The microbiome represents a diverse community of microbes, archaea, and viruses—and their genes—that collectively accounts for a genome 100 times the size of ours. In truth, many scholars claim that host genome and the microbiome, collectively account for a shared “metagenome” [
1] often described as our microbial organ [
2]. Large international ventures like the National Institute of Health’s Human Microbiome Project (HMP) has enhanced our understanding of these complex communities in and on our bodies [
3]. Gut microbial communities have some of the highest cell densities seen in nature, but paradoxically, sparse diversity exists at the super-kingdom level [
2]. Bacteria are the predominant members of the gut microbiome, encompassing upwards of 99% of the gene catalogue within the gut [
4]. The gut harbors the largest abundances of these microbes (or microbiota), with estimates of 10
13 bacterial cells [
5] and over 1000 different species [
4] dominated by four main phyla, Bacteroidetes and Firmicutes (which make up roughly 90–99%), Actinobacteria and Proteobacteria [
1]. Importantly, the gut microbiota is highly diverse at the species and strain level. Microbial lineages are inherited from mothers [
2] and change over time, particularly during infancy in humans [
6,
7]. However, the community is stable throughout much of the lifespan and is unique to each individual—approximately 1/3 of the community is similar to parents. In 2010, Qin et al. [
4] used metagenomic sequencing to analyze fecal samples from 124 European individuals and found, even with the most common 57 species present in at least 90% of samples, significant interindividual variability occurred, ranging from 12- and 2187-fold differences between communities. However, their results confirmed Bacteroidetes and Firmicutes having the largest abundance of reads [
4]. Several species, such as
Bacteroides spp. create stability in the gut ecosystem with their arsenal of glycoside hydrolases and appropriate polysaccharide-binding proteins, even in the absence of dietary polysaccharides [
2]. Arumugam et al. [
8] described three robust clusters, or enterotypes within the human gut microbiome, where Bacteriodes, Prevotella and Ruminococcus are represented across 39 samples and cluster divergently from one another. The underlying basis for such enterotype clustering, however, remains unknown [
8]. This microbial organ has many functions for the host: harvesting energy from undigested foodstuffs [
2]; increased fat storage [
9]; synthesizing vitamins [
10]; and overall improving colonic health. Recently, rapid alterations of gut microbial communities have been shown to occur as result of dietary alterations [
11] (
Figure 1). What is important for the host, however, is functional redundancy and community stability remain fairly consistent over time [
3] and, thus, key processes remain unaffected by changes in diversity [
2]. Therefore, describing an optimal microbiome for host health proves problematic as to the staggering variability from person to person.
For the past few years, there has been considerable interest in the microbiome and its role in health and human disease [
12]. Gut dysbiosis occurs when an imbalance between beneficial and harmful bacteria transforms the community, where normally dominating species are outcompeted by otherwise underrepresented microbes increasing in abundance; several groups have shown increases in mucus degradation and subsequent decreases in the intestinal lining, which produces systemic “low-grade inflammation” [
13,
14,
15], which is known to be involved in several chronic diseases, namely obesity and type-2 diabetes [
16]. However, what remains to be defined is whether gut dysbiosis is the cause or consequence of host disease state. Still, dysbiosis has been implicated in several host disease states like, obesity [
9,
14,
17] and type-2 diabetes mellitus [
2,
14,
18,
19], cancer [
20] and inflammatory bowel diseases [
21]. An early study out of Jeff Gordon’s lab demonstrated the now widely cited reduction in abundance of Bacteroidetes and proportional increase in Firmicutes in the obese state in mice [
2]. In another study, Bakhed et al. [
22] examined the effects of the microbiota on host fat storage, showing germ-free (GF) mice (no microbiota) were protected from obesity via upregulation of adenosine monophosphate kinase (AMPK) activity, which elicited increased fatty acid oxidation via acetylCoA carboxylase (ACC-P) and carnitine-palmitoyltransferase (CPT1) in skeletal muscle and liver tissue. Furthermore, knockout mice lacking an inhibitor to lipoprotein lipase, fasting-induced adipose factor (Fiaf), were not protected from dietary-induced obesity, suggesting GF mice are protected from obesity by two independent mechanisms: increased AMPK activity and levels of Fiaf, known to upregulate the peroxisomal proliferator-activated receptor coactivator (PGC-1α) [
22]. Turnbaugh et al. showed in 2006 an obese microbiome has the capacity for increased energy harvest where, obese (
Ob/Ob) ceacal microbiome samples were enriched for environmental gene tags (EGTs) encoding enzymes involved in initial breakdown, further importation and metabolism of indigestible dietary polysaccharides, and also end-products of fermentation, namely short-chain fatty acids (SCFAs) [
19]. Obese mice have increase concentrations of butyrate and acetate, probably due to the increase in abundance of Firmicutes phyla; Firmicutes are known butyrate producers [
19]. Notably, the effects of
Ob/Ob microbiome were transferable with fecal transplant to GF mice. Later papers out of Gordon’s lab demonstrated that transplantation of fecal material from obese mice to GF mice, increased fat deposition in the GF mice compared to lean donors [
23,
24], supporting the contribution of the gut microbiota to obesity. Notably, studies in humans confirm these alterations described in animal models. Vrieze et al. demonstrated the transfer of a lean gut microbiota to obese subjects improved insulin sensitivity in 6 weeks [
25]. In a recent study, Zhang et al. demonstrated improvements in patients’ body weight, BMI, fasting glycaemia, lipid profile (total cholesterol, LDL) and systemic markers of inflammation (C-reactive protein and IL6) following a dietary intervention consisting of a diet rich in non-digestible carbohydrates [
17]. Of note, [
17] showed that similarly, transplantation of a genetically obese human microbiota (Prader-Willi syndrome (PWS)) to GF mice produced larger adipocytes and a higher inflammatory response (increased liver, colonic and ileum TNF-α, TLR4 and IL6 gene expression, respectively) than did GF mice administered a post-intervention transplantation. In 2018, Zhao et al. [
26] conducted a clinical trial using the same high fiber diet used by Zhang et al. 2015 [
17] to improve hemoglobin A1c (HbA1c) and glucagon-like peptide-1 (GLP-1) production in clinically diagnosed T2DM patients [
26]. These studies provide evidence for the transmissible effects of an obese microbiota to impact host physiology; however, the underlying mechanisms remain elusive. In a seminal paper, Cani et al. demonstrated that infusion of lipopolysaccharide (LPS), formed from the degradation of Gram-negative bacteria in the gut, had similar effects when compared to a high-fat diet (HFD) at increasing fasting glycaemia, insulinemia and whole-body, hepatic, and adipose tissue weight gain [
14]. Furthermore, the study showed increases in hepatic, but not whole-body insulin resistance, as well as adipose F4/80-postive cells and markers of inflammation were reported with infusion of LPS. Lastly, CD14 mutant mice resisted most of the LPS and HFD-induced features of metabolic disease [
14]. Collectively, these studies provide evidence for the role of the gut microbiota to increase host inflammatory responses, and therefore disease status, namely through the production of LPS. In the present review, we address the interaction of the gut microbiota in modulating host inflammatory responses in the context of dietary lipid consumption. Particular attention is paid to the role of microorganisms in host energy regulation, LPS and HFD-induced inflammation, as well as associated changes in the gut microbiota leading to increased gut permeability. We also highlight exciting new areas of microbiome research regarding dietary protein intake and the endocannabinoid system.