multiple organ systems. This work has led to emerging themes by which hosts benefit from their microbial
residents. This SnapShot depicts each of the body’s major organ systems and summarizes the homeostatic defects that lead to disease in that organ system based on
germfree and gnotobiotic animal studies. In many cases, specific members of the microbiota can enhance a process while others inhibit it. The resulting outcome of
these interactions on the host are often context dependent. Importantly, many of these diseases stem from either a loss or an imbalance of healthy host-microbe interac-
tions, illustrating the universal importance of these pathways to overall health.

Emerging themes by which microbes can influence the host

Barrier function. The microbiota produces factors that enhance tight junctions within the epithelia, increase mucus, stimulate wound repair, and enhance stem cell
proliferation. These factors ensure that contents within the intestine are contained. Decreased barrier function leads to leakage of microbial organisms or their products
that can inappropriately gain access to systemic sites, often altering the inflammatory environment (Zheng et al., 2020).
Immune modulation. Specific microbes from the microbiota produce metabolites or express molecules on their surface that can direct either inflammatory or tolerant
immune pathways. These can act at local sites where these microbes reside, such as the skin (Byrd et al., 2018), intestine (Zheng et al., 2020), lung (Zhang et al., 2020),
and mouth (Willis and Gabaldón, 2020), or have systemic effects on the brain, lymph nodes, heart, or pancreas (Tang et al., 2017; Zheng et al., 2020).
Colonization resistance. The microbiota prevents the colonization of harmful organisms that could cause or exacerbate disease through the production of toxins or
detrimental metabolites or through use of nutrients (Ducarmon et al., 2019).
Development. Resident microbes can produce molecules that directly impact the development and function of cells within various tissues. This is true of immune cells
within the bone marrow and thymus and non-immune cells of the pancreas, intestine, brain, and more (Burns and Guillemin, 2017; Zheng et al., 2020).

Microbial products frequently found to impact host processes

Outer membrane components. Some of the most commonly recognized components of microbes are found in their outer membranes and cell walls. These common
molecules often come into direct contact with host tissues and are among the most abundant microbial products in the gut. For instance, peptidoglycan (PGN) is a
universal ingredient in all bacterial membranes and activates many immune signaling pathways (Zheng et al., 2020). Similarly, lipopolysaccharide (LPS) is a major part
of the cell wall in gram-negative bacteria and is a potent systemic immune activator (Zheng et al., 2020). Flagellins, which are also widely expressed across a multitude
of different bacterial taxa, are highly immunostimulatory (Zheng et al., 2020). However, these molecules can also promote immune tolerance and development. For
example, the capsular polysaccharide, polysaccharide A (PSA), found in the commensal B. fragillis, is important for balancing immune cell populations in the gut (Zheng
et al., 2020). These somewhat ubiquitous molecules, along with many others not mentioned, are commonly recognized by Toll-like receptors on multiple host tissues and
modulate host physiology both locally and systemically (Zheng et al., 2020).
Metabolic products. A diverse and healthy microbiota produces abundant metabolites, which have many different effects on host signaling processes. Three major
kinds of metabolites have far-reaching influence: short chain fatty acids (SCFAs), secondary bile acids, and tryptophan metabolites. Fermentation of dietary fiber pro-
duces the SCFAs acetate, butyrate, and propionate. SCFAs generally promote beneficial outcomes for the host, such as reduced obesity and diabetes, tolerogenic
immunity, and even brain development (Cryan et al., 2019; Thomas and Jobin, 2020; Zheng et al., 2020). Some bacteria can metabolize bile acids that are secreted into
the gut from the liver. These secondary bile acids can have a range of impacts on the host, most prominently in endocrine signaling affecting metabolic homeostasis and
the liver-gut disease axis (Molinero et al., 2019). The metabolic products of tryptophan, such as indole, can impact inflammation, neurotransmitter expression, barrier
function, and hormone secretion (Zheng et al., 2020).
Novel products. The majority of genetic material produced by our commensal microbiota encodes putative proteins with currently unknown functions, sometimes
referred to as genetic dark matter. Some microbial products with interesting and important influences on host biology have been characterized from previously unde-
scribed genes. The high-throughput zebrafish model has proven particularly effective for mining microbial dark matter, uncovering the secreted bacterial proteins AimA
and BefA, which modulate neutrophil activity and β cell proliferation, respectively (Burns and Guillemin, 2017). Continuing to investigate this source of novel biological
material will surely uncover many new modulators of host health.

REFERENCES
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2796.e1 Cell 184, May 13, 2021 © 2021 Elsevier Inc. DOI https://doi.org/10.1016/j.cell.2021.04.026 legends and references