Methanogens: vital but threatened members of the human microbiome?

Abstract

Methanogens are an ancestral group of archaea that occupy a unique niche within the human gut microbiome by virtue of their methane production. In this process, they serve as hydrogen sinks, allowing continued bacterial fermentation and influencing short-chain fatty acid production. Available evidence suggests that methanogen abundance may be declining in parallel with the broader reduction in gut microbial diversity accompanying industrialization. We describe the evolution of methanogens, their ecological roles in the human microbiome, and evidence for their apparent decline. If confirmed, reductions in methanogen prevalence and abundance may have substantial metabolic consequences, reframing these archaea as keystone species in need of scientific attention and conservation efforts.

Methanogens in the gut microbiome

The term ‘methanogen’ (see Glossary) refers to archaea within the phylum Methanobacteriota [1] (previously classified in the phylum Euryarchaeota) [2]. Despite being prokaryotes like bacteria, archaea represent a distinct domain of life, characterized by unique cell structures and cell replication mechanisms that may be more similar to those of eukaryotes [3]. Humans have evolved in a world where methanogens predominantly occupy anoxic environments, producing methane through several pathways [4,5]. While methanogens have been detected at several sites in humans [6], we focus on their biology in the gut, which is their primary ecological niche. Methanobrevibacter smithii (M. smithii) dominates in both prevalence and abundance, followed by Methanobrevibacter intestini and Methanosphaera stadtmanae (Table 1) along with other lower-abundance Methanobrevibacter, Methanobacterium, and Methanomassiliicoccus species [6–11].

Table 1.

Reported prevalence (proportion of participants testing positive for each species) and relative abundances (proportion of the overall microbiome) of primary human-associated methanogens

Species	M. smithii		M. intestini		M. stadtmanae
Ref.	Prevalence (%)	Abundance (%)	Prevalence (%)	Abundance (%)	Prevalence (%)	Abundance (%)
[7]	95.7a	–	–	–	29.4a	–
[6]	84.0b	–	–	–	32.0b	–
[8]	70.7c	–	–	–	33.1c	–
[9]	91.3d	0.6e	90.0d	0.1e	18.1d	0.03e
[10]	–	4.4f	–	1.8f	–	0.7f

^aqPCR, fecal samples, n = 700, and prevalence.

^bNested PCR, gut biopsy samples, n = 25, and prevalence (calculated based on available data).

^cMetagenomic sequencing, fecal samples, n = 792, and prevalence.

^dMetagenomic sequencing, gut biopsy samples, n = 691, and prevalence (calculated based on available data).

^eMetagenomic sequencing, gut biopsy samples, n = 691, and read fraction (rounded to the first decimal place for consistency, where possible).

^fMetagenomic sequencing, fecal samples, n = 109, and relative abundance (rounded to the first decimal place for consistency).

Colonization with methanogens begins early in childhood, with transient detection of Methanobrevibacter in infants younger than 12 months of age [12], followed by consistent M. smithii detection in children from 2 years of age [7]. Twin studies have provided evidence for M. smithii heritability, which may also explain early colonization [13]. Methanogens are consistently detected in adulthood and increase in prevalence and abundance with age, albeit with declining alpha diversity [14,15]. Multiple human-associated M. smithii strains exist [16], with variation in both genome size and the presence of unique protein-coding sequences, permitting adaptation to specific body sites [17]. Adhesinlike proteins may also contribute to differences in colonization between methanogen species [18].

There is growing attention to the ecological and clinical roles of methanogens in the archaeome within the gut microbiome [19–21]. Concurrently, over the last few centuries, human populations have transitioned from preagricultural and rural communities to increasingly industrialized societies [22]. With this has come a decline in gut microbiome diversity due to dietary and lifestyle changes and medical exposures [22,23]. We propose that methanogens—slow-growing specialist archaea that have evolved in relation to stable ecological niches [24]—may be particularly susceptible to environmental changes associated with industrialization. Later, we discuss the evolution, metabolism and physiology, ecology, and clinical significance of human-associated methanogens, as well as current evidence pointing to their decline.

Detection of gut methanogens

Variability in the detection of gut methanogens poses substantial challenges in understanding their physiological and clinical consequences. Previous studies have relied on the use of breath methane studies, whose interpretation is limited by variation in readings [25], diet [26], and oral hygiene practices [27]. Cultivation is also used for methanogen detection under defined anaerobic conditions with appropriate substrates [28]; however, the inability to fully replicate the in vivo microbial environment and partial pressures results in incomplete assessment.

As molecular methods have advanced, detection of methanogens has improved. qPCR is commonly used, often targeting the alpha subunit of the methylcoenzyme M reductase (MCR) enzyme involved in methanogenesis, mcrA (discussed later) [29], or a conserved RNA polymerase beta subunit, rpoB [7]; new targets continue to emerge [30]. More recently, genomic analyses involving 16S rRNA genes or shotgun metagenomics have provided a new level of specificity in identifying methanogen species and subspecies and their gene expression [9]. While promising, these methods are limited by the low relative abundances of methanogens in the gut, challenges in preparing archaeal DNA, and primers that are usually biased toward bacterial cells [31]. For example, a recent metagenomic study was only able to detect the three most common species (M. smithii, M. intestini, and M. stadtmanae) [10], despite the presence of less abundant species [11]. These issues, combined with interindividual variation [9,10] and a notable lack of large-scale, cross-community studies assessing archaeal abundance and presence, limit the present understanding of gut methanogen ecology; however, this also provides an exciting prospect for future research.

Methanogenesis and its relevance in the gut microbiome

Methane derived from archaeal methanogenesis was likely a primary terrestrial gas prior to the bloom of photosynthetic organisms around 2 billion years ago [32]. Developing first in an environment devoid of oxygen, methanogenic archaea evolved to rely on anaerobic metabolism [5] and are distinguished from other microbiome constituents specifically by their methanogenesis (Figure S1 in the Supplemental information online).

In humans, fermentation by colonic bacteria yields acetate, propionate, and butyrate as the dominant short-chain fatty acids (SCFAs) [33], hydrogen gas (H₂) [34], and carbon dioxide (CO₂) [35]. To produce methane, certain members of the order Methanobacteriales (e.g., M. smithii) consume H₂ and CO₂ as substrates in a process termed hydrogenotrophic methanogenesis [36,37]. By enzymatic action, H₂ reduces the protein ferredoxin, which then serves as a reducing agent for CO₂, shunting it toward the next substrate, formylmethanofuran [38] (Figure S1). At a later step in the pathway, a key intermediate, methyl-H₄MPT, is produced (discussed further later) [37]. In addition to H₂, formate is an energetically favorable substrate for methanogenesis; M. smithii possesses genes needed for its utilization, as well as for H₂ and CO₂ [35,39,40].

Methylotrophic methanogenesis, using methylated compounds (e.g., methanol, produced by Bacteroides and other genera) as the starting substrate among other components, can be subdivided into the cytochrome-dependent and H₂-dependent cytochrome-independent pathways, with M. stadtmanae using the latter [41–43]. The order Methanomassiliicoccales uses trimethylamine (TMA), a product of bacterial metabolism of carnitine and choline, as a substrate in methylotrophic methanogenesis [44]. TMA is converted in the liver to trimethylamine-N-oxide (TMAO), which promotes atherosclerotic plaque formation [45]. By consuming TMA, Methanomassiliicoccus luminyensis (and possibly M. smithii, which possesses the genes required for methylotrophic methanogenesis [37]) may prevent TMAO accumulation and thus have therapeutic implications in cardiovascular disease, consistent with the concept termed ‘archaeobiotics’ [46,47].

Acetoclastic methanogenesis, with acetate as its initial substrate in the pathway to produce methyl-H₄MPT (similar to the hydrogenotrophic pathway), is not a significant methanogenic pathway among human-associated archaea [4,11,37]. The three pathways converge when methyl-H₄MPT is converted to methyl-coenzyme M (Figure S1), which is also a product of methylotrophic methanogenesis, followed by reduction to methane via MCR [36,37]. The predominance of M. smithii and M. intestini in the human a rchaeome dictates that hydrogenotrophic methanogenesis is the primary pathway [7,9,10,37]. Together, M. smithii, M. intestini, and M. stadtmanae comprise approximately 0.72–7% of the human gut microbial population as determined by metagenomic sequencing [9,10]; in comparison, only four bacterial phyla have a relative abundance more than 1% [48].

Methanotrophs are not well established in the gut, likely due to the lack of oxygen within the gut microbiome, particularly in areas of active methanogenesis, an anaerobic process. Recent detection of the methanotroph M. intestini in human feces may provide tentative evidence of methane oxidation within the microbiome [49].

Methanogen–bacterial cometabolism

Hydrogenotrophic methanogens

The ecological roles of methanogens involve complex relationships with bacteria through shared utilization of H₂ (Figure 1). The major H₂-producing bacteria in humans belong to the phylum Bacteroidota, with additional contributions from Bacillota and Actinobacteria [34]. H₂ utilization by M. smithii (and others) constitutes end-product removal, facilitating continued bacterial fermentation due to reduced feedback inhibition [24,39] (Figure 1). This syntrophic relationship was shown in coculture of M. smithii and Bacteroides thetaiotaomicron; M. smithii was able to grow without H₂ and CO₂ when B. thetaiotaomicron was present, highlighting the sufficiency of B. thetaiotaomicron to support M. smithii energy metabolism [24]. Adding M. smithii to B. thetaiotaomicron cultures increased the growth of both [24]. In vivo, inoculation of germ-free mice with M. smithii, B. thetaiotaomicron, or both resulted in the highest colonization when both were present, reflecting mutualism via more efficient bacterial fermentation and increased access to formate for methanogenesis [39]. M. smithii and Christensenella minuta, another H₂-producer, are also syntrophic; coculture with C. minuta led to greater methane production than with B. thetaiotaomicron [50], but this was not confirmed in a recent study [28]. The cooccurrence of M. smithii and C. minuta across human populations provides in direct evidence of the biological significance of their syntrophy [50]. Microbial syntrophy could also be advantageous to hosts when food resources are scarce; co-colonization of mice with M. smithii and B. thetaiotaomicron enhanced host energy storage with increased hepatic fatty acid synthase activity and triglyceride production [39].

Figure 1. Model of the physiological interactions between M. smithii, H₂, and gut bacteria.

The top half displays relationships between methanogens and hydrogen producers, while the bottom details relationships with other hydrogen consumers. Direct links between M. smithii and bacterial species are marked in purple, while short-chain fatty acid (SCFA) stimulation and inhibition are shown in blue and red, respectively. The production and use of H₂ are depicted with black dotted and dashed lines, respectively. These relationships, along with other minor ones, are noted in the key on the right side of the figure. Figure created using BioRender (http://biorender.com/) (See [24,35,39,50–57].).

A second major metabolic activity of hydrogenotrophic methanogens is competition with other H₂-utilizing microbiota, including sulfate-reducing bacteria (SRB), such as Desulfovibrio species, which use H₂ to reduce sulfate to produce hydrogen sulfide, and homoacetogens, such as Blautia hydrogenotrophica, which use H₂ for acetate production [58]. In a mathematical model based on the growth of SRB, homoacetogens, and methanogens that investigated competition, simulated settings with high H₂ and sulfate allowed SRB to dominate over the methanogens and homoacetogens [59]. The model permitted two classes of hydrogenotrophs to co-colonize, but not all three [59]. Coculture of Desulfovibrio piger, M. smithii, and the acetogen B. hydrogenotrophica showed that sulfide production inhibited the growth of methanogens [51]. These microbes also differ in the sites they colonize within the colon. Of the three taxa, methanogenic archaea are highest in absolute abundance in all colonic regions [60]. Homoacetogens show greater absolute abundance than SRB in the left colon and rectum, while SRB show greater absolute abundance than homoacetogens in the right colon, although of uncertain statistical significance [60]. These findings are consistent with niche specialization rather than interspecies competition between these species. Aside from hydrogen levels, other factors may also influence growth, including alternative substrates for each hydrogenotroph, such as lactate, polysaccharides, and acetate [52], and pH, with methanogens inhibited by acidic pH [58].

Bacterial fermentation products

The three key SCFA byproducts (butyrate, acetate, and propionate) of bacterial fermentation are closely linked to H₂ metabolism [33]. Butyrate and acetate production both yield H₂, with the primary butyrate-producing pathway using acetate itself as a substrate [53–55]. Conversely, propionate production consumes H₂ [53] (Figure 1). In humans, high methane production is associated with increased propionate, which is related to syntrophic relationships between methanogens and propionate producers [52], despite potential competition for H₂. Coculture of M. smithii with either B. thetaiotaomicron or C. minuta increases acetate production [39,50], suggesting that, through their H₂ utilization, methanogens shift fermentation toward H₂-yielding processes, potentially supporting other hydrogenotrophic bacteria and altering SCFA levels in the gut, as discussed below. This shift toward H₂-yielding processes may allow other hydrogenotrophic populations to outcompete methanogens or, conversely, select for higher methanogen abundance, depending on the availability of other substrates [52]. Acetate assimilation by M. smithii for biomass [24,35] may further contribute to its syntrophic relationship with bacterial partners, although the net effect of loss of methanogens on acetate availability remains uncertain. In contrast, M. smithii generally decreases butyrate production. C. minuta produces butyrate and H₂; M. smithii coculture reduces butyrate concentrations [50], despite its H₂ consumption relieving H₂-mediated negative feedback. With M. smithii coculture, expression of genes involved in butyrate production in B. thetaiotaomicron is also inhibited [39]. However, in a nine-species synthetic community, M. smithii removal led to decreased growth of the butyrogen Eubacterium rectale, pointing to more complex interactions in vivo than in reductionist settings in vitro [54].

Methanogens and the decline in microbial diversity

The broader loss of gut microbial diversity accompanying industrialization [22,23] raises the possibility that methanogenic archaea may be undergoing a similar decline. Several independent population studies are consistent with this interpretation, although standardized cross-cohort analyses and meta-analyses will be required to determine its magnitude. Evidence of declining methanogen abundance comes from intrapopulation studies. M. smithii and other archaeal taxa were relatively enriched in rural Chinese persons compared with urbanites, who also showed decreased α-diversity of the fecal archaeome [8]. Comparisons highlighting the Christensenellaceae–Methanobrevibacter–Oscillibacter trophic network show intergenerational effects, with relative decreases in younger Turkish and Dutch subjects compared with their parents [61]. Methanobacteriota, encompassing all methanogens, were at lower relative abundance in Chinese subjects living in more industrialized areas [62].

Similar trends are also apparent in cross-population comparisons. Russian populations had lower relative Methanobrevibacter abundances than Amerindian populations but higher than in Chinese, Danish, and American populations [63]. The Matses, a preagricultural community, had high relative Methanobrevibacter abundance compared to industrialized populations from North America, Europe, Asia, and Oceania [64]. Among the Hadza hunter-gatherers of Tanzania, archaeal diversity and the prevalences of M. smithii and M. stadtmanae were higher than in more industrialized communities in Nepal and California [65]. Children in a highly rural Amerindian community had the highest relative M. smithii abundance, followed by those in communities with a less traditional lifestyle, then by those from the United States [66]. Similarly, Methanomassiliicoccaceae were higher among the Yanomami people of the Amazon compared to the transitioning Guhaibo Amerindians and to communities within the United States and Malawi [67]. Collectively, these studies suggest that gut methanogens may be sensitive to lifestyle transitions associated with industrialization. However, differences in study design, sampling, sequencing methods, and detection thresholds currently preclude firm conclusions regarding the magnitude or universality of this trend. We anticipate that prevalence is also affected, but our understanding of variation in prevalence (Figure 2; Table S1 in the Supplemental information online) is limited by differences in the subpopulations sampled within a country, the sampling and analysis methods, and the detection threshold for methanogen presence.

Figure 2. Geographical distribution of methanogen prevalence, as determined by genomic identification of Methanobrevibacter or M. smithii, in healthy populations in five studies.

The coloration of the included countries represents the prevalence, as noted in the legend. The prevalence is also represented with a black circle within or next to each included country. For countries with multiple reported prevalences, the mean is displayed. Please see Table S1 for a further breakdown of reported prevalences across the world. Figure created using BioRender (http://biorender.com/) (See [8,65,68–70].).

Drivers of methanogen decline

Broad shifts in the gut bacteriome

Prevotella dominates in rural, preindustrial populations, compared to Bacteroides in industrialized areas [61,71]. In the rumen, the presence of Prevotella is generally inversely associated with methane production [56,72,73], possibly due to Prevotella-mediated diversion of H₂ to propionate. Since Bacteroides are key intestinal H₂ producers [34], the syntrophic methanogen–Bacteroides cocultures [24,39] suggest that increased Bacteroides proportions would favor methanogens. However, the indications of substantial archaeal loss discussed above [8,61–67] imply that additional ecological and environmental factors are likely to contribute.

Diet

Relative Methanobrevibacter abundance and methane production in humans have both been associated with carbohydrate intake [68,74] and with fiber-degrading bacteria [52]. This may be related to the syntrophic interactions in which methanogens promote bacterial fiber degradation, increasing energy generation for the host. In human populations eating high-fiber diets, the high methane producers also had greater metabolizable energy [52]. Such interactions might have provided strong selection for methanogen carriage over the course of human evolution. Thus, the low fiber intake of modern diets [75] may contribute to early evidence indicating decreasing gut methanogen populations.

Pharmaceuticals

With industrialization has come widespread, essentially universal, antibiotic use, leading to microbial diversity losses [76]. First used in industrialized countries, antibiotics are now used most in middle-income countries [77]. M. smithii and M. stadtmanae are resistant to most of the antibiotics commonly used around the world; however, considering the scale of use, even minor inhibition, especially by metronidazole and related agents, could select against them [78].

Antibiotics also may affect methanogens via broader effects by altering bacterial numbers and diversity [79,80]. Considering the significant cometabolism between gut methanogens and bacteria (discussed previously), antibiotics may diminish methanogen growth because of the absence of substrates (e.g., H₂) necessary for growth and methanogenesis. Statins, whose prescriptions nearly doubled in the United States between 2008 and 2019 [81], also inhibit methanogen proliferation [82,83] and promote propionate production, limiting H₂ availability [84,85]. Environmental pesticide exposures diminish archaeal diversity, also calling into question the effects of these chemicals in vivo [86].

Implications of possible methanogen loss for the gut microbiome

Hydrogenotrophic bacteria

Current ecological understanding suggests that a reduction in the abundance of M. smithii could increase access to H₂ for the competing hydrogenotrophic SRBs and homoacetogens, such as Desulfovibrio and Blautia, respectively, facilitating their overgrowth.

The equilibria between these groups of microbes may also be affected by diet. Intake of animal-based protein, including sulfur-containing amino acids (SAAs), and inorganic sulfur increases average fecal sulfide concentrations [87], indicating that dietary sulfur, including that from animal-based protein, may influence SRB concentrations. However, human study participants consuming a high-SAA animal-based protein diet compared to a low-SAA plant-based diet did not differ in Desulfovibrio or Bilophila levels [88]. Mice fed a diet high in saturated fatty acids showed increased SRBs compared with those fed a diet high in polyunsaturated fatty acids [89]; however, the administration of partially hydrogenated oils (used frequently in processed foods) increased Desulfovibrionaceae relative abundance [90]. A similar increase in Bilophila wadsworthia was seen in humans receiving an animal-based diet [91]. While further studies with larger sample sizes are required to provide clarification, given that the Western diet often exceeds the recommended daily SAA intake [92] and is high in saturated fat [75], we speculate that the combination of suspected methanogen loss and the excess-SAA Western diet may promote a relative shift toward SRBs, though this phenomenon may be obscured by an ongoing pattern of broader SRB and homoacetogen loss [61,63–67]. Fiber-rich and starch-rich diets support unique acetogen communities, with starch promoting H₂-based acetogenesis, compared to overall increased acetogen load and diverse substrate utilization with fiber-rich diets [93,94]. In total, the available evidence suggests that the low-fiber Western diet [75] provides increased access to H₂ for hydrogenotrophic acetogens, reducing their reliance on methanogens and thus less selection for methanogen persistence.

Overgrowth of competing hydrogenotrophic bacteria may have clinical implications, with SRBs linked to ulcerative colitis [95] and to increased cardiovascular-related, cancer-related, and all-cause mortality [96]. In contrast, homoacetogen overgrowth increases acetate levels, with beneficial effects for cardiovascular health [97]. While homoacetogens and SRBs consume hydrogen, they can often use other substrates, such as glucose and lactate [52], further affecting the balance of gut hydrogenotrophs beyond hydrogen availability alone.

SCFA production

We anticipate that the overabundance of H_2, along with reduced methanogen populations, may shift the balance of production among the three major SCFAs: propionate, acetate, and butyrate. In ruminants, statin-utilizing diets that decrease methanogen load and methane production may increase propionate [84], although not consistently [98,99], suggesting that propionate may be an alternative H₂ sink to methanogenesis, with a reduction in methanogen abundance hypothesized to favor propionate production.

The effects of decreased methanogens on acetate and butyrate are less clear (Figure S2 in the Supplemental information online ). Because the bacterial–methanogen energetic interactions in hindgut fermenters have been little studied, the rumen provides a conceptual model. In ruminants, when methane production decreases, butyrate and acetate production increase [98] or are unchanged [84,99], depending on context. The growth of butyrogens in high H₂ environments, potentially mimicking an absence of methanogens, also led to increased butyrate and lactate (as a minor fermentation product) and decreased acetate production [54]. Although both processes are H₂-producing, the differences in acetate and butyrate production may relate to distinctions in H₂ production during their generation. While butyrate production may proceed through multiple pathways [55], these pathways converge at the reduction of crotonyl-CoA via oxidation of NADH through electron bifurcation [100], thereby recycling NAD+ for use in earlier fermentative steps. The remaining electrons after crotonyl-CoA reduction are used to reduce ferredoxin. The net yield of H₂ from butyrate production is two moles [101]. Conversely, acetate production does not require NADH and thus does not directly regenerate NAD+. NADH instead regenerates NAD+ through ‘external’ hydrogenases [34], a process that generates a net yield of 4 moles of H₂ [101]. We speculate that under high H₂ conditions in the intestinal chemostat, there is selection for processes that limit additional H₂ production (e.g., butyrogenesis), while inhibiting processes with greater H₂ yield (e.g., acetogenesis) [54,55]. The utilization of acetate in butyrate production may further contribute to the observed net decrease in acetate levels in such conditions. However, this relationship is confounded by the possibility of relative acetate buildup in the absence of its use by methanogens [24,35], making the balance of fermentation product shifts in vivo a frontier to investigate.

Thus, on average, a suspected loss of M. smithii is predicted to alter SCFA production, favoring propionate and butyrate over acetate, which would diverge from the reported 3:1:1 ratio of acetate:butyrate:propionate in the colon [102]. However, individual variation in the proportions of SCFA producers might affect this conclusion [103]. Although propionate is generally considered beneficial to cardiovascular health [104], excess levels (propionic acidemia) contribute to cardiac, neurologic, and metabolic burden, likely through dysregulated oxidative stress and energy metabolism [105].

Clinical consequences of reduced methanogen abundances

A diminishing gut methanogen profile may impact overall microbiome composition and stability, as well as the development of disease. Associations between methanogens and disease states, such as colorectal cancer, inflammatory bowel disease, and neurological disorders, have been reported (Table S2 in the Supplemental information online) [11,19–21], in addition to associations with oral pathologies [106]. Of these, the connection to colorectal cancer may be especially strong, with recent evidence showing that H₂ utilization by M. smithii may enhance the growth of an associated pathogen, Fusobacterium nucleatum [107,108]. While causal links are yet to be established, sequencing studies will better clarify the role of methanogens in disease, with implications for disease development following suggested alterations in methanogen prevalence and abundance.

Concluding remarks

We offer a perspective on the evo-ecological position of methanogens in the gut microbiome and their roles in human health. With industrialization, human microbial diversity is decreasing [23], and human methanogen abundance and prevalence appear to mirror the general phenomenon, though this evidence is preliminary; increased exposure to medications and changing diets may be key factors. With methanogen decline, propionate and butyrate production may increase, and other H₂ users, including SRBs and acetogens, may bloom. Combined, these microecological changes have implications for host energy utilization, intestinal transit times, and clinical outcomes (Figure 3, Key figure). The current literature is often conflicting, especially regarding human health. The past reliance on breath methane studies, without strict diagnostic criteria, has limited our understanding of the underlying metabolic and ecological relationships. In vitro studies or well-defined animal models that directly assess the influence of methanogens on H₂ availability and competition, fermentation, and energy metabolism will better establish functional roles in the gut. Further studies of methanogen abundances across high- and low-industrialization communities in parallel are needed to provide context (see Outstanding questions), while longitudinal studies on disease development will provide crucial insights into possible causal relationships.

Figure 3. Key figure. Schematic of the impact of industrializatio nongutmethanogens.

With modernization, the diversity of the gut microbiome is declining, a trend that is affecting gut methanogens as well. We posit that as this process continues, equilibria in the gut will move toward hydrogen accumulation due to reduced hydrogenotrophic methanogenesis, leading to shifts toward other hydrogenotrophs, such as SRBs and homoacetogens, and a predominance of propionate and butyrate over acetate. Such a dysregulated microbiome may have clinical implications, with preliminary evidence that the incidence of metabolic, inflammatory, and neoplastic diseases has been affected in varying ways. Figure created using BioRender (http://biorender.com/). SRBs: sulfate-reducing bacteria.

Outstanding questions.

How do hydrogenotrophic and methylotrophic methanogenesis differentially influence the survival of human-associated methanogenic archaea?

Which factors allow M. smithii to thrive in the gut microbiome compared to other methanogens?

Which specific environmental factors associated with the societal process of industrialization drive changes in gut microbiome composition?

What species-specific changes in methanogen abundance and prevalence are observed with industrialization?

Which factors, if modulated, may drive a restoration of gut methanogen abundance and diversity?

Given our limited knowledge and the fact that methanogens occupy a unique niche within the human microbiome, the evidence of their decline is concerning. Dietary modifications (e.g., increased fiber and decreased caffeine) may enhance methanogen stability or growth, and improved medication stewardship may limit their loss. Biodiversity banks such as the Microbiota Vault, storing human microbial samples from populations across the globe [109], may facilitate conservation. Expanding knowledge about our long coexistence with methanogens will likely better inform conceptions of human health.

Supplementary Material

Supplemental information

Supplementary information associated with this article can be found online at https://doi.org/10.1016/j.tim.2026.08.008.

Highlights.

While long known to be found in the environment and in other animals, archaea, specifically methanogens, are also inhabitants of the human body, with substantial abundance in the gut compared with other body sites.

In the gut microbiome, methanogens function as hydrogen consumers via methanogenesis.

Through serving as hydrogen sinks, methanogens influence the fermentative activities of gut bacteria that produce the three primary short-chain fatty acids: acetate, butyrate, and propionate.

The rise of industrialization has been associated with shifts in gut microbiome composition, with possible implications for human health.

Westernization appears to be associated with decreased methanogen loss, with hypothesized secondary effects on bacterial fermentation, including altered short-chain fatty acid levels and possible changes in the abundance of hydrogenotrophic bacteria.

Glossary

Acetoclastic methanogenesis

the process of producing methane using acetate as the starting substrate.

Archaea

an ancient class of prokaryotes that occupy various niches across the environment and within the microbiomes of humans and other species.

Archaeome

the collection of archaea within the human gut microbiome.

Hydrogenotrophic methanogenesis

the process of methane production that uses H₂ with CO₂ or formate as starting substrates; it is the primary pathway among human-associated methanogens.

Industrialized/industrialization

the process of environmental evolution away from agricultural communities toward larger societies associated with increased reliance on antibiotics and other pharmaceuticals, altered diets (including loss of fiber and more processed foods), and a loss of microbial diversity.

Methanogen

the primary class of archaea found within the human gut microbiome that possess the unique ability to generate methane gas.

Methanogenesis

the process of methane gas production by methanogenic archaea, with various compounds serving as the initial substrate (see ‘Acetoclastic’, ‘Hydrogenotrophic’, and ‘Methylotrophic’ methanogenesis).

Methylotrophic methanogenesis

the process of methane production that uses methylated compounds, such as methanol, as starting substrates.

Microbiome

the collection of bacteria, archaea, fungi, and viruses found in the gut and reproductive tracts and on the skin of humans and other species; these ecosystems are vulnerable to multiple environmental factors, including diet, antibiotic use, and mode of delivery.

Short-chain fatty acids (SCFAs)

products of bacterial fermentation that have significant clinical implications, with three key SCFAs being acetate, butyrate, and propionate.